Designing Smart Polymer Conjugates for Controlled Release of

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Designing Smart Polymer Conjugates for Controlled Release of Payloads Farzad Seidi, Ratchapol Jenjob, and Daniel Crespy* Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology, Rayong 21210, Thailand ABSTRACT: Incorporating labile bonds inside polymer backbone and side chains yields interesting polymer materials that are responsive to change of environmental stimuli. Drugs can be conjugated to various polymers through different conjugation linkages and spacers. One of the key factors influencing the release profile of conjugated drugs is the hydrolytic stability of the conjugated linkage. Generally, the hydrolysis of acid-labile linkages, including acetal, imine, hydrazone, and to some extent β-thiopropionate, are relatively fast and the conjugated drug can be completely released in the range of several hours to a few days. The cleavage of ester linkages are usually slow, which is beneficial for continuous and prolonged release. Another key structural factor is the water solubility of polymer−drug conjugates. Generally, the release rate from highly water-soluble prodrugs is fast. In prodrugs with large hydrophobic segments, the hydrophobic drugs are usually located in the hydrophobic core of micelles and nanoparticles, which limits the access to the water, hence lowering significantly the hydrolysis rate. Finally, self-immolative polymers are also an intriguing new class of materials. New synthetic pathways are needed to overcome the fact that much of the small molecules produced upon degradation are not active molecules useful for biomedical applications.

CONTENTS 1. Introduction 2. Chemistry of Polymer Cleavage and Degradation 2.1. Degradation of Nonlabile Bonds 2.1.1. Ester Bonds 2.1.2. Amide Bonds 2.2. Cleavage of Labile Bonds 2.2.1. Acid-Labile Bonds 2.2.2. Disulfides as Redox-Labile Linkages 2.3. Self-Immolative Bonds 3. Polymers with Active Agents as End Groups 3.1. Drug-Initiated Polymerization 3.2. End-Functionalization of Polymers with Drugs 3.3. Self-Immolative Conjugates with Terminal Active Agents 4. Polymers with Active Agents As Side Chains 4.1. Chain-Growth Polymerizations of Polymerizable Drugs 4.2. Postmodification of Side Chains with Drugs 4.2.1. Postmodification via Hydrazone Bonds 4.2.2. Postmodification via Other Labile Linkages 4.2.3. Postmodification with Nonlabile Linkages 4.3. Self-Immolative Polymers 5. Dendritic Prodrugs 5.1. Dendrimers with Labile Bonds 5.2. Self-Immolative Dendrimers (SIDs) © XXXX American Chemical Society

6. Conclusions and Outlook Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

A B D D D F F I J J K

BK BK BK BK BK BK BL BL

1. INTRODUCTION The pollution of the environment and its consequence on public health and climate change is a global concern that are addressed by developing new synthetic pathways in the frame of sustainable chemistry. Unwanted pollution by release of chemicals in the environment can be reduced by the creation of materials that release suitable payloads only on demand so that they are not leached directly. This concept is also very useful for biomedical applications because drugs are toxic above a certain concentration and need to be delivered precisely with the right dosage and at the right location. We discuss here the various approaches that are followed to design polymers that can release active payloads upon an external trigger. We describe the polymer structure and polymer architecture in which the payloads are covalently linked to the polymer with a focus on labile linkages. As shown in Table 1, this field is

N T U U AB AB AU AW AY AZ AZ BG

Received: January 4, 2018

A

DOI: 10.1021/acs.chemrev.8b00006 Chem. Rev. XXXX, XXX, XXX−XXX

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Table 1. List of the Drugs Used for Preparation of Drug Conjugates (The Sites for Possible Conjugations Are Highlighted with Different Colors)

a

7-Ethyl-10-hydroxycamptothecin. b2-(4-Aminophenyl)-6-methylbenzothiazole. cLosartan carboxylic acid.

2. CHEMISTRY OF POLYMER CLEAVAGE AND DEGRADATION

particularly rich when the payload is a drug. Conjugation bonds that are labile include β-thiopropionate, imine, hydrazone, acetal, disulfide, and boronate ester groups. These linkages can be cleaved in mild acidic or basic conditions as well as by their oxidation and reduction. Another approach is the design of selfimmolative polymers that allow for a catastrophic and continuous degradation of their structure upon activation with an external trigger. When a payload is conjugated to the structure of self-immolative polymer, degradation of the main chain, and release of the payload occur simultaneously. The cleavage of self-immolative polymers yields only small molecules so that no polymer remains after the release of the payload.

On the basis of the degradation mechanism, prodrug conjugates can be categorized in two groups: (i) the so-called “selfimmolative” conjugates142−146 that usually are completely converted to free drugs and other small inactive molecules after activation, (ii) “polymer−drug conjugates” or “polymeric prodrugs”147−151 that produce free drugs and remaining polymers after degradation or activation. For both categories, the degradation and release of the active agents usually require an external stimulus such a change of pH value,2−10,67,84,110,151−155 an enzyme,57,58,127,156−162 irradiation,163−169 chemicals, or electrochemical oxidation or reduction.65,77,80,85,86,139,169−173 For self-immolative polymers and dendrimers, the stimulus is used for cleaving the bond B


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Figure 1. Schematic structures of the drug conjugates before and after drug release. (a) Prodrugs with end−drug conjugation, (b) prodrugs with side chain−drug conjugation, (c) self-immolative prodrugs, (d) dendrimer prodrugs.

Figure 2. Hydrolysis of ester bond by acid-catalyzed (AAC2) and base-catalyzed (BAC2) mechanisms.180

Table 2. Effect of Substituents in the α-Position of the Acyl Group on the Base-Catalyzed Hydrolysis of Esters180 and on the Phenyl Ring on the Hydrolysis of CH3COOAr in Neutral Medium188

Table 3. Hydrolysis Rate of Ethyl Esters of Different Substituted Benzoate Esters (X-C6H4COOEt) in 60% Ethanol−Water at ∼100 °C in the Presence of Benzene Sulfonic Acid (0.05 M)180

α-substituted ethyl acetate

k [L/mol·s]

X

EtOOCCH2S− EtOOCCH2SCH3 EtOOCCH2SOCH3 EtOOCCH2SO2CH3 EtOOCCH2S+(CH3)2

6.4 × 10−4 0.92 4.20 12.8 205

H p-Me p-Cl p-Br p-MeO p-HO m-NO2 p-NO2 o-NO2

Ar C6H5 p-MeC6H5 p-ClC6H5 p-NO2C6H5 3,4-(NO2)2C6H5 2,4-(NO2)2C6H5

0.066 0.039 0.063 0.846 4.60 11.1

k (L/mol·s) 9.0 7.8 7.9 8.3 6.2 4.5 8.38 10.6 0.5

× × × × × × × × ×

10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

nisms (see Figure 1) that are discussed in this section. On the other hand, the “polymer−drug conjugates” or “polymeric prodrugs” contain repeating units that are attached via bonds that are usually not easily cleavable. Only the bond between the polymer and the attached drug is cleavable in suitable conditions (Figure 1).

linked to the so-called trigger group (Figure 1c). When the trigger bond is cleaved, depolymerization and immolation continue. Indeed, the repeating units of self-immolative polymers are cleavable via various depolymerization mechaC


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and lipases.180−182 The base-catalysis mechanism (BAC2) progresses through direct nucleophilic addition of hydroxide ions to the carbonyl ester groups. In the acid-catalysis mechanism (AAC2), protonation of carbonyl oxygen and subsequently nucleophilic addition of water are responsible for bond cleavage (Figure 2).180,183,184 Different factors including polar and steric effects of the acyl (R1) and alkoxy groups (OR2) influenced the hydrolysis rate of ester bonds.180 In the alkaline and neutral hydrolysis of esters, EWG substituents in either the acyl or the alkoxy group accelerate the cleavage of ester bonds. The conjugation of electron-releasing groups (ERG) with carbonyl groups in esters results in a lower hydrolysis rate.185−187 Studies of the hydroxide-ion catalyzed hydrolysis of various derivatives of αsubstituted ethyl acetate in water (Table 2) showed that for substituents with more electron-withdrawing capability, faster cleavage of ester bonds occurred.180 Similarly, it was proved that the presence of EWG groups on the phenyl ring of phenyl acetate esters enhance hydrolysis rates in neutral medium (Table 2).188 Furthermore, the hydrolysis rate in alkaline and neutral media decreases significantly with increasing the steric effect of alkoxy groups. Indeed, the alkaline hydrolysis of methyl, ethyl, n-propyl, isopropyl, sec-butyl, and tert-butyl esters of acetic acid were measured to be around 0.179, 0.108, 0.066, 0.026, 0.017, and 0.001 L/mol·s, respectively.188 In the same way, alkaline hydrolysis of the ethyl esters of formate, acetate, propionate, butyrate, and iso-butyrate were determined to be around 25.7, 0.108, 0.059, 0.035, and 0.023 L/mol·s, respectively.188 Conversely, the polar effect on the acyl group has little effect on the hydrolysis of esters in acidic medium (Table 3). However, strong electron withdrawing groups such as nitro groups can slightly increase the hydrolysis rate in acidic conditions.180 Stronger steric effects can decrease the hydrolysis rate in acidic medium. The effect of acyl substituents on the acid-catalyzed hydrolysis of various ethyl esters is summarized in Table 4. When the R2 substituents of the alkoxy groups of esters such as tert-butyl and benzyl can produce stable carbocations, the acid-catalyzed hydrolysis and to some extent the neutral hydrolysis occur mainly through the cleavage of alkyl-oxygen bond (AAL1 mechanism). In these cases, the acidic-hydrolysis of esters are usually fast.180 β-Thiopropionate esters (RSCH2CH2COOR′) are a specific group of esters that are very sensitive to the presence of acid. These esters are readily hydrolyzed in mild acidic aqueous medium by protonation of sulfur and subsequent formation of a six-membered ring intermediate via intramolecular hydrogen bonding (Figure 3).190 2.1.2. Amide Bonds. Like esters, amides can be categorized in aliphatic, aromatic, or cyclic (or lactams) amides. Moreover,

Table 4. Effect of Substituents on the Rate of Acid-Catalyzed Hydrolysis of Ethyl Esters189 R-COOEt

k (L/mol·s)

R-COOEt

k (L/mol·s)

H CH3 CH3CH2 CH3(CH2)2 CH3(CH2)3

3360 44.7 37 19.6 17.9

CH3(CH2)4 CH3(CH2)5 CH3(CH2)6 CH(CH3)2 C(CH3)3

17.7 16.4 15.5 13.5 1.3

Figure 3. Mechanism of acid-catalyzed hydrolysis of β-thiopropionate esters.190

It is worth mentioning that there are also other mechanisms and triggers that can lead to the degradation of a polymer structure. One of the recently developed methods is the breaking of covalent bonds using mechanical stress.174−176 Mechanochemical chain scission in polymers has an inherent threshold molecular weight, and below that, mechanochemical energy is not sufficient to break a covalent bond.177,178 For example, chain scission by sonication in polystyrene occurred only when the molecular weight was higher than 30000 g· mol−1.179 For poly(o-phthalaldehyde) with Mw = 12000 g· mol−1, ultrasonication led to the heterolytic unzipping of the polymer chain at room temperature while no degradation occurred in the case of a sample with Mw = 3500 g·mol−1.176 In all of the mentioned prodrug conjugates, the release of the drug is controlled by the cleavage of the conjugate linkage. Different linkages have been applied for designing polymer conjugates. Overall, it is possible to classify the conjugation bonds in three categories: (1) nonlabile bonds, (2) stimulilabile bonds, and (3) self-immolative bonds. These types of conjugate bonds are discussed in detail below. 2.1. Degradation of Nonlabile Bonds

Linkages including esters, amides, and carbamate are the most frequently used nonlabile bonds to create a conjugation of a polymer with a drug. In these cases, the degradation is slow and a complete release of the drug requires a long time. 2.1.1. Ester Bonds. Esters are a group of carboxylic acid derivatives with the general formula of R1COOR2 that can be classified as aliphatic, aromatic, and cyclic (or lactone) esters. The hydrolysis of ester bonds in aqueous medium can be achieved by the cleavage of the acyl−oxygen bond, sometimes through cleavage of the alkyl−oxygen bond, and can be catalyzed by acids, bases, or special enzymes such as esterases

Figure 4. Hydrolysis of amide linkage by acid-catalyzed and base-catalyzed mechanisms.192 D


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Table 5. Hydrolysis Rate of Benzamide Derivatives in 60% Ethanol−Water at ∼100 °C in the Presence of Benzene Sulfonic Acid (0.025 M) or Sodium Hydroxide (0.025 M)193 amide

alkaline hydrolysis k × 106 (L/mol·s)

amide

acidic hydrolysis k × 106 (L/mol·s)

p-nitrobenzamide p-chlorobenzamide benzamide p-methylbenzamide o-methylbenzamide

2270 502 338 188 13.5

p-nitrobenzamide p-chlorobenzamide benzamide p-methylbenzamide o-methylbenzamide

124 206 195 197 13.9

Figure 6. Selective hydrolysis of acylic acetal in the presence of cyclic acetal.208

occurs due to the direct attack of hydroxide ions to the carbonyl groups of the amide (Figure 4). The alkaline hydrolysis of amides is faster than the acidic hydrolysis.193 The polar and steric effects of the substituents R1 and R2 are very similar to the case of esters. For instance, the presence of EWG substituents on the acyl group (R1) enhances the acidichydrolysis rate of amide bonds. The relative hydrolysis rates for p-nitrobenzamide, benzamide, and p-toluamide were determined to be around 1.40, 0.23, and 0.13 h−1 in HClO4 (7.19 M) at 95 °C, respectively.194 The acidic and alkaline hydrolysis rates of various benzamide derivatives are summarized in Table 5.193 The hydrolysis of amides in alkaline conditions is faster than in acidic conditions. Furthermore, these data showed that EWG substituents increase the hydrolysis rate in alkaline

Figure 5. Hydrolysis of acetal in acidic medium.

they can be subdivided in primary, secondary, or tertiary amides. Because of the electron delocalization between nonbonding electrons of nitrogen with the carbonyl group, amides are less reactive than esters toward hydrolysis. The hydrolysis of amide bond in aqueous medium involves a cleavage of acyl−nitrogen bond and can be catalyzed by acids, bases, or enzymes such as amidase, proteases, and acylases.191,192 The mechanism of acid-catalyzed hydrolysis of amides involves the attack of water to the protonated form of the amide group. In the base-catalyzed mechanism, the hydrolysis

Table 6. Approximate Rate Constants (kH+) for Hydrolysis of Acetals in Aqueous Acidic Medium207

E


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Figure 7. Selective removal of the acetal of ketone in the presence of the acetal of aldehyde.210

Carbamates can be considered as “ester−amide” hybrid structures, and their reactivity is lower than esters and higher than amides. Therefore, the hydrolysis rate of carbamates is normally faster than amides and slower than esters. 2.2. Cleavage of Labile Bonds

Labile bonds have been used for conjugation to allow for a more controlled and selective release of drugs. The conjugated linkages are cleaved in response to specific stimuli. Acid-labile and redox-labile linkages are two types of the most frequently used linkages for the synthesis of prodrug conjugates. These prodrugs can release the conjugated drug in mild acidic medium or in response to the presence of reducing agents in the release medium, respectively. 2.2.1. Acid-Labile Bonds. Imine, acetal, hydrazone, 3thiopropionate ester, and boronic esters are well-known acidlabile functional groups that are used for conjugating drugs with polymer/dendrimers. All these acid-cleavable bonds are rapidly hydrolyzed almost in mild acidic conditions (pH ∼ 4.0−6.5) in aqueous medium. Two main factors affect the hydrolysis of these linkages: (1) the external factors including pH value and temperature of the hydrolysis medium and (2) the structural factors including steric effects, resonance effects, and induction effects. The hydrolysis of these acid-labile linkages is accelerated at lower pH values and higher temperatures. In fact, the nitrogen or oxygen atoms in these linkages act as a Lewis base and its protonation activates it to be more easily attacked by a water molecule. Herein, we focus on the important structural factors that affect the hydrolysis rate of common acid-labile linkages. Acetal Bonds. Acetals, sometimes called ketals for the ketone derivatives, are acid-cleavable groups that have been extensively used as important protecting groups for carbonyl groups or 1,2- and 1,3-glycol molecules.195−197 Acetals are fairly stable in basic conditions, but due to the presence of lone electron pairs on oxygen atoms, they act as Lewis base and are quite labile in the presence of Lewis or protic acids. The degradation rate in the presence of Lewis acids depends on the element, usually a metal, of the Lewis acid. For example, most cyclic acetals are stable in the presence of halides of Li, Mg, and Zn while stronger Lewis acids derived from Al, Ti, and B can cleave acetal bonds. Acetal linkages can be created by the reaction between carbonyl and alcohols198,199 or between vinyl ether and alcohol or phenols,200−202 both in the presence of acid catalysts. The

Figure 8. Relative hydrolysis rate of acetal in 0.003 M HCl in dixoane/ water (70:30) at 30 °C.211

Figure 9. Example of the protection of hydroxyl groups via tetrahydropyranyl acetal structures.215

Figure 10. Structure of 2′-O-tetrahydropyranyluiidine.

conditions. However, the rate of hydrolysis is decreased in acidic medium. In this case, the effect of EWG on acidcatalyzed hydrolysis in amides is the contrary of the effects observed on esters. Moreover, more sterical hindrance at the ortho-position results in a decrease of the hydrolysis rate in both alkaline or acidic conditions.

Figure 11. Acid-catalyzed hydrolysis of imine bonds. F


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Figure 12. Electron delocalization in hydrazone linkages.

Five-membered acetal rings (1,3-dioxolanes) usually are more stable toward hydrolysis than six-membered acetal rings (1,3-dioxanes) (Figure 8). However, there are other factors that affect the hydrolysis rate. For instance, the presence of basic groups such as amino groups in the substrate slows down significantly the hydrolysis rate of acetals. Indeed, the protonation of basic amino groups and the subsequent formation of ammonium cations prevent the second protonation of the oxygen of acetal that would lead to positive−positive charge repulsion. For example, 2hydroxymethyl-2-aminomethyl-1,3-dioxolane hydrochloride is stable in the presence of diluted aqueous HCl solutions at 0 °C.212 The tetrahydropyranyl acetal has also been used extensively in organic chemistry as protecting group. Some derivatives of 3,4-dihydro-2H-pyran such as 3,4-dihydro-2H-pyran-2-methanol or (3,4-dihydro-2H-pyran-2-yl)methanamine have the potential to be inserted in a polymer backbone thanks to the presence of OH or NH2 groups in their structure and then be used for conjugation with hydroxyl group of drugs to form acetal bonds. Acetals of 3,4-dihydro-2H-pyran have been prepared easily under mild conditions in different solvents and in the presence of various catalysts (for instance see Figure 9).213,214 Tetrahydropyranyl acetals are highly stable in basic conditions. Nevertheless, they can be easily hydrolyzed in mild acidic medium. Thus, the hydrolysis of 2′-O-tetrahydropyranyluiidine (Figure 10) at 22 °C displayed a half-time of only 67 and 4 min in 0.01 and 0.1 M of HCl, respectively. Imine and Hydrazone Bonds. The reaction between primary amines (RNH2) with carbonyl groups of aldehydes or ketones lead to the formation of carbon−nitrogen double bonds (CN) known as imine, Schiff base, or azomethine (Figure 11).216−218 As shown in Figure 11, each step of the reaction is reversible and catalyzed in mild acidic medium. The formation and stability of imines toward hydrolysis were extensively studied.219−224 Imines usually tolerate neutral and basic conditions, but they are almost readily hydrolyzed in aqueous acidic media. The hydrolytic stability of imine bonds depends on the pH value of the medium as well as the basicity of the imine nitrogen and the structural effects of the neighboring groups. Imines with higher basicity are more easily protonated, which increases the reactivity of imine toward hydrolysis. In the hydrolysis reaction, the substituents R1, R2, and R3 can be aryl or alkyl groups (Figure 11). Imines with aryl groups are more stable toward hydrolysis than imines with alkyl groups due to the conjugation between the aromatic ring and imine bond. Furthermore, the presence of electronwithdrawing groups (EWG) enhances the rate of the hydrolysis of imines in acidic medium.224 Iminium salts (R1R2C N+R3R4) are very sensitive to the presence of water and can

Figure 13. Structure of various hydrazone linkages with alkyl, acyl, and ammonium substituents.226

Table 7. Half-Lives (t1/2) of the Hydrolysis Reaction of Various Hydrazone Linkages at Different pH Values226 entry 1 2 3 4 5 6

pH ∼ 5.0

pH ∼ 6.0

pH ∼ 7.0

pH ∼ 8.0

pH ∼ 9.0

9 min 7.4 min 2.4 min 8.5 min 7.5 min 10.3% hydrolysis in 17 days

24.5 min 11.3 min 21.4 min 36.0 min 12.4 min ND

1h 32 min 2h 3.8 h 14 min no hydrolysis in 22 days

4.2 h 2.0 h 10.17 h 12.3 h 23 min ND

19.5 h 11.7 h 4.2 d 2.9 d 1.0 h ND

acid cleavage of acetal bonds is a reversible reaction shown in Figure 5. The mechanism of the hydrolysis reaction of various acetal groups has been extensively described in the literature.203−207 The effect of the substituents in acetal groups on the acidcatalyzed hydrolysis is shown in Table 6.207 Cyclic acetals are more tolerant toward hydrolysis in comparison with their similar acyclic acetals so that it is possible to cleave acyclic acetal selectively in the presence of cyclic acetal (Figure 6).208 The comparison between acetals 1−5 in the Table 6 shows that the presence of carbocation-stabilizing substituents in acetal groups accelerates significantly the hydrolysis rate. Furthermore, the hydrolysis rate of acetals derived from ketones in acidic aqueous solutions is usually faster than acetals derived from aldehydes. Indeed, 1,3-dioxolan molecules prepared by the reaction between ethylene glycol and formaldehyde, acetaldehyde, and acetone display relative hydrolysis rates around 1, 5000, and 50000, respectively.209 As shown in Figure 7 for the same molecule, the acetal of a ketone is more labile in comparison with the acetal of an aldehyde.210 G


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Figure 14. Structure of hydrazones derived from aliphatic and aromatic aldehydes.228

Table 8. Half-Lives (t1/2) of the Hydrolysis of Various Hydrazone Linkages in PBS Buffers at 37 °C228 entry

pH ∼ 5.5

pH ∼ 7.4

(1) (2) (3) (4) (5) (6) (7)

72 h >72 h >72 h

Figure 16. Reduction of disulfide bond with trialkyl phosphines.233

Because of the electron delocalization in hydrazone structures (Figure 12), the hydrazone linkages (C1N1-N2) are more stable toward acid-hydrolysis in comparison with imines.226 This charge delocalization enhances the density of negative charge on the carbon, which leads to a decrease of its electrophilicity. Moreover, it has been explained that electron− electron repulsion between electron lone pairs of nitrogens decreased due to the delocalization.227 The hydrolytic cleavage of carbon−nitrogen double bonds is reversible. The hydrolytic stability of different hydrazone linkages (Figure 13) were investigated by Kalia et al. at different pH values.226 They found that hydrazone linkages with a positive charge on the nitrogen (trimethylhydrazonium ion 6) were highly stable toward hydrolysis. Its hydrolysis at pH > 5.0 was very slow (Table 7). Even though neither electron

Figure 15. Thiol−disulfide interchange reaction.237

readily hydrolyze at any pH values.225 Therefore, the iminium salts are not suitable for the preparation of polymer conjugates due to their highly instability in aqueous medium.

Table 9. Comparison of the Rate of Thiol−Disulfide Exchange Reaction with Various Reagents237 entry

thiol

disulfide

pKa (SH/S−)

kobsd [L/mol·min]

T [°C]

1 2 3 4 5 6 7

mercaptoethanol 3-mercaptopropanoic acid mercaptoethanol propanethiol thiophenol dithiothreitol dithiothreitol

glutathione disulfide glutathione disulfide Ellman’s disulfide Ellman’s disulfide Ellman’s disulfide papain-SSCH3 2-hydroxyethyl disulfide

9.6 10.6 9.6 10.5 6.6 9.2 9.2

8.7 3.2 3.7 × 104 2.0 × 104 9.6 × 105 3.3 × 103 2.3

30 30 30 25 30 30 25

H


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Figure 17. Self-immolative mechanisms through 1,8-, 1,6-, or 1,4-quinone methide degradation pathways.143

Figure 18. Self-immolative mechanisms through 1,5- or 1,6-cyclization pathways.143,244−247

reactivities are quite different. Disulfides are more stable and are not prone to explosion. The dissociation energy of the S−S bond in dialkyl disulfides is higher than that of diaryl disulfides, 55.0 and 74.0 kcal/mol for PhS-SPh and MeS-SMe, respectively.229 This means cleavage of aryl disulfides is therefore easier than the cleavage of alkyl disulfides. Disulfide bonds can be cleaved readily to thiols via reduction. Suitable reducing agents are biocompatible thiols, including glutathione (GSH) and dithiothreitol (DTT)),230 coenzyme A,231 and dihydrolipoamide,232 phosphines such as tris(2-carboxyethyl)phosphine (TCEP), 233 carbohydrates (such as D -glucose),234,235 and ascorbic acid.236 Disulfide reduction with thiol reagents involve the thiol− disulfide interchange reaction which follows a SN2 mechanism (Figure 15).237 The active agent in this reaction is the thiolate. In fact, the reactivity of the thiol is dictated by the fraction of its thiolate form as well as the nucleophilicity of the thiolate anion. A thiol reagent with lower pKa has a higher fraction of the thiolate form, but its thiolate anion has lower nucleophilicity

delocalization nor repulsive lone pair exist in trimethylhydrazonium ions, the protonation of N1 is highly avoided by the adjacent quaternary ammonium group due to extremely undesirable positive−positive charge repulsion. Therefore, trimethylhydrazonium has a very hydrolytic stability. The stability of hydrazones were compared by determining the halflives (t1/2) of the hydrolysis reactions at various pH values (5.0−9.0) (Table 7). The hydrazone linkages are shown to be more stable with higher pH values. In another report, stability of various hydrazone linkages derived from aliphatic and aromatic aldehydes (Figure 14, Table 8) at pH ∼ 5.0 and 7.4 were compared.228 Half-lives of the hydrolysis of these hydrazone bonds (Table 8) show that hydrazones derived from aliphatic aldehydes have low hydrolytic stability even in neutral medium with t1/2 = 20−150 min, but aromatic aldehyde-derived hydrazones have more stability in both neutral (t1/2 > 3 d) and mild acidic (t1/2 > 2 d) media. 2.2.2. Disulfides as Redox-Labile Linkages. Disulfides (R-S-S-R′) may look similar to peroxides (R-O-O-R′), but their I


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methide, or thioquinone methide, respectively. All of them can be attacked by even weak nucleophiles such as water to produce related phenol, aniline, or thiophenol derivatives, respectively. Some factors controlling the degradation rates include the nature of the substituents on the aromatic ring, the type of the degradation (1,8-, 1,6-, or 1,4-elemination) and the effectiveness of the leaving group (Z). The presence of the electron donating substituents such as OCH3 and NHCH3 on the aromatic ring increases the electron density in the aromatic ring and accelerates the degradation. Furthermore, electron withdrawing substituents such as NO2 and COOCH3 lead to the decrease of electron density in the aromatic ring and retard the degradation. Usually the rates of degradation for 1,6- and 1,4eliminations are similar. However, 1,6-elimination is more preferred and happen first in systems that include both types of degradations. Better leaving groups facilitate the degradation and increase the self-immolation rate so that degradation with a carboxylate group as a leaving group is more than 1000 times faster than with an alkoxide group. Self-immolative degradation through cyclization reactions can happen with spacers which lead to the formation and elimination of five- or six-membered cyclic rings. In these reactions, an internal nucleophilic attack by deprotected lone pairs of oxygen, nitrogen, or sulfur usually can occur to a carbonyl group, leading to the formation and elimination of cyclic products. Various structures that can lead to cyclization are shown in Figure 18. The electrophilicity and nucleophilicity of the related centers in these mechanisms can control the rate of the cyclization effectively. Thiols are better nucleophiles in comparison with amines, therefore replacing of the amino groups with thiols enhances the degradation rate. The carbonyl of carbonate groups is also a better electrophilic center than that of carbamate. Thus, using carbonate in the architecture of the conjugates can increase the degradation rate around 500 times. However, cyclization usually has a slower rate in comparison with quinone methide elimination mechanisms. In conjugates with degradation involving both cyclization and quinone methide elimination, cyclization is usually the ratedetermining step in the degradation process.

than the thiolate derived from a thiol with higher pKa. The rate of thiol−disulfide interchange is faster for a thiol with a pKa approximately equal to the pH of the solution, i.e., a thiol with pKa ∼ 7 displays the highest rate of thiol−disulfide interchange at pH ∼ 7.237,238 Because the thiolate is the active agent, the reaction is significantly hindered in acidic media. For a thiol with pKa ∼ 10, only around 0.1 and 1% of thiolate are present at pH ∼ 7.0 and 8.0, respectively. Therefore, the rate of thiol− disulfide interchange at pH ∼ 8.0 is about 10 times faster than the rate at pH ∼ 7.0.237 The rates of thiol−disulfide interchange at pH ∼ 7 in water for various reagents were investigated and are summarized in Table 9.237 According to this table, aromatic disulfides are much more reactive than aliphatic disulfides. Thus, the reaction of mercaptoethanol with Ellman’s disulfide is significantly faster than with glutathione disulfide. More acidic thiols with lower pKa values are more reactive239 as shown in Table 9). Steric hindrance in the α carbon in either thiol or disulfide decrease the rate of thiol−disulfide interchange. For this reason, the rate of thiol−disulfide interchange at pH ∼ 7.4 between penicillamine HOOC-CH(NH2)-C(CH3)2SH with mixed disulfide of penicillamine and glutathione is 105 times slower than for the reaction of penicillamine with the less sterically hindered glutathione disulfide.240 The steric hindrance in the β carbon is less critical so that the thiol−disulfide interchange between bovine serum albumin (BSA) with Ellman’s disulfide is only about 14 times slower than for the reaction with the less hindered cystamine.241 Trialkyl phosphines are another group of reducing agents that are able to quantitatively reduce disulfide linkages in water according to the reaction depicted in Figure 16.242 Conversely to the thiol−disulfide interchange reaction, the reduction of disulfide bonds by phosphines is irreversible due to the strength of the formed PO bond. Tris(2-carboxyethyl)phosphine (TCEP) is an odorless airstable solid that can be readily dissolved in water and reduce rapidly disulfide bonds (72 >50 15 5.5 0.5 1 2.0

controlled in comparison with Mg-drug analogues.66 The catalyst was particularly interesting for the selective conjugation of Dox through its hydroxyl group. In addition to the −OH groups present in Ptx, Dtx, CsA, Cpt, and Dox, Dox has an amino group. This group is more reactive and more susceptible to taking part in conjugation reactions via formation of a more stable amide bond.250,251 The conjugation of Dox through its hydroxyl groups leads to the formation of ester bond, which can be cleaved more easily than amide bond. To selectively couple Dox via its hydroxyl group to PLA, it is possible to use protection/deprotection strategies to protect the amino groups. However, a simpler method is to synthesize a metal-alkoxide (RO-M) from Dox by its in situ complexation with [(BDI)MN(TMS)2] (M = Mg, Zn) and then perform ring-opening polymerization of lactic acid with the complex.66 On the basis of the drug structure and as well the Mn of the polymer, ∼3−47 wt % of drug was loaded in the polymeric prodrug conjugates. The polymer prodrugs prepared via the ROP strategy are biodegradable hydrophobic polyesters. Their M


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Figure 27. Chemical structures of polymer prodrugs synthesized by conjugation of Dox to the amino group of polymers. (a) Dox-polylactic acidblock-polyethylene glycol (Dox-PLLA-b-PEG),48 (b) Dox-poly(lactic-co-glycolic acid)-block-polyethylene glycol (Dox-PLGA-b-PEG),60 (c) Doxpoly(lactic-co-glycolic acid) (Dox-PLGA),251 (d) folic acid-polyethylene glycol-Dox (Fol-PEG-Dox),214 (e) polyethylene glycol-block-peptide-Dox (PEG-b-peptide-Dox),256 (f) folic acid-polyethylene glycol-block-polycaprolactone-Dox (Fol-PEG-b-PCL-Dox),11 (g) polyethylene glycol-Dox (PEG-Dox),12 (h) pluronic F127-Dox (F127-Dox),47 (i) Dox-aconitic acid linker-polyethylene glycol (Dox-CA-PEG),45 (j) Dox-succinic acid linkerpolyethylene glycol (Dox-SA-PEG).45

3.2. End-Functionalization of Polymers with Drugs

Biscarboxylic acid terminated polyethylene glycols of different molecular weights (HOOCCH2O-PEG-OCH2COOH) (Mw = 5000, 20000, 40000 g·mol−1) were conjugated with paclitaxel through ester bonds (Figure 26)78 to prepare watersoluble prodrugs of Ptx. The polymers contained ∼4−22 wt % of Ptx. In vitro cytotoxicity of these prodrugs for murine leukemia cell lines P388/O and L1210/O was studied (Table 10). The cytotoxicitiy of prodrugs 1−3, having an ester linkage between Ptx and PEG, were very close to the cytotoxicity of

Post modification of the polymer end groups via various chemical reactions can produce prodrugs with a drug at the end of the polymer chains (Figure 25). The postfunctionalization could be performed through stimuli-sensitive bonds such as hydrazine, oligopeptide, acetal, and imine groups or through more stable bonds, including ester, amide, and carbamate bonds. In the latter case, their cleavage can be accelerated in the presence of enzymes. N


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Figure 28. Chemical structure of polymer prodrugs created by the attachment of the carbonyl group of Dox with polymers. (a) Dox-polylactic acidblock-polyethylene glycol (Dox-PLLA-b-PEG),48 (b) folic acid-polyethylene glycol-block-polycaprolactone-Dox (Fol-PEG-b-PCL-Dox),11 dendritic polyrotaxane-Dox (PR-Dox),14 polyethylene glycol-Dox (PEG-Dox).13

Figure 29. Procedure for the preparation of methoxypoly(ethylene glycol)-block-lysinol(Dox)-poly(lactic acid) (mPEG-b-Lys(Dox)-PLLA) block copolymer.49

Figure 30. Synthesis of linear and Y-shaped methoxypoly(ethylene glycol)-block-poly(lactic acid)-cabazitaxel (mPEG-b-PLLA-CBZ) prodrugs.138

O


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Figure 31. Synthesis of polyethyelene glycol-paclitaxel prodrugs containing ester108,257 or acetal111 linkages.

Figure 32. Synthesis of monomethoxypoly(ethylene glycol)-block-poly(lactide) (mPEG-b-PLLA-Ptx).79

Figure 33. Synthesis of monomethoxypoly(ethylene glycol)-block-poly(lactide)-curcumin mPEG-b-PLLA-Cur and monomethoxypoly(ethylene glycol)-block-poly(lactide)-tris(hydroxymethyl)aminomethane-curcumin mPEG-b-PLLA-Tris-Cur.118

Figure 34. Synthesis of polyethylene glycol-dopamine (PEG-DA) conjugate.120

rate did not depend on the molecular weight of the PEG, and therefore the PEG-Ptx prodrugs with various molecular weights showed the same hydrolysis rates. Moreover, an acceleration of the hydrolysis in plasma was observed in the presence of esterase enzymes in the plasma. Doxorubicin (Dox) was attached either via its amino group (Figure 27) or carbonyl (Figure 28) group to various polymers by urethane, amide, or imine bonds. Poly(lactic-co-glycolic acid) (PLGA) containing 3.6 wt % Dox (Figure 27) was prepared by activation of the terminal −OH group of PLGA (Mw = 8020 g·mol−1) through production of 4-nitrophenyl carbonate and its reaction with the NH2 group of Dox.251 The nanoparticles of Dox-PLGA conjugates with size ∼360 nm were prepared by the emulsion-solvent diffusion method. Comparing the Dox release in PBS solution from nanoparticles of Dox both conjugated and encapsulated in PLGA showed that after 2 days ∼85% Dox was released from the nanoparticles of nonconjugated polymer while only ∼10% Dox was released from nanoparticles of the Dox-PLGA conjugates. After 8 days,

Table 12. Amount of Released Drug from PEG-DA Conjugates at Different pH Values after 6 h120 release [%]

a

pH value

PEG4000-DA

PEG6000-DA

PEG10000-DA

1.1 7.4 9.0 8.0 8.0a

90 100 82 NA NA

72 100 60 84 90

54 60 44 NA NA

Enzyme α-chymotrypsin with a concentration of 0.01 mM.

free Ptx, which implies the release of Ptx by hydrolysis of the ester bond. On the other hand, the prodrug 4 that has a carbamate linkage between Ptx and PEG showed very low cytotoxicity due to the difficult hydrolysis of carbamate linkage. The half-lives of ester linkages during hydrolysis in prodrugs 1− 3 in various conditions showed that ester hydrolysis was enhanced in more alkaline media (Table 11). The hydrolysis P


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Figure 35. Synthesis route of folate-polyethylene glycol-block-polylactic acid-docetaxel (FOL-PEG-PLLA-Dtx).76

Figure 36. Preparation of methoxy poly(ethylene glycol)-block-poly(γ-benzyl L-glutamate)-disulfide-docetaxel (mPEG-b-PBLG-SS-Dtx) prodrug.77

Figure 37. Conjugation of polyethylene glycol-block-polycaprolactone (PEG-b-PCL) with Cpt via two different linkers.71

Figure 38. Conjugation of curcumin (Cur) to methoxypoly(ethylene glycol)-block-poly(lactic acid) mPEG-b-PLLA via two different linkers.119

Figure 39. Synthesis of bis(poly(ethylene glycol)-b-poly(L-lactide))-cisplatin [Bi(PEG-PLLA)-Pt(IV)] prodrugs.258

Q


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Figure 40. Synthesis of folate-targeting taxoid SB-T-1214 conjugate.259

Figure 41. Synthesis of self-immolative conjugates of Cpt.72

around 50 nm were prepared via their self-assembly in PBS solution. The release behavior of PEG-SA-Dox nanoparticles in PBS at various pH values (7.4, 6.8, 5.5) during 3 days showed that the release was independent of pH. Around 28−30% of Dox was released after 3 days. Because CA, on the contrary to SA, possesses an acid-labile linkage, the drug release from PEG-CADox nanoparticles was dependent on pH and reached from 40% (pH 7.4) to 93% (pH 5.5) in 3 days. NH2-PEG-PCL-OH as an amphiphilic block copolymer was prepared by ROP of CL using of mono(imidazole carboxylate)polyethylene glycol (CDI-PEG-OH) as initiator following by replacement of imidazole with ethylenediamine. Then the copolymer was conjugated to folic acid by amidation as targeting agent. Furthermore, the OH-end group was conjugated to Dox via a hydrazine group (Figure 27) as a acid-labile linkage and a carbamate group (Figure 28) as a relatively acid-stable linkage.11 Micelles of these prodrugs with sizes ∼71 nm (Dox hydrazone) and ∼87 nm (Dox carbamate) were prepared by the solvent evaporation method.254,255 The release of Dox from these prodrugs at 37 °C during 2 days

all Dox was released from the nanoparticles of nonconjugated polymer, whereas a release of 90% from Dox-PLGA conjugates required about 25 days. In another report, poly(ethylene glycol)-Arg-Gly-Asp peptide (PEG-cRGD) was grafted on the surface of the Dox-PLGA NPs via EDC/NHS coupling.253 The authors studied the effect of targeting with cRGD on the performance of the Dox prodrugs to malignant integrin expressing cancer cells. About 80% of the Dox was released in a sustained way in 12 days in PBS buffer (pH 7.4, 37 °C) solutions. NH2-PEG-COOH (MW = 3400 g·mol−1) was conjugated with the NH2 group to folic acid via amide bond and with the COOH group also via amidation to produce Fol-PEG-Dox as a targeted prodrug (Figure 27).44 Nanoaggregates of this prodrug with sizes around 200 nm were produced. The Fol-PEG-Dox nanoparticles have more cytotoxicity against cancer cell in comparison with free Dox or untargeted PEG-Dox prodrug. In another work, Dox was conjugated to PEG (Mn = 2000 g· mol−1) with succinic acid (SA) or cis-aconitic acid (CA) linkers.45 Micelles of PEG-SA-Dox and PEG-CA-Dox with sizes R


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and polymer end group.14 Self-assembly of this prodrug containing ∼1.8 wt % Dox in aqueous solution produced micelles with sizes of 110 nm. The release profile from these micelles at 37 °C showed that after 300 h around 25, 73, and 85% Dox was released at pH 7.4, 6.0, and 5.0, respectively. In another work, PEG-disulfide-hydrazide (Mw = 2000 g·mol−1) was prepared and connected to galactosamine as targeting group and then conjugated to Dox via hydrazone linkage.13 Prodrugs with 20 wt % Dox self-assembled into micelles with a diameter of 140 nm in an aqueous medium. Study of the release behavior of these micelles showed that the pH value and the presence of reducing agents affected significantly the amount of the released Dox. The release of Dox from the micelles at neutral medium with pH ∼ 7.4 was slow (only 15% release after 120 h), while in acidic reducing medium (pH ∼ 5.0 in the presence of 10 mM of DTT), which mimicked the intercellular conditions in tumors, more than 90% of drug was released during the same period. Amino-protected lysinol was used as initiator for ROP of lactide. Then, one of the deprotected amino groups of lysinol was attached via a carbamate group to the methoxypolyethylene glycol (mPEG) and the other amino group was conjugated with Dox-COOH by DIC coupling amidation (Figure 29).49 Micelles with sizes around 159−177 nm were prepared from this prodrug and the release behavior of Dox at 37 °C showed that around 17 and 28% of the drug is released at pH values of 7.4 and 4.5, respectively. mPEG (Mn = 2300 g·mol−1) was esterified with bis(hydroxymethyl)propionic acid, and after protection of one of the −OH groups of the product, it was used as an initiator for the polymerization of lactide. After acetylation of the −OH end group of the PLLA segment and deprotection of another −OH present between the two blocks (see Figure 30), mPEGb-PLLA with a free hydroxyl between the two blocks was produced.138 The hydroxyl group of the block copolymer was then conjugated to cabazitaxel (CBZ) by an ester bond to produce a Y-shaped prodrug. In parallel, linear shaped PEG-bPLLA with a free −OH group at the end of PLLA segment was also produced and conjugated to CBZ (Figure 30). Nanoprecipitation of these prodrugs that contained around 8 wt % of CBZ produced well-defined spherical nanoparticles with sizes of 27 and 35 nm for linear and Y-shaped prodrugs, respectively. The in vitro release of CBZ at 37 °C showed that Y-shaped prodrugs displayed faster release rates. After 24 h, around 24 and 47% of CBZ was released from linear and Y-shaped prodrugs. The reason for faster release from Y-shaped in comparison with linear prodrugs was that CBZ was located at the core−shell interface of the nanoparticles and therefore offered a better accessibility for a hydrolysis reaction. Polyethylene glycol (Mn = 6000 and 20000 g·mol−1) with two Ptx end groups were prepared by click chemistry (Figure 31) and used for selective Ptx delivery to mouse lungs.108,257 After intratracheal administration to mice, it was revealed that the PEG-Ptx prodrugs showed lower toxicity but higher antitumor efficacy than Taxol. Moreover, larger PEG chain increased the retention time of Ptx in the lungs, which in turn enhanced the efficiency of the drug. In another report, an acrylate derivative of Ptx containing an acetal spacer was prepared and then conjugated with PEG-SH by a thiol-Michael addition reaction.111 The Ptx content in the prodrug was around ∼44 wt %, which was claimed as the highest amount of Ptx in Ptx-conjugated prodrugs. This amount was further increased to around ∼60 wt % by encapsulation of free Ptx in

showed that Dox release from the prodrug with carbamate linkage is around 21% and 19% at pH values of 5.0 and 7.4, respectively, which showed that the release is independent of the pH value. Conversely, the release of Dox from prodrug nanoparticles containing the hydrazone linkage was dependent on pH and reached from 26% at pH 7.4 to 93% at pH 5.0. Veronese et al. prepared a series of polyethylene glycol Dox conjugates (Mw of PEG = 5000−20000 g·mol−1) with different peptide linkers (GFLG, GLFG, GLG, GGRR, and RGLG). The drug content was between 2.7 and 8.0 wt % (Figure 27).46 The release profiles of these conjugates in vitro in the presence of lysosomal enzymes revealed that conjugates with GFLG linker released ∼30% of Dox after 5 h. The release rate with GLFG linkers was higher, 57% Dox after 5 h, while for the other peptide linkers less than 16% of Dox was released during the same time. Pluronic F127-Dox conjugate (Mw = 13,400 g·mol−1) was prepared through amide linkage and could be cleaved in lysosomal medium47 (Figure 27). The release of Dox in PBS buffers revealed that in 10 days, 90% of Dox was released at pH 3.0, whereas at pH 5.0 less than 42% of Dox was released. At pH 7.2, only around 20% of the drug was released in the same period (10 days). These results revealed that the F-127-Dox conjugate was relatively stable in neutral medium. Aldehyde-terminated polyethylene glycol (PEG-CHO, Mn = 2000 g·mol−1) was conjugated to the amino group of Dox through an acid-labile imine bond (Figure 27).12 In parallel, cholate grafted poly(L-lysine) (PLL-CA) was prepared by amidation of some pendant amino groups of PLL with cholic acid. The coassembly of PEG-Dox with PLLA-CA produced vesicular aggregates. In fact, the use of low content of PEG-Dox in the coassembly process led to both PLL-CA/PEG-Dox vesicles and free PLL-CA micelles, whereas only vesicles of PLL-CA/PEG-Dox were produced with higher content of PEG-Dox. It was found that at a pH value of 6.5, the release of Dox via imine hydrolysis was started but was not complete because the vesical architecture was not much affected. However, the imine bond was completely cleaved at lower pH values (pH < 5.0) because the vesicles were destabilized. The terminal end group of poly(L-lactide)-block-poly(ethylene glycol) (PLLA-b-PEG) was connected to Dox via hydrazone or cis-acotinyl bonds48 (Figures 27 and 28). In another report, Dox was conjugated to poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) by a nonlabile carbamate linkage60 (Figure 27). The release profile from the prodrugs micelles (∼89 nm) with hydrazone linkages showed that the release rate of Dox at pH 3 was twice that of the one measured at pH 7. Around 40 and 20% of conjugated Dox were released after 24 h at pH 3 and 7, respectively. Most of the Dox was released in 5 h at pH 3.48 The release of Dox from Dox-PLLA-b-PEG nanoparticles containing hydrazone linkage after 24 h in neutral medium was 5 times higher than the release from Dox-PLGA-b-PEG nanoparticles with a carbamate group for linking the drug and the polymer. After 2 weeks from the Dox-PLGA-b-PEG prodrug micelles with nonlabile carbamate linkages, around 50% Dox was released.60 For the prodrug micelles with cis-acotinyl linkages, about 60% of Dox was released at pH 3 during 24 h and therefore was faster than the release from micelles with hydrazone linkages.48 In several reports, Dox was conjugated to the terminal groups of polymers via hydrazone bond.11,13,14,48 pH-sensitive dendritic polyrotaxane conjugate (PR-g-Dox in Figure 28) was prepared by Kang et al. with a hydrazone bond between Dox S


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that after 120 h about 40% of Dtx in the presence of DTT (50 mM) was released while only about 10% of that is released in the absence of DTT. N-Boc-protected PEG diamine (Boc-PEG-NH2) was used for ROP of ε-CL to synthesize NH2-PEG-b-PCL-OH block copolymer. Cpt was conjugated to the terminal −OH group of the PCL segment through dithiodipropionic acid to form a disulfide spacer. To obtain tumor-targeting prodrug, the terminal NH2 group of the PEG section was connected to folic acid (FA) (Figure 37).71 The micelles of these prodrugs with sizes around 200 nm were prepared via the solvent evaporation method. The release behavior of these micelles at 37 °C in PBS (pH 7.4) during 100 h revealed that in the absence of glutathione (GSH) only about 10% of Cpt was released while using of 10 and 40 mM of GSH the amount of released Cpt reached 38 and 53%, respectively. Moreover, the use of succinic acid instead of dithiodipropionic acid as spacer showed that the release of Cpt after 100 h was only about 10% and was not dependent on the presence of GSH. The benefit of the presence of both folic acid and disulfide linkage in the prodrug was a significant increase of cytotoxicity. The in vitro cytotoxicity of prodrug micelles for human lung adenocarcinoma cells A549, human breast carcinoma cells MCF-7, and human ovarian carcinoma cells SKOV-3 were studied. The results showed that the IC50s of prodrug micelles with dithiodipropionic acid spacer were around two or three times lower than the IC50 of the prodrug micelles with the succinic acid as spacer. Hydroxypropyl-modified curcumin was conjugated to methoxypolyethylene glycol-block-poly(lactic acid) (mPEG-bPLLA) either by an acetal or an ester bond (Figure 38).119 The dialysis method was used for the preparation of micelles with sizes around 100 nm from these conjugates. The release behavior from these micelles at 37 °C at various pH values (5.0, 6.0, 7.4) confirmed that the release behavior of acetalconjugated micelles was strongly dependent on the pH value. The amount of released curcumin from acetal-conjugated micelles after 2 days was around 20% at pH 7.40 and 46% at pH 5.0. Ester-conjugated micelles were not much affected by change of pH value, so that in the same period, the amount of released curcumin was around 14% at pH 7.40 and 18% at pH 5.0. The ROP of lactide using HOOC-PEG-OH (Mn = 3500 g· mol−1) as initiator and then conjugation of cisplatin to that via acid-cleavable hydrazone bonds led to the formation of amphiphilic polymer prodrug bis(poly(ethylene glycol)-bpoly(L-lactide))-cisplatin (Bi(PEG-PLLA)-Pt(IV)) (Figure 39).258 The amount of loaded cisplatin was between 0.3 and 1.1 wt %, which could be adjusted by changing the feed ratio of the cisplatin to PEG-b-PLLA. Nanoprecipitation of this copolymer created NPs with sizes smaller than 100 nm. The release of the drug from the NPs at 37 °C revealed that 50% of cisplatin was released at pH 5.0, 6.0, and 7.4 during 4, 6, and 22 h, respectively. After 50 h, around 63, 87, and 90% of the cisplatin was released at pH 7.4, 6.0, and 5.0, respectively.

the hydrophobic core of prodrug micelles. The concentration of Ptx in the micellar solution was around 3665 μg·mL−1, which is about 1800 times more than the solubility of free Ptx in water. The release of Ptx after 3 days from Ptx-prodrug micelles (∼100 nm) without encapsulated Ptx was around 8 and 84%, respectively, at pH ∼ 7.4 and 5.0. The release of Ptx from the micelles containing both conjugated and free Ptx reached 31 and 90% at pH ∼ 7.4 and 5.0. Monomethoxy-poly(ethylene glycol)-block-poly(lactide) (mPEG-b-PLLA-Ptx) conjugate (with Mn = 8100 g·mol−1) with an ester bond between the drug Ptx and the polymer end group was synthesized in several steps (Figure 32).79 The hydrolysis of all the existing ester bonds induced the polymer degradation and release of Ptx. In a similar work, the end group(s) of biodegradable amphiphilic mPEG-b-PLLA were conjugated with one or three molecules of curcumin (Cur) via ester bond(s) to produce new types of prodrugs (Figure 33).118 Micelles with sizes below 100 nm were prepared from these prodrugs by the dialysis method. About 4% or 10% (w/w) of curcumin was loaded via conjugation to mPEG-PLLA with or without tris(hydroxymethyl)aminomethane (Tris) linker. Only about 2.3% (w/w) of drug can be normally encapsulated with mPEG-b-PLLA. The amount of the loaded curcumin drug in mPEG-b-PLLA-Tris-Cur and mPEG-b-PLLA-Cur conjugates was increased to about 9 and 19 wt %, respectively. The release of drugs in vitro at 37 °C in PBS at pH 7.4 was controlled mainly by hydrolysis. After 12 h, no more release was observed. Dopamine (DA) was conjugated to three different molecular weights (4000, 6000, 10000 g·mol−1) of PEG with a spacer composed of succinic acid by an amide bond (Figure 34).120 In vitro release profile of these prodrugs at various pH values (1.1, 7.4, 8.0 and 9.0) revealed that the amide bond can hydrolyze in these conditions and release the drug according to Table 12. Moreover, the rate of drug release from PEG10000-DA was slowest among the other PEG conjugates. In addition, it was proved that the presence of α-chymotrypsin, an enzyme that can cleave amide bonds, led to an increase of the rate of drug release. PEG-block-PLLA amphiphilic copolymer was conjugated to docetaxel (Dtx) from the PLLA block by hydrazine bond through a levulinic acid (LEV) spacer (Figure 35).76 In addition, for targeting delivery of Dtx, the PEG block of this copolymer was connected to folic acid. The self-assembly of this prodrug in aqueous medium created micelles with a size around 180 nm and a polydispersity of 0.29. Profile release of Dtx from the prodrug micelles at 37 °C showed that after 2 weeks about 33% and 75% of Dtx was released at pH 7.4 and 5.0, respectively, which confirmed the strong pH-dependence of the release behavior of PEG-b-PLLA-Dtx prodrugs. Methoxypoly(ethylene glycol)-block-poly(γ-benzyl L-glutamate) (mPEG-b-PBLG) block copolymers with different molecular weights (mPEG2000-PBLG1750 and mPEG5000PBLG1750) were prepared by ROP of 5-benzyl-L-glutamate-Ncarboxyanhydride with mPEG-NH2 as initiator77 and then conjugated with docetaxel with dithiodipropionic acid as disulfide spacer (Figure 36). The amount of the drug in mPEG2000-PBLG1750 and mPEG5000-PBLG1750 prodrugs was around 13.9 and 9.2 wt %. Their self-association in aqueous media via dialysis led to the formation of micelles with sizes around 100 and 150 nm and PDI 0.14 and 0.18, respectively. These micelles were stable for more than 30 days. The release behavior of these micelles in PBS (pH = 7.4) at 37 °C showed

3.3. Self-Immolative Conjugates with Terminal Active Agents

Self-immolative conjugates can contain drugs or other active molecules at the end of the conjugates. A taxoid S-BT-1214 conjugate containing a disulfide self-immolative linker was prepared by a convergent method and targeted against tumor cells by folic acid as shown in Figure 40.259 Water-soluble folate T


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4.1. Chain-Growth Polymerizations of Polymerizable Drugs

containing Glu-Arg dipeptide and azidoethyl triethylene glycol was prepared and, in parallel, taxoid was conjugated to cyclooctyne-PEG-amine via a disulfide self-immolative linker. Then, these two compounds were attached together by copperfree click chemistry. Comparison of cytotoxicity of this conjugate with free taxoid for normal and tumor cells showed that free taxoid is highly toxic for both cell lines with IC50 around 1.89 and 4.89 nM for human breast and normal human lung fibroblast cells, respectively, whereas IC50 values for these cells were 3.43 and higher than 5000 nM, respectively. The existing hydroxyl group in Cpt and its analogues such as irinotecan and SN-38 produce intramolecular hydrogen bonds with the carbonyl group of the lactone segment that facilitate the hydrolysis of lactone ring and produce carboxylate derivatives that do not have antitumor activity.260,261 Furthermore, protecting of the −OH group in these drugs simply yielded prodrugs with lower antitumor activity and higher stability against hydrolysis.262,263 Two prodrugs of Cpt containing a carbamate group with enzyme-labile triggers and self-immolative spacers were synthesized as shown in Figure 41.72 The cleavage of amide bond in phenylacetamide was catalyzed by PGA while the antibody 38C2 catalyzed a retroaldol retro-Michael cleavage reaction. The toxicity of these prodrugs in the absence of an appropriate enzyme was very low (about 1000-fold less toxic than free Cpt). However, the enzymes could activate the prodrugs to induce the release of Cpt. The toxicity was then increased significantly.

Monomers connected via labile or stable bonds to the drugs can be synthesized and copolymerized with various hydrophobic/hydrophilic monomers in order to adjust the hydrophobicity and solubility of the polymer and the amount of the loaded drug in the final prodrug (Figure 42). Ring-opening metathesis polymerization (ROMP) is one of the most used methods applied for preparation of polymer prodrugs. One representative example is the polymerization of drug-containing norbornene monomers. Several norbornene derivatives containing three different drugs including indomethacin (IND), chlorambucil (CBL), and 2-(4-aminophenyl)-6methylbenzothiazole (Apbt) were polymerized successfully by ROMP (Figure 43).121 Block and random copolymers were prepared from these drug-monomers. To increase the water solubility of the final prodrugs, a norbornene derivative with a small PEG moiety was also prepared and copolymerized with the drug-containing monomers. The same group prepared a series of amphiphilic diblock copolymers with Mn in the range of 19600−37900 g·mol−1 containing IND by ROMP of functional norbornene derivatives (Figure 44).123 In this case, a norbornene monomer containing a small mPEG segment was also selected to produce a copolymer with a hydrophilic block. The molar ratio IND:mPEG in the copolymers was adjusted to be in the range of 1.2−8.1. Because the prepared prodrugs were not soluble in water, nanoparticles were prepared by dissolving the copolymers in DMSO. The solution was then mixed with water to produce aggregates with sizes from 94 to 993 nm as determined by TEM. Increasing the length of the polymer chain yielded larger aggregates. Around 12 and 20% of IND was released from the nanoparticles after 48 h at pH ∼ 3 at 25 and 37 °C, respectively. A norbornene monomer was conjugated with Dox with a carbamate linkage for preparing amphiphilic block copolymers (Figure 45).50 The homopolymer of norbornene-Dox monomer was not soluble in organic solvents. To prepare amphiphilic block copolymers, the first block was prepared by ROMP of a monomer substituted with hexa(ethylene oxide) and the Dox-monomer. The prepared block copolymer, named as A15-b-B15, produced unimodal nanoparticles with sizes around 230 nm in aqueous medium. The in vitro release studies showed that the prodrug was stable at neutral medium and no detectable Dox was released, whereas at pH ∼ 4.0, around 50% of Dox was released in 24 h. Norbornene macromonomers containing PEG (Mn(PEG) ∼ 3000 g·mol−1) and drug molecules (Dox or Cpt) were prepared according to Figure 46 by Johnson et al. Their homo- or copolymerization by ROMP with different monomer:catalyst ratios produced various amphiphilic prodrug polymer brushes (Table 13).61 The amount of the loaded drug in the polymers was adjusted by changing the molecular weight of PEG and reached ∼8.5 wt % for Cpt and 12.5 wt % for Dox. The drugs were connected to the polymer via a photolabile bond, and therefore the light-responsive release of the drugs was studied at λ = 365 nm by the authors. After 10 min irradiation, around 50% of Dox and 64% of Cpt were released. Moreover, cytotoxicity experiments showed that toxicity of polyCpt and polyDox prodrugs toward cancer cells increased around 10 times after irradiation due to the release of anticancer drugs. Remarkably, the irradiation of polyDox50-polyCpt50 prodrug that already contains both Cpt and Dox led to around 30-fold increment toxicity toward cancer cells.

4. POLYMERS WITH ACTIVE AGENTS AS SIDE CHAINS As mentioned before, only a low amount of drug can be conjugated to the end of polymer chains. Thus, various

Figure 42. Schematics for the chain-growth copolymerizations of drug-based monomers for the preparation of polymer prodrugs.

Figure 43. Synthesis procedures of norbornene derivatives conjugated with indomethacin (IND), 2-(4-aminophenyl)-6-methylbenzothiazole (Apbt), and chlorambucil (CBL) drugs.121

methods have been proposed to modify side chains of polymers with drugs to increase the amount of the loaded drug. Similarly to the chemistry discussed in the section 2, various bonds including labile-, self-immolative, or more stable bonds have been used to prepare the conjugation. Two main strategies are used for preparing these kinds of polymer conjugates that will be discussed in the following sections. U


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Figure 44. Synthesis of amphiphilic block conjugates containing IND by ROMP. TEM image reprinted with permission from ref 104. Copyright 2004 American Chemical Society.

Figure 45. Synthesis and self-assembly of amphiphilic block conjugates of Dox via ROMP.50 TEM image and picture of the nanoparticle reprinted with permission from ref 50. Copyright 2005 Royal Chemical Society.

Figure 46. Synthesis of photoresponsive drug-norbornene monomers and their polymerization for the preparation of amphiphilic prodrugs.61

Norbornene macromonomers containing PEG and Dox but without photolabile bonds were also prepared.62 Their polymerizations by ROMP produced brush prodrugs that were cross-linked with a acetal-based bis-norbornene. Brush-

arm star polymers (BASPs) with a cross-linked core which was acid-degradable were formed as a novel prodrug of Dox (Figure 47). Prodrug nanoparticles with sizes around 50 nm and Dox loading of 11.4 wt % were prepared by this method and were V


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Table 13. Characteristics of Polymer Brushes Prepared from Norbornene-Drug Macromonomers Conjugated with Doxorubicin (PolyDox)61 entry

macromonomer:Ru Grubb’s catalyst [mol:mol]

Mn × 10−3 [g·mol−1]

PDI

Dh [nm]

polyDox01 polyDox02 polyDox03 polyCpt01 polyCpt02 polyCpt03 polyCpt04 polyCpt05 polyDox50-polyCpt50

10 50 100 15 25 100 150 200 100

33.2 227 352 55.4 111 276 394 499 393

1.07 1.05 1.04 1.09 1.17 1.38 1.61 1.70 1.13

6 12 15 7 9 na na na na

Figure 47. Synthesis of brush prodrugs of Dox with a cross-linked core. TEM image and picture of the nanoparticles reprinted with permission from ref 62. Copyright 2014 American Chemical Society.

Figure 48. ROMP of amphiphilic acid-sensitive Dox-prodrugs.15

were quite toxic and exhibited IC50 values of 1.3 and 8.4 μM, respectively. An amphiphilic block copolymer (Mn = 38000 g·mol−1, PDI = 1.05) was prepared via sequential ROMP of norbornene-PEG macromonomer and a norbornene-Dox monomer using a second generation Grubb’s catalyst (G2) (Figure 48).15 The prepared amphiphilic conjugate could form micelles with sizes around 100 nm in aqueous solution. Negligible amount of Dox was released from the nanomicelles at pH ∼ 7.4 during 24 h. Because of the presence of hydrazone bond, around 45% of Dox was released during the same time at pH ∼ 6.0. A polymerizable monomer containing disulfide and Ptx was prepared by esterification of HEMA and Ptx with 3,3′dithiodipropionic acid (DTPA) as spacer. Free-radical copolymerization of this monomer with mPEG-acrylate yielded an

Figure 49. Synthesis of monomeric and polymeric prodrugs of Ptx.80

stable at pH values between 6.0 and 7.4. Cell viability of HeLa cells in response to Dox-BASP, non-Dox loaded BASP, and free Dox was studied for 3 days and revealed that non-Dox loaded BASP had no toxicity. In contrast, free Dox and Dox-BASP W


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Figure 50. Synthesis route of gold-glycopolymers of poly(4-AuPEt3) and poly(HEA)-block-poly(4-AuPEt3).264

Figure 51. Synthetic route to multiblock biodegradable poly(2-hydroxypropyl methacrylamide)-doxorubicin (PHPMA-Dox) conjugates.51

the deacetylated form of auranofin as a small molecule analogue. A series of linear multiblock HPMA copolymer drug conjugates with different molecular weights containing around 8 wt % of Dox were synthesized by RAFT polymerization (see Figure 51).51 The antitumor activity of these water-soluble prodrugs for human ovarian carcinoma A2780/AD cells showed that the poly(2-hydroxypropyl methacrylamide) (PHPMA) had no effect on the tumor growth while the copolymer prodrug with nonbiodegradable backbone had a little inhibition effect on the tumor growth. Conversely, the multiblock backbone biodegradable copolymers displayed the highest inhibition effect for cancer cells. However, the prodrugs with molecular weights of 94000 and 184000 g·mol−1 showed almost the same activity and were more effective than the polymer with the highest molecular weight, i.e., 348000 g· mol−1. Indeed, higher hydrophobic interactions changed the conformation of the polymer into compact coils which had lower water solubility and displayed a slower enzymatic degradation. Polymerizable cyclic carbonate of CBL and Cpt were prepared and copolymerized with trimethylene carbonate (TMC) using mPEG5000 as hydroxyl initiator by ROP to

amphiphilic random copolymer containing 23 wt % Ptx (Figure 49).80 Self-assembly of this prodrug in aqueous medium produced micelles with an average size of 210 nm. The release behavior from this prodrug was studied by in vitro investigation of its cytotoxicity for HEK-293 and HeLa cells and found that cell viability in both cell lines was reduced with increasing concentration of prodrug. The prodrug was more effective for HeLa cells in comparison with HEK-293 cells. Indeed, after 48 h, the cell viability of HEK-293 and HeLa cells were decreased to about 90 and 52% at concertation of 0.1 μg/mL Ptx. A glycomonomer acrylate with a thiol-protected group was synthesized and its homopolymerization or copolymerization with 2-hydroxyethyl acrylate (HEA) by RAFT was investigated to design well-defined gold-glycopolymers. These materials can mimic the deacetylated auranofin, which is a well-known gold complex drug, classified as an effective antirheumatic agent (Figure 50).264 After polymerization and thiol deprotection, complexation of Au with the pendant thiol groups occurred. Around 70−75% of the thiol groups of homo- and block copolymer took part in the complexation for form polymeric polymeric Au(I) complexes. The micelles formed from the block copolymers had a higher activity for OVCAR-3 cells than X


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Figure 52. Synthesis of polymer drug conjugates by ROMP of cyclic carbonates.137

prepare several amphiphilic prodrugs (Figure 52).137 The polymerizable carbonate monomers had higher reactivity than TMC so that their almost complete consumption during the polymerization process made the purification of the product simple. By using various feed ratios and compositions, different copolymers of the biodegradable polyester prodrugs with various amounts of drug content were prepared (see Table 14). Moreover, to create a prodrug with biocleavable bond, a

polymerizable cyclic carbonate of Cpt with disulfide linker was prepared and polymerized with TMC (entry 7, Table 14). After 24 h, only about 15% and more than 75% of Cpt were released by the prodrug 7 in the absence and presence of GSH (10 mM), respectively. Furthermore, the nonresponsive prodrug 6 was not sensitive to the presence of GSH and displayed a slow release, i.e., only about 16% of Cpt released after 24 h. Y


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Table 14. Feed Ratios of the Monomers M1 (Trimethylene Carbonate, TMC), M2 (Carbonate Chlorambucil, CarbCL), M3 (Carbonate Diethylene Glycol Chlorambucil, Carb-O-CPT), M4 (Carbonate Disulfide Chlorambucil, Carb-SS-CPT), and Initiator I (mPEG), and Characteristics of Prepared Prodrugs137 drug [wt %] −1

entry

M1

M2

M3

M4

I

Mn [g·mol ]

PDI

CBL

Cpt

Dh [nm]

1 2 3 4 5 6 7 8

45 43 40 35 40 37 40 43

5 8 10 15 0 0 0 5

0 0 0 0 10 3 0 0

0 0 0 0 0 0 5 3

1 1 1 1 1 1 1 1

12100 13400 16300 17400 15800 10600 12400 14000

1.17 1.19 1.23 1.29 1.19 1.27 1.19 1.20

10% 17% 25% 30% 0 0 0 11%

0 0 0 0 21% 6.6% 11.2% 5%

35 40 43 49 37 31 30 33

Figure 53. Synthesis of monomer and biodegradable polymer prodrugs from tartaric acid and drugs containing carboxylic acid group.124

Figure 54. Synthesis of biodegradable poly(anhydride-ester) prodrugs from salicylic acid,265 morphine,128 and ferulic acid (FA).129

synthesized by melt-condensation polymerization (see Figure 54).265 Investigation of the degradation of the polymer backbone and the release of the salicylic acid revealed that this process was highly pH dependent. Indeed, no detectable salicylic acid was released at pH ∼ 3.5 even after 90 days, whereas all polymer was degraded and 100% drug was released at pH ∼ 10 after 38 h. At pH ∼ 7.4, the release was slower: 50% drug was released after 20 days while full degradation was achieved after 90 days. In 2012, the same group prepared a diacid derivative of the drug morphine by reacting morphine and glutaric anhydride. It was then converted to polymorphine by activation with acetic anhydride followed by meltcondensation polymerization (Figure 54).128 The prepared poly(anhydride-ester) of morphine (MW ∼ 26000 g·mol−1 with a relatively narrow PDI of 1.14) could be degraded gradually in aqueous medium and release morphine. Because the cleavage of anhydrides are easier than ester bonds, the polymer was first degraded to diacid, then to monoacid, and finally to morphine.

Dibenzyl tartrate was attached through its hydroxyl groups to anti-inflammatory drugs (ibuprofen and naproxen) to produce polymerizable diacid monomers after the deprotection of the benzyl groups.124 Biocompatible biodegradable polyesters with about 65−67 wt % of drug loading were formed by polycondensation of the drug-monomers and 1,9-octanediol (Figure 53). The in vitro drug release at pH ∼ 7.4 was slow without any burst release. After 10 days, only about 7% of drug was released and estimated that about 7−12 months were needed to reach a complete release. Various poly(anhydride-ester) conjugates with different drugs chemically incorporated into the polymer backbone and not as side chain were prepared.128,129,265 The benefits of these systems were the very high loading of the polymer with the drug, i.e., up to 100 wt % of polymer was formed with the drugs, and the complete degradability of the prodrug due to the presence of anhydride and ester bonds. Poly(anhydride-ester) (Mw = 6000 g·mol−1, PDI = 1.2) from salicylic acid was Z


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Figure 55. Synthesis of polymer-conjugates containing Pt (IV).266

Figure 56. Schematics describing the post modification strategy for preparing polymer prodrugs from vinylic monomers.

during this time, and discs became thinner but did not disappear. Diamminedichlorodihydroxyplatinum (DHP) as dihydroxy derivative and diamminedichlorodisuccinatoplatinum (DSP) as dicarboxyl derivative of cisplatin were used as polymerizble monomers to prepare various polymers containing Pt(IV) in the main backbone (see Figure 55).266 Condensation polymerization of DSP with various types of dialcohols failed and no polymer was obtained while its copolymerization with piperazine (PA) and ethylenediamine (EDA) successfully yielded prodrugs containing ∼27−30 wt % of platin. Furthermore, the condensation polymerization of DHP with cyclobutane-1,2,3,4-tetracarboxylic dianhydride (CBTA) created a polyester with pendant carboxylic acid groups that were poorly soluble in water. For this reason, the carboxylic acid groups were modified with PEG (Mn = 550 g·mol−1) moieties to create water-soluble products with around 10 wt % conjugated platin. The release of platin drug mainly occurred due to intracellular reduction, which led to the regeneration of active cisplatin. However, the degaradation and release was accelerated in acidic medium. IC50 of DHP, DSP, P(DHP-DA)PEG, P(DSP-EDA), and P(DSP-PA) for MDA-MB-468 cell lines were around 1.5, 46.9, 3.3, 19.9, and 16.7 μM, respectively. These values showed that P(DSP-EDA) and P(DSP-PA) had higher cytotoxicity than monomer DSP, maybe due to the easier reduction to active Pt(II) in tumor cells. The specific cleavage of disulfide bonds upon reduction was also advantageously used for applications in materials with anticorrosive properties. The corrosion inhibitor mercaptobenzothiazole was convereted to a methacrylate monomer that contained a disulfide linkage. The monomer was copolymerized either with hydrophilic monomers267 or hydrophobic monomers268 to yield nanoparticles and nanocapsules, respectively. The corrosion inhibitor could be released upon chemical reduction of the nanomaterials. In another approach, polymer

Figure 57. Synthesis of methoxypoly(ethylene glycol)-block-poly(allyl glycidyl ether)-epirubicin (mPEG-b-PAGE-EPI) conjugates with two different linkages.67

The degradation to obtain the monoacid was relatively fast. Indeed, all the polymer hydrolyzed to monoacid at pH ∼ 7.4 (37 °C) after 1 day. However, the hydrolysis of monoacid to morphine was very slow. After 30 days, the monoacid was still present. In a similar work, the authors prepared a poly(anhydride-ester) of ferulic acid (FA), a natural antiaging antioxidant applied in formulations of biomedicals and cosmetics to prevent skin cancer (see Figure 54).129 Ferulic acid decomposes at high temperatures so that meltcondensation polymerization could not be applied for the synthesis. Therefore, the authors used phosgene in the presence of triethylamine to proceed the polymerization. The final polymer conjugate had a Mw of 21700 g·mol−1 and PDI of 1.7 and contained about 80 wt % of FA. In vitro degradation via hydrolysis of the polymer backbone and release of FA was investigated using polymer discs (8 mm × 1 mm) during 30 days at physiological pH. Only about 6.2% of FA was released AA


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Figure 58. Synthesis of poly(N-(2-hydroxypropyl)methacrylamide)-block-poly(2-(2-pyridyldisulfide) ethyl methacrylate) (PPDSM-b-PHPMA) cross-linked micelles and their conjugations with Doxorubicin (Dox). Picture of the cross-linked polymers reprinted with permission from ref 10. Copyright 2008 American Chemical Society.

ester,87,122 and carbamate18,67,272 have been used for the conjugation between drug and polymer backbone. Some of these bonds can be cleaved in response to specific stimuli such as acid, reducing agents, or enzymes. 4.2.1. Postmodification via Hydrazone Bonds. Methoxypoly(ethylene glycol)-block-poly(allyl glycidyl ether) (mPEG-b-PAGE) were prepared by ROP of allyl glycidyl ether by mPEG/CsOH initiator, and the pendant allyl groups were converted to present available −OH groups after a reaction with 2-mercaptoethanol (MCH). Finally, these −OH groups were activated by converting them to active 4-nitrophenyl carbonate groups. The epirubicin (EPI) anticancer drug was then connected to the polymer via acid-labile hydrazine bonds and acid-stable carbamate bonds (Figure 57).67 Micelles of these prodrugs with sizes around 23−60 nm were produced by the solvent evaporation method. The pH-dependence behavior of these micelles was evaluated by investigation of the release at three different pH values (5.0, 6.5, and 7.4). The release from micelles of prodrug with the carbamate group was independent of the pH value. In all media, only around 10% of EPI was released after 120 h. However, for hydrazone-containing prodrug micelles, about 39, 33, and 27% of EPI was released after 72 h at pH 5.0, 6.5, and 7.4, respectively. Furthermore, hybrid micelles were produced by coassembly of these prodrugs with cRGD-b-PEG5k-b-PLLA3k (RGD = arginine-glycineaspartic acid peptide) to produce targeting prodrug micelles with higher performance for tumor cells.

Figure 59. Preparation of PHPMA-Dox prodrugs with various spacers.19

nanoparticles build directly from corrosion inhibitors linked by disulfide bonds in the main chain could be depolymerized upon reduction to release the corrosion inhibitor.269 4.2. Postmodification of Side Chains with Drugs

The synthesis of polymers with desired structures, functional groups, and subsequently the modification of their side chains with drugs is a common method for the preparation of polymer prodrugs (Figure 56). It can also be advantageous to use appropriate spacers such as levulinic acid or 4-acetyl benzoic acid81 to promote for example the release rate of the drug. Bonds such as hydrazine,16,130,270 acetal,17,110,152 boronic acid ester,126,154 cis-aconitic,52,155 disulfide,65,85,86,139 imine,271

Table 15. Characteristics of PHPMA-Dox Prodrugs Fabricated with Different Spacers and Cleavable Units19

a

entry

spacer

responsive bond

Mw [g·mol−1]

PDI

Dox [wt %]

release at pH ∼ 7.4 [%]

release at pH ∼ 5.0 [%]

1 2 3 4 5 6 7 8 9

GlyGly Gly Gly-L-LeuGly β-Ala 4-aminobenzoic acid 6-aminohexanoic acid Gly-DL-PheLeuGly Gly-DL-PheLeuGly Gly-DL-PheLeuGly

hydrazone hydrazone hydrazone hydrazone hydrazone hydrazone hydrazone hydrazone amide

25700 15800 21100 25600 38400 35700 19600 115000 23000

1.45 1.63 1.72 1.41 2.1 1.48 1.4 6.5 1.9

9.5 7.89 5.78 6.75 6.8 4.7 10.5 7.4 6.57

11 12 8 7 16 7 6 5 NA

86 87 77 (88a) 70 93 96 77 (97a) 74 (50a)

In the presence of cathepsin B (0.5 μM) at pH ∼ 5.0. AB


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Figure 60. Synthetic procedure for the preparation of prodrugs based on poly(ethylene glycol)-block-poly(aspartate-hydrazide) (PEG-p(Asp-Hyd) with two different linkers.81

stability of the micelles against high dilutions. Release of Dox from these prodrugs in PBS buffers at 37 °C revealed that after 2 days around 22% and 80% of Dox were released at pH 7.4 and 5.0, respectively. To study the effect of a spacer on drug release and in vitro cytotoxicity, Ulbrich research group prepared several HPMA prodrugs of Dox containing acid-labile hydrazone linkage with various amino acid or peptide spacers (Figure 59, Table 15) by free radical polymerization.19 All polymer conjugates released small amounts (∼5−16%) of Dox at pH ∼ 7.4. However, at pH ∼ 5.0, the drug was released in significant amounts (∼72− 96%). As shown in Table 15, the release rate of Dox entirely depended on the length and structure of the spacer. The highest rates were obtained for the hydrolysis of the hydrazone bond in acidic medium of prodrug conjugates with long aliphatic (6-aminohexanoyl, 96% release in 48 h) or aromatic (4-aminobenzoyl, 93% release in 48 h) spacers. Conversely, the lowest release was detected for the prodrug with β-alanine as spacer that released around 70% of Dox during 48 h. Moreover, the release rate from prodrugs with biodegradable spacers (GlyDL-PheLeuGly or Gly-L-LeuGly) was enhanced in the presence of cathepsin B whereas the release rate from conjugates with nondegradable spacers did not change. The conjugate with GlyDL-PheLeuGly as biodegradable spacer displayed a slightly faster release rate compared to the release of conjugate with the 6-aminohexanoyl spacer. mPEG-NH2 (Mn = 12000 g·mol−1) was used as initiator for ROP of β-benzyl-L-aspartate N-carboxyanhydride (BLA-NCA) to produce poly(ethylene glycol)-block-poly(aspartate-hydrazide) (PEG-p(Asp-Hyd)) according to Figure 60 after deprotection and hydrazidation. The hydrazide was linked to the carbonyl group of levulinic acid (LEV) or 4-acetyl benzoic acid (4AB) as linker via hydrazone bond, and then carboxyl groups of these linkers were conjugated to Ptx to produce PEGp(Asp-Hyd-LEV-Ptx) and PEG-p(Asp-Hyd-4AB-Ptx) watersoluble prodrugs.81 Micelles of PEG-p(Asp-Hyd-LEV-Ptx) or PEG-p(Asp-Hyd-4AB-Ptx) with sizes around 42 and 137 nm, respectively, and also hybrid-micelles with 1:1 and 1:5 molar

Figure 61. Synthesis of poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PEO-b-PAGE) prodrugs.5,20

Figure 62. Synthetic route for poly(ethylene glycol)-block-poly(2ethoxy-2-oxo-1,3,2-dioxaphospholane-co-2-allyl ethylene-2-oxo-1,3,2dioxaphospholane)-doxorubicin (PEG-b-P(EEP-co-AEP)-Dox) or PPEH-Dox prodrugs.6

Biocompatible water-soluble poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) was linked to poly(2-(2pyridyldisulfide)ethyl methacrylate) (PPDSM) to produce amphiphilic PPDSM-b-PHPMA. The disulfide bonds were reduced to thiol groups using tris(2-carboxyethyl)phosphine (TCEP). Then, conjugation of maleimide-modified Dox to the pendant thiol groups and cross-linking of the prodrug via production of disulfide bonds was performed in one pot (Figure 58).10 Micelles with a core that was cross-linked by disulfide bonds with sizes around 60 nm could be obtained. The presence of biocleavable disulfide bonds improved the

Figure 63. Preparation of charge-tunable Dox-prodrugs.21 AC


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Figure 64. Dox-functionalized poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-b-PPO-b-PEO) copolymer via a hydrazone group. TEM image reprinted with permission from ref 22. Copyright 2008 Americal Chemical Society.

Figure 65. Synthetic procedure of folate-poly(ethylene glycol)-block-poly(aspartate hydrazide-Dox) (FOL-PEG-p(Asp-Hyd-Dox)) prodrug.8,9

Figure 66. Procedure for the synthesis of peptide-targeted poly(2-hydroxypropyl methacrylamide)-doxorubicin (PHPMA-Dox) prodrugs.7,23,24

modified to introduce hydrazide groups on the polymer structure. Finally, these hydrazide groups were connected to Dox via a hydrazone bond (Figure 61).5,20 The prodrugs with 3% and 17% wt % Dox could form micelles with diameters around 104 and 75 nm, respectively. These prodrugs could release around 16 and 43% of conjugated PEG at pH 7.4 and 5.0, respectively. In another similar work, amphiphilic poly(ethylene glycol)block-poly(2-ethoxy-2-oxo-1,3,2-dioxaphospholane-co-2-allyl ethylene-2-oxo-1,3,2-dioxaphospholane) (PEG-b-P(EEP-coAEP)) was prepared by ROP of cyclic phosphoester using mPEG initiator and then pendant alkene groups modified with hydrazide groups by the reaction with 3-mercaptopropanehydrazide. Dox was then conjugated to the polymer via hydrazone linkage (Figure 62).6 Self-assembly of this prodrug in aqueous solution by dialysis created micelles with sizes around 60 nm as observed by transmission electron microscopy. Around 80% and 20% of Dox were released from these micelles after 140 h

ratios of PEG-p(Asp-Hyd-LEV-PTX):PEG-p(Asp-Hyd4ABPtx) with sizes about 85 and 113 nm, respectively, were produced by solvent exchange method. Their release behavior at pH values of 5.0 and 7.4 were studied. They found that after 24 h, 4AB-Ptx was not released from PEG-p(Asp-Hyd-4ABPtx) at pH 5.0 or 7.4, whereas the release of LEV-Ptx from PEG-p(Asp-Hyd-LEV-Ptx) was increased from about 29 to 58% when pH decreased from 7.4 to 5.0. Even for the mixed micelles, only release of LEV-Ptx was detected in the medium. The release from the hybrid-micelles was pH-dependent. At the molar ratios of 1:1 and 1:5 of PEG-p(Asp-Hyd-LEV-Ptx):PEGp(Asp-Hyd-4ABPtx), around 34 and 19% of LEV-Ptx was released at pH 7.4, respectively, whereas these values reached to 44.9 and 28% at pH 5.0, respectively. The amphiphilic copolymer poly(ethylene oxide)-blockpoly(allyl glycidyl ether) (Mw(PEO) = 5000 and Mw(PAGE) = 1600 g·mol−1) was prepared by ROP of allyl glycidyl ether with mPEG as initiator and then the pendant alkene groups were AD


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Figure 67. Synthesis of of poly(5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one)-graf t-12-acryloyloxy dodecyl phosphorylcholine-co-6-maleimidocaproyl-doxorubicin PMAC-g-(ADPC-co-Mal-Dox).3

Figure 68. Synthesis of pH and temperature-responsive polyaspartic acid based Dox prodrug.4

Figure 69. Synthetic route for preparing poly(ethylene glycol)-block-poly(2-hydroxyethyl methacrylate-co-ethyl glycinate methacrylamide) PEG-bP(HEMA-co-EGMA) Dox prodrugs.2

Dox to prepare prodrugs with around 8.32 wt % of Dox connected with a hydrazone bond (see Figure 63).21 Because of the presence of acid- and base-groups on the polymer structure, self-assembly of this copolymer in water produced chargetunable nanoparticles with sizes around 27 nm. These nanoparticles displayed a negative surface charge at pH ∼ 7.4. An incubation of the nanoparticles in PBS at pH ∼ 6.8 changed the surface charge to be positive. The switching of the nanoparticles charge enhanced their uptake by tumor cells via endocytosis.273,274 As expected, the release of Dox from these prodrug micelles was found to be pH dependent: ∼25% of Dox was released at pH ∼ 7.4 and 6.8, while more than 75% was released at pH ∼ 5.0. A poly(ethylene oxide)-block-poly(propylene oxide)-blockpoly(ethylene oxide) (PEO-b-PPO-b-PEO) triblock copolymer with pendant −OH groups next to the PPO block was prepared in a three reaction steps as shown in Figure 64. These hydroxyl groups were chemically modified with hydrazide groups, and

Table 16. Properties of Polymer Hydrazide Precursors and Dox-Prodrugs Nanogels Prepared from PEG-b-P(HEMA-coEGMA)2 PEG-b-P(HEMA-co-GMA-hydrazide)

PEG-b-P(HEMA-co-GMA-Dox)

Mn [g·mol−1]

PDI

hydrazide [mol %]

Dox [wt %]

8800 9500 8800

1.27 1.31 1.25

8.5 15.0 18.5

3.9 5.7 11.7

a

Rha [nm] 114 75 66

0.15 0.27 0.22

Hydrodynamic radii determined by DLS.

at pH values of 5.0 and 7.4, respectively. In comparison with free Dox, these micelles had enhanced circulation time in the blood that yielded an increase of Dox accumulation in tumor cells. Another similar copolymer with pendant carboxylic acid and primary amino groups was prepared and conjugated to MalAE


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Figure 70. Synthetic route for the formation of folate-targeted doxorubicin-conjugated triblock copolymers.25

Figure 71. Conjugation of Dox and folic acid to methoxy-poly(ethylene glycol)-block poly(lactide-co-2,2-dihydroxymethylpropylene carbonate mPEG-b-P(LA-co-DHP).18

nitrophenyl ester (MA-GG-ONp). Afterward, part of the side chains of these copolymers were conjugated with Dox via liable hydrazone bonds and connected to appropriate targeting peptides such as E-selectin binding peptide (cysteine-harboring Esbp), scrambled Esbp (Scrm), or vascular endothelial growth factor receptor (VEGFR)-1 peptide (Figure 66).7,23,24 These peptide targeted prodrugs were more toxic for tumor cells in comparison with the nontargeted prodrugs. Growth inhibitory activity experiments for immortalized vascular endothelial cells (IVECs) were performed with free Dox, Esbp-Dox prodrug, Scrm-Dox prodrug, and nontargeted Dox prodrug. IC50 of free Dox was 10000 times lower than the IC50 of the nontargeted Dox prodrug. The cytotoxicity of targeted prodrugs was relatively high so that Esbp-Dox and Scrm-Dox prodrugs were about 150 and 3 times more toxic than none-targeted Dox prodrug.7 A biodegradable polycarbonate with pendant thiol groups was prepared through ROP of 5-methyl-5-allyloxycarbonyl-1,3dioxan-2-one (MAC) followed by a thiol−ene click reaction. Afterward, some of the thiol groups were reacted with 6-

Dox was conjugated to them through acid-labile hydrazone bond.22 Self-assembly of these polymers with and without Dox in aqueous solution produced micelles with sizes around 165 and 89 nm, respectively, which shows that conjugation with Dox in the core yielded larger micelles. Dox release from this prodrug micelles revealed that around 84 and 40% of the Dox is released at pH values of 5.0 and 7.4 after 26 h, respectively. Folate-poly(ethylene glycol)-block-poly(aspartate hydrazide) copolymer was prepared by ROP of ethylene oxide and βbenzyl L-aspartate-N-carboxyanhydride and then conjugation with doxorubicin via hydrazone bonds (Figure 65).8,9 The micelles with sizes in the range of 60−90 nm were produced in aqueous solutions from this prodrug. The presence of a folate targeting group and an acid-labile hydrazone bond yieled the micelles with pH sensitivity and receptor selectivity, which overall led to the enhancement of the performance of these prodrugs for antitumor cells. Random copolymers were prepared by free-radical copolymerization of HPMA with methacryloyl-glycylglycine hydrazide-Boc (MA-GG-HZBoc) and methacryloyl-glycylglycine pAF


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Figure 72. Synthesis of copolymers based on polylactic acid followed by conjugation with folic acid, RhB, and Dox.26

revealed this prodrug is quite effective for some cancer cells such as HepG2 and HeLa cells. Polysuccinimide (PSI) was prepared from thermal condensation of aspartic acid. The amylolysis of PSI with N,Ndiisopropylaminoethyl amine and hydrazine yielded to the pHand thermosensitive polyaspartic acid, which was conjugated sequentially with PEG-CHO and Dox via hydrazone linkage (Figure 68).4 Conjugation with Dox inserted the hydrophobic parts into the polymer structure which induced the selfassembly of prodrug in water to yield nanoparticles with size around 240 nm containing ∼6.3 and 21.5 wt % of free and conjugated Dox, respectively. At pH 7.4, the amount of released Dox after 50 h reached from 17 to around 25% by increasing the temperature from 37 to 42 °C, whereas at pH ∼ 5.0 around 35 and 65% of drug was released at 37 and 42 °C, respectively. Poly(ethylene glycol)-block-poly(2-hydroxyethyl methacrylate-co-ethyl glycinate methacrylamide) (PEG-b-P(HEMA-coEGMA)) copolymers with different molecular weight and compositions were prepared by RAFT copolymerization with various feed ratios of HEMA and EGMA using a PEG macroinitiator (Figure 69). Then, the ethyl ester groups were reacted with hydrazine to create hydrazide groups on the polymer backbone. These hydrazide groups were subsequently conjugated with Dox via hydrazone linkages to yield prodrugs

Figure 73. Preparation of poly(2-(methacryloyloxy)-ethyl phosphorylcholine)-block-poly(2-methoxy-2-oxoethyl methacrylate hydrazideDox) PMPC-b-P(MEMA-hydrazide-Dox).27

maleimidocaproyl-doxorubicin (Mal-Dox) and some of them were reacted with 12-acryloyloxy dodecyl phosphoryl choline (ADPC) as a hydrophilic segment (Figure 67).3 The dialysis of a DMSO-MeOH solution of the amphiphilic prodrug in water induced self-assembly of micelles with an average size of 78 nm. Because Dox was conjugated via an acid-labile hydrazone linkage to the polymer, release behavior of Dox from the prepared micelles was pH-dependent. At 37 °C, around 15% and 35% of Dox was released after 48 h at pH 7.4 and 5.0, respectively. Furthermore, in vitro cell cytotoxicity studies

Figure 74. Procedure for the synthesis of poly(ethylene oxide)-Dox (PEO-Dox) prodrugs.28 AG


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Figure 75. Scheme depicting the one-pot synthesis of poly(2-methylene-1,3-dioxepane-co-poly(ethylene glycol) methyl ether methacrylate-copyridyldisulfide ethyl methacrylate) (P(MDO-co-PEGMA-co-PDSMA)) terpolymers followed by conjugation with Dox.29

Figure 76. Synthesis of poly(oligo(ethylene glycol) methyl ether methacrylate)-block-poly(hydroxyethyl methacrylate) (POEGMEMA-b-PHEMA) and conjugation with cisplatin drug.275

Figure 77. Synthesis of hollow particles of polymethacrylic acid-Dox (PMA-Dox) prodrug. Pictures of the nanoparticles reprinted with permission from ref 30. Copyright 2012 John Wiley & Sons.

Figure 78. Synthesis of RGD4C-poly(ethylene oxide)-block-poly(α-carboxyl-ε-caprolactone-Dox) (RGD4C-PEO-b-PCCL-Dox) prodrugs.31,32

with ∼4, 6, and 12 wt % of Dox (Table 16).2 Nanogels with sizes between 60 and 120 nm were prepared from the corresponding polymer prodrugs by dispersing them in phosphate buffer. More than 85% drug was released at pH 5.0, while less than 35% was released at pH 7.4 after 2 days. PCL-based ATRP macroinitiator was used for polymerization of poly(ethylene glycol) methacrylate) (PEGMA) to synthesize the triblock copolymer pPEGMA-b-PCL-b-pPEGMA according

to Figure 70. Afterward, this copolymer was conjugated with Dox via hydrazone bonds and targeting properties were obtained by further conjugation with folic acid.25 Nanoprecipitation of these prodrugs in the presence of 1% Pluronic F68 as surfactant produced nanoparticles with sizes around 140 nm. To increase the cellular uptake and dual-targeting, the surface of nanoparticles was further modified with AS1411 aptamer using EDC/NHS chemistry. After 2 days, around 25% AH


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Figure 79. Scheme depicting the synthesis of dendrimer Dox-heparin prodrug.33

Figure 80. Synthesis of heparin−dexamethasone prodrugs.1

Figure 81. Synthetic procedure for the preparation of hyaluronic acid−Dox conjugates and its targeting with lactoferrin (Lf).34,35

Figure 82. Synthesis of pullulan−Dox prodrug conjugate.17

folate/aptamer NPs were ∼10 and 100 times higher compared to the uptake of nontargeted nanoparticles. Methoxy-poly(ethylene glycol)-block poly(lactide-co-2,2-dihydroxymethylpropylene carbonate mPEG-b-P(LA-co-DHP) was conjugated to include 15 and 18 wt % of Dox in the polymer structure via a carbamate or hydrazone bond. In parallel, mPEG-b-P(LA-co-DHP) was conjugated via ester bond to the targeting molecule folic acid (20 wt %) (Figure 71).18 Hybrid micelles with sizes around 70−100 nm were produced by the coassembly of FOL- and Dox-containing polymers. Prodrug nanoparticles with a carbamate group could release around 23, 47, and 90% of Dox after 20 days at pH ∼ 7.4, 6.0, and 5.0, respectively. The prodrug with the hydrazone group was more sensitive to pH change. Indeed, around 11 and 63% of Dox was released after 20 days at pH ∼ 7.4 and 6.0, whereas more than 90% of Dox was released after only 10 days at pH ∼ 5.0. Three conjugated polymers with molecular weights around 10000 g·mol−1 containing Dox as the anticancer drug in side

Table 17. Characteristics of Poly(ethylene glycol)-blockpoly(N-(2-hydroxypropyl)methacrylamide) (PEG-bPHPMA) Conjugates16

a

Mn [g·mol−1]

PDI

folate [mol %]

Dox [mol %]

Dha [nm]

36400 39400 45700 53100 51200 63600

1.09 1.15 1.18 1.12 1.40 1.34

0 3.1 6.9 9.8 0 9.0

0 0 0 0 8.3 8.3

2 4 11 15 12 21

Determined by DLS.

and 70% of Dox was released in vitro at pH 7.4 and 5.0, respectively. Moreover, the amount of cellular uptake of the nanoparticles was higher in targeted prodrugs in comparison with nontargeted prodrugs. The fluorescence experiments on MCF-7 and PANC-1 cells showed that the uptake of nanoparticles in cells that were functionalized by folate and AI


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Figure 83. Synthesis of polyMPC−Dox conjugates with a (a) one-pot strategy, or (b) postpolymerization conjugation.36

Figure 84. Synthesis of polymer conjugates containing doxorubicin (Dox), folic acid (Fol), and fluorescein (FITC).16

around 23, 6, and 0.3 wt % of Dox, RhB, and Fol, respectively. Their coassembly in water formed micelles with sizes in the range of 150−300 nm. Because Dox was attached to the

chains, Rhodamine B as the imaging agent in side chains, and folic acid as the targeting agent at the end group were prepared as shown in Figure 72.26 The prepared polymers contained AJ


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Figure 85. Synthesis of poly(2-hydroxypropyl methacrylamide) (PHPMA)−isoquinoline conjugates.130

Figure 86. Synthesis of polyethylene glycol-block-poly(acrylic acid) (PEG-b-PAA) via RAFT polymerization and conjugation with Ptx.110

Figure 87. Synthesis of pH- and temperature-responsive copolymers of poly(lilial methacrylate-co-polyethylene glycol methacrylate).293

Figure 88. Synthesis of statistical82 and block83 polynorbornene copolymer prodrugs of Ptx by ring opening metathesis polymerization. Selfassembly structures reprinted with permission from ref 83. Copyright 2015 Royal Chemical Society.

investigation of the biodistribution by fluorescent experiments showed that targeting enhanced significantly the cellular uptake of the nanoparticles in tumor cells.

polymer via acid-labile hydrazone linkage, its release was pHdependent. After 15 days, around 28, 60, and 90% Dox was released at pH ∼ 7.4, 6.0, and 5.0, respectively. The AK


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Figure 89. Ring opening metathesis polymerization for preparing polylactide-based Ptx prodrugs.84

Figure 90. Synthesis of acid-stable cholesteryl-modified pullulan (acS-CHP) and acid-labile cholesteryl-modified pullulan (acL-CHP).294

Figure 91. Synthesis of pH-sensitive methoxypolyethylene glycol-b-poly(L-lysine)-cholesterol (mPEG-b-PLL-Chol) as carrier for Dox.154

Figure 92. RAFT polymerization of naproxen (Nap) prodrugs containing redox-responsive boronate ester linkage.126

A phospholipid polymer based on poly(2-(methacryloyloxy)ethyl phosphorylcholine)-block-poly(2-methoxy-2-oxoethyl methacrylate) PMPC-b-PMEMA was prepared by ATRP and conjugated with Dox via a hydrazone bond by Wang et al. according to Figure 73.27 The prepared prodrug possessed 10.6

wt % of Dox, and its self-assembly by dialysis in water produced micelles with an average size of 142 nm. The shell of the micelles was constituted of phosphorylcholine as in cell membranes. This feature enhanced the uptake of the micelles into cancer HepG2 cells as confirmed by fluorescent experiAL


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Figure 93. Synthesis of glycol chitosan−Dox prodrugs.52

Figure 94. Synthesis of polypeptide-based 6-mercaptopurine (6-MP) prodrug.139

Figure 95. Synthesis of methoxy ploy(ethylene glycol)-block-poly(L-lysine)-Ptx (mPEG-b-PLL-Ptx) prodrugs.85

Figure 96. Synthesis of stearyl chitosan−Dox (CSO-SA-Dox) prodrugs.65

simultaneous ROP of ethylene oxide (EO) and allyl glycidyl ether (AGE). The alkene groups were subsequently modified using methyl mercaptoacetate to insert hydrazide groups in the polymer structure. The hydrazide group was beneficial for conjugation with Dox through hydrazone bonds (Figure 74).28 These prodrugs contained 5.6−9.0 wt % Dox with sizes ∼10 nm in water that were gradually released by hydrolysis of the hydrazone bond. The in vitro release of Dox showed that after 120 h, around 83 and 92% of Dox was released at pH ∼ 6.0 and 5.0, whereas only about 23% of Dox was released at pH ∼ 7.4.

ments. Because of the cleavage of the hydrazone bond and the consequently gradual exclusion from the micelles of the hydrophobic Dox parts in acidic medium, the structure of micelles became looser and larger aggregates were produced. The release of Dox from this prodrug at 37 °C showed that around 6 and 54% of Dox was released at pH ∼ 7.4 and 5.0, respectively. Poly(ethylene oxide) (PEO) containing pendant alkene groups forming polymers with different molecular weights (Mn ∼ 8900−22400 g·mol−1, PDI ∼ 1.08−1.19) were prepared by AM


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Figure 97. Synthesis of polyethylene glycol-block-poly(2-hydroxyethyl) methacrylate-Ptx (PEG-b-PHEMA-Ptx) prodrug.86

toxicity, which confirmed its biocompatibility, whereas PEODox was highly toxic. Indeed, the cell viability after 72 h at a concentration of 60 μg Dox equiv/mL decreased to 13.8, 17.4, and 23.2% for RAW 264.7, 4T1, and HeLa, respectively. Different molecular weights (Mn ∼ 11000−24000 g·mol−1) of biodegradable terpolymers with relatively broad molar mass dispersity (1.58−2.41) were prepared by copolymerization of mixtures of 2-methylene-1,3-dioxepane (MDO), poly(ethylene glycol) methyl ether methacrylate (PEGMA), and pyridyldisulfide ethyl methacrylate (PDSMA) in a one-pot radical ringopening polymerization. Afterward, the pyridyldisulfide groups were in situ converted to free thiol groups using TCEP and reacted with Mal-Dox via thiol−ene click chemistry (Figure 75).29 P(MDO-co-PEGMA-co-PDSMA) terpolymer (Mn ∼ 11100 g·mol−1) could self-assemble into 180 nm micelles by dialysis. It was revealed that after 2 days, around 12 and 52% of Dox was released at pH ∼ 7.4 and 5.0, respectively. Moreover, cell viability tests showed that P(MDO-co-PEGMA-coPDSMA) exhibited no toxicity for HUVECs and was biocompatible whereas the prodrug micelles were highly toxic and an activity similar to the activity of free Dox for inhibiting the growth of A549 cells. Poly(oligo(ethylene glycol) methyl ether methacrylate)block-poly(hydroxyethyl methacrylate) (POEGMEMA-bPHEMA) (Mn ∼ 23000, PDI ∼ 1.07) copolymer was prepared by RAFT polymerization. After hydrazidation, the diblock copolymer was conjugated to the cisplatin drug via a hydrazone bond (see Figure 76).275 By changing the time of conjugation reaction, two prodrugs were prepared in which 61 and 100% of diamino ligand of the polymer side chains were reacted with the platinum complex. These prodrugs self-assembled into micelles and aggregates with sizes of 27 and 1000 nm, respectively. The

Figure 98. Synthesis of prodrugs based on poly(styrene-alt-maleic anhydride).295

Figure 99. Synthesis of ciprofloxacin prodrugs by selective ring opening of epoxides in trifluoroethanol (TFE) as solvent.131

The in vitro cytotoxicity of PEO-hydrazide and PEO-Dox prodrugs was investigated with three different cancer cell lines (HeLa, RAW 264.7, and 4T1). PEO-hydrazide showed no

Figure 100. Preparation route of paclitaxel (Ptx) prodrugs based on chitosan99 and trimethylchitosan (TMC).105 AN


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Figure 101. Synthesis of paclitaxel (Ptx) prodrugs based on hyaluronic acid (HA) using the modification of its primary hydroxyl104 or sodium carboxylate groups.94

first be uptaken by cells via endocytosis. The drug release occurs due to the acidity of endosome and lysosome. However, whereas endocytosis for small particles is easy, it is very unlikely to happen for the larger ones. Polymethacrylic acid (PMA) was partially thiolated with a reaction with pyridine dithioethylamine (PDA) and DTT. Parts of the thiol groups were conjugated to Dox via thiol-maleimide click chemistry to obtain a prodrug with acid-labile hydrazone linkage (Figure 77).30 Afterward, the Dox prodrug with MW ∼ 20000 g·mol−1 was infiltrated into amino-functionalized 700− 900 nm mesoporous silica nanoparticles and the free thiol groups were subsequently converted to disulfide bonds with of chloramine T. Finally, the mesoporous silica template was removed by hydrofluoric acid to yield cross-linked hollow particles of the polymer prodrug. It was shown that after 24 h and 37 °C more than 80% of Dox was released at pH ∼ 5.5 whereas less than 25% was released at pH ∼ 7.2. Moreover, cell viability tests for LIM1899 human colorectal cancer cells revealed that PMASH was not toxic. Conversely, the prodrug particles were very toxic. Remarkably, they displayed a lower IC50 (28.5 nM) in comparison with free Dox (62.1 nM). Acetal-poly(ethylene oxide)-block-poly(α-carboxyl-ε-caprolactone) (acetal-PEO-b-PCCL) was prepared by ring-opening polymerization as shown in Figure 78 and then conjugated with Dox via a hydrazone or an amide bond. The terminal section of the PEO block of the prodrug was functionalized with RGD peptides as a targeting agent by a reductive amination

Figure 102. Synthesis of a water-soluble paclitaxel (Ptx) prodrug based on a polypeptide backbone.106

large size for the particles with high drug loading is presumably related to intermolecular complexation and cross-linking between micelles leading to aggreagtes. All of the hydrazone bonds were cleaved at pH ∼ 5.5, while only around 20% were cleaved at pH ∼ 7.4 at 37 °C after 200 min. Cell availability tested with ovarian cancer cell line OVCAR-3 indicated that the polymer without conjugated drug displayed no toxicity in the concentration range of 2−250 μg·mL−1. Micelles of 27 nm were highly toxic, whereas 1000 nm particles showed almost no toxicity despite the fact that they contained higher amount of drug. This is due to the fact that the prodrug particles should

Figure 103. Synthesis of amphiphilic paclitaxel (Ptx) prodrugs using conjugation via pendant carboxylic acid groups. Top: Poly(ethylene oxide)block-poly(ε-caprolactone) (PEO-b-PCL).109 Bottom: Poly{(lactic acid)-co-[(glycolic acid)-alt-(L-glutamic acid-paclitaxel)]}-block-poly(ethylene glycol)-block-poly{(lactic acid)-co-[(glycolic acid)-alt-(L-glutamic acid-paclitaxel)]} P(LGG-Ptx)-PEG-P(LGG-Ptx).98 AO


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Figure 104. Synthetic method for the preparation of poly(ethylene oxide)-block-polyphosphester-paclitaxel (PEO-b-PPE-g-Ptx) prodrug.87

Figure 105. Synthesis of polypeptide−Ptx prodrugs based on poly(L-glutamic acid) (PGA)88,89 and poly(L-γ-glutamyl-glutamine (PGG).89

Figure 106. Synthesis of poly(ethylene glycol)-block-poly(ε-caprolactone)-b-poly(L-lysine)-bortezomib (mPEG-b-PCL-b-PLL-BTZ) prodrugs.132

Polysaccharides are nontoxic, biodegradable, and biocompatible polymers which attracts much attention in the biomedical applications such as drug delivery,276−278 gene delivery,279,280 antibacterial,281 and wound healing.282,283 Polysaccharides were also used for the preparation of polymer−drug conjugates.1,17,33−35 Heparin,284−286 a glycosaminoglycan (GAG) polysaccharide, is one of the oldest biological drugs for thrombosis and hemostasis. Mucosal tissues of some animals such as porcine intestines or cattle lungs are used for extraction of heparin.286 Prodrugs based on heparin were recently prepared by chemical modification of carboxylate groups. For example, dendronized heparin Dox prodrug (Figure 79) was synthesized to form a pH-sensitive drug conjugate for breast tumor therapy.33 First, a mono alkyne-terminated lysine-based dendrimer was prepared and conjugated with Dox via hydrazone bonds and then attached to an azido-heparin derivative by click chemistry. The prepared prodrug contained 9.0 wt % Dox and self-assembled into nanoparticles of 90 nm. Because of the presence of hydrazone linkages, the release behavior of Dox from these micelles was quite pH-dependent so that only around 20% of Dox is released at pH 7.4 after 56 h at 37 °C while more than 80% of Dox is released at the same condition at pH ∼ 5.0. Moreover, in vitro toxicity tests with

Figure 107. Synthesis of poly(ethylene oxide)-block-poly(glycerol monomethacrylate)-IND (PEO-b-PG2MA-IND) prodrugs.122

reaction.31,32 Around 11 and 33% of the pendant carboxyl groups were conjugated with Dox by amide and hydrazine bonds. The self-assembly of these prodrugs in water formed micelles with sizes around 60−90 nm. No detectable Dox was released from these micelles at pH = 7.2 for both types of prodrugs. At pH ∼ 5.0 and after 2 days, around 10 and 30% of Dox was released from prodrugs with amide and hydrazone bonds, respectively. Cell uptake experiments for the wild-type (WT) cancer cells including Dox-sensitive MDA-435/LCC6WT and Dox-resistant MDA-435/LCC6MDR showed that micelles functionalized with the targeting agent RGD4C increased significantly the accumulation of Dox in cancer cells. AP


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Figure 108. Synthesis of degradable poly(ethylene glycol)-paclitaxel-graf t-polylactide (PEG-Ptx-g-PLA) prodrugs.91

Figure 109. Synthesis of poly(ethylene glycol)-block-poly(ε-caprolactone)-block-polylysine/platinium (mPEG-b-PCL-b-PLL/Pt) prodrug and drug release pathways through hydrolysis or reduction.298

were used for the encapsulation of Dox (∼19 wt %). The release of conjugated dexamethasone and encapsulated Dox from the micelle at 37 °C at different pH values revealed that 18 Dex and 23 Dox were released at pH 5.0. Hyaluronic acid also called hyaluronan (HA) is a glycosaminoglycan made of D-N-acetylglucosamine and Dglucuronic acid units which are linked via β-1,4 and β-1,3 glyosidic bonds.287 HA is separated from bacteria and from animal sources such as rooster combs and pig skin. HA also is produced by the cells of human body and is the main part in connective tissues.288 Similarly to the experiments with heparin,1 a hydrazide derivative of HA was prepared and conjugated with Dox via a hydrazine bond (Figure 81) to form a prodrug containing ∼6 wt % Dox.34,35 Subsequent thiolation yielded a thiolated prodrug polymer that showed a fast selfgelation ability by oxidation of the thiol groups in disulfide cross-links in the presence of air.34 The prepared hydrogels had both pH- (hydroazone) and reduction-responsive (disulfide) properties so that 11.2, 26.0, and 29.8% of Dox was released after 24 h at pH ∼ 7.4, 6.0, and 5.0, respectively. Furthermore, the presence of a reducing agent could accelerate the release of Dox release. Indeed, at pH ∼ 5.0 in the presence of 10 and 50 mmol of GSH, the amount of released Dox reached to around 41 and 48% after 24 h. In another work, HA-Dox prodrugs were conjugated with lactoferrin (Lf) (Figure 81) for glioma, a type of invasive malignant brain tumor, dual-targeted treat-

Figure 110. Synthesis of amphiphilic polyphosphazene−platinum conjugates.299,300

mouse breast cancer cell line (4T1) for 48 h indicated that heparin was not toxic whereas heparin-Dox displayed a IC50 around 300 ng/mL, i.e., about 11 times more toxic than free Dox. In another work, a heparin derivative with hydrazide groups was prepared and conjugated with different amounts of dexamethasone to prepare prodrugs containing ∼6−13 wt % of dexamethasone (Figure 80).1 These amphiphilic prodrugs self-assembled into micelles with sizes in the range of 140−170 nm. The micelles of prodrug with ∼13 wt % dexamethasone AQ


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Figure 111. Synthesis of (a) water-insoluble and (b) water-soluble self-immolative comb polymers.301

Figure 112. Self-immolative disassembly of a low molecular weight conjugate in the presence of piperidine.301

Figure 113. Synthesis of poly(2-hydroxypropyl methacrylamide) (PHPMA)-based panobinostat (PANO) conjugate containing self-immolative redox-responsive linkages.140

ment.35 CD44 receptor exists at high levels in cancer cells and can bind to HA, so intrinsically HA is able to target the glioma. To increase the specificity, additional targeting was carried out by further conjugating the HA-Dox with lactoferrin, a glycoprotein of the transferrin family. The in vitro release behavior from this targeted prodrug revealed that 12, 35, and 45% of Dox was released at pH ∼ 7.4, 6.0, and 5.0, respectively. Furthermore, in vivo and in vitro experiments on mice showed that targeting with Lf increased the cellular uptake and drug accumulation in tumor cells. Pullulan, a linear homopolysaccharide of glucose, was conjugated with Dox through its hydrazide derivative according to Figure 82.17 Prodrugs with ∼14−29 wt % of Dox were synthesized. These prodrugs self-assembled to form core−shell nanoparticles with sizes in the range of 57−105 nm. In vitro

release of Dox from these nanoparticles showed that around 11−15% and 83−91% of drug was released at pH ∼ 7.4 and 5.0, respectively. Moreover, pullulan on the surface of the prodrug nanoparticles can act as a targeting agent toward hepatic cells because it can interact effectively with asialoglycoprotein receptor (ASGPR). The comparison between the cellular uptake of free Dox and pullulan−Dox for three cell lines, HepG2, HeLa, and L929, indicated that free Dox entered the cells without any preference. On the contrary, the uptake of pullulan−Dox nanoparticles in HepG2 cells was comparable with free Dox whereas less uptake by HeLa and L929 cells was observed in comparison with free Dox. The ASGPR on HepG2 surface that detected pullulan was facilitating its endocytosis. AR


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Figure 114. Chemical structure of the fourth-generation (G4) polyamidoamine (PAMAM).

Two prodrugs of Dox based on poly(methacryloyloxyethyl phosphorylcholine) (PMPC) were prepared with a one-pot polymerization/conjugation or by postpolymerization conjugation methods by Chen et al.36 In the one-pot strategy, ATRP of methacryloyloxyethyl phosphorylcholine (MPC) and trimethylsilyl-protected propargyl methacrylate was carried out in the presence of Dox-N3 to prepare the prodrug. In postpolymerization strategy, a copolymer of MPC and 2-tert-butoxy-2-oxoethyl methacrylate (TBOEMA) was first prepared and then conjugated to Dox through hydrazone linkage according to Figure 83. Although the one-pot strategy is an easy method for the preparation of the conjugates, it suffered from a low amount of drug loading (3−5 wt %). On the contrary, it was possible to

Figure 115. Synthesis of polyamidoamine−doxorubicin (PAMAMDox) prodrug and targeting with recombinant receptor-binding fragment of α-fetoprotein (rAFP3D).53

Figure 116. Synthetic routes of PEGylated-polyamidoamine (PAMAM)-Dox prodrugs with acid-labile/nonlabile linkages.54 AS


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Figure 117. Synthesis of PEGylated polyamidoamine (PAMAM) prodrugs of Dox containing cis-aconityl and succinic acid linkages.55

Figure 118. Synthesis of folic acid-targeting PEGylated polyamidoamine (PAMAM)-Dox prodrugs.37

Figure 119. Preparation of methoxypoly(ethylene glycol)−polyamidoamine−doxorubicin (mPEG-PAMAM-Dox) prodrugs.38

Figure 120. Synthesis of losartan carboxylic acid (EXP3174) prodrugs based on polyamidoamine (PAMAM) or 8armPEG-NH2 dendrimers.133

Figure 121. Synthesis of poly(ethylene glycol)-modified polyamidoamine−doxorubicin (PEG-PAMAM-Dox) prodrugs with labile and nonlabile groups.39

increase the drug loading up to the 45 wt % via postpolymerization conjugation. Because of the presence of hydrophobic and hydrophilic segments in the conjugates, they could self-assemble to form nanoparticles (7−16 nm) in

aqueous medium. It was revealed that around 10−15% of Dox was released at pH ∼ 7.4 during 24 h while about 70−80% of Dox can release at pH ∼ 5.0 in the same period. Moreover, cytotoxicity experiments showed that polyMPC was biocomAT


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folate-targeting prodrug 6, free Dox, and none-targeted prodrug 5, respectively. To study the effect of steric hindrance on the acidic hydrolysis of the hydrazone linkage, Sedlácek et al. prepared a series of polymer conjugates from hydrazide-containing PHPMA with various isoquinoline derivatives (Figure 85).130 Isoquinoline was used as a model for ellipticine. Ellipticine is a natural alkaloid with a structure similar to isoquinoline, which acts as an effective antineoplastic.289−291 The low water solubility of ellipticine is a limitation for its application in clinical trials, and so its quaternary ammonium derivatives with higher water solubility were prepared.292 No release was observed at pH ∼ 7.4, which is related to the strong electronwithdrawing effect of positive charge on the β position of the hydrazone linkage. However, at pH ∼ 5.0, the release rate depended on the steric hindrance. After 2 days, around 88, 69, 25, and 13% of the drug model was released for conjugates of derivatives a, b, c and d, respectively. This effect revealed that an increase of the steric hindrance decreased significantly the release rate. It was also found that when the positive charge transferred to the γ or δ position of the hydrazone linkage (e and f), its electron-withdrawing effect decreased and subsequently the hydrolysis rate and release of drug increased. Even at pH ∼ 7.4, large amounts of released drugs (36% for e and 77% for f) were reported. All results showed that sample “a” had the best release profile for anticancer drugs. Therefore, ellipticine was modified in the same manner as “a” and conjugated to PHMA through hydrazone linkage. It showed similar release profile as the “a” conjugate so that at pH ∼ 7.4 a negligible amount of drug was released while at pH ∼ 5.0 around 50% of ellipticine was released after 48 h. 4.2.2. Postmodification via Other Labile Linkages. Although hydrazone is the most used acid-labile bond for conjugation of drugs to polymers, some other labile bonds such as acetal, cis-aconityl, boronate ester, and disulfide also have been reported. A RAFT macroinitiator based on PEG (Mn = 5000 g·mol−1) was used for polymerization of acrylic acid in the presence of α,α′-azobis(isobutyronitrile). Afterward, the PEGb-PAA copolymer was conjugated with various amounts of Ptx drug via acetal bonds to produce three prodrugs with 21.6, 27.0, and 42.8 wt % of Ptx (Figure 86).110 Micelles with sizes in the range of ∼160−180 nm were produced and displayed release profiles that were dependent on the pH values of their environments. The polymerizable methacrylate monomer of lilial (LMA), a volatile aldehyde used as a perfume in cosmetics, containing an acid-labile acetal bond, was prepared and copolymerized with ratios with PEGMA to obtain statistical amphiphilic copolymers (Figure 87).293 By changing the ratio of LMA:PEGMA, 100:0, 75:25, and 25:75, copolymers were synthesized with Mn around 26500, 44800, and 32800 g·mol−1, respectively, with a relatively broad PDI (2.00−3.67). The self-assembly of a copolymer with ratio of 25:75 in aqueous media formed micelles with sizes

Figure 122. Synthesis of a prodrug of polyamidoamine conjugated with doxorubicin via a hydrazone as acid-labile linkage and collagen.40

Figure 123. Dicyclohexylcarbodiimide (DCC) mediated synthesis of hyperbranched polyol−ibuprofen (Ibu) prodrugs.125

patible and not toxic. However, polyMPC-Dox conjugate was found to be toxic and displayed an IC50 around 1.5−16 μM for MCF-7, MDA-MB-231, and COLO 205 cancer cell lines. Poly(ethylene glycol)-block-poly(N-(2-hydroxypropyl)methacrylamide) (PEG-b-PHPMA) copolymers were prepared by RAFT polymerization technique using PEG-CTA as a chain transfer agent (CTA). To enable the copolymers for post modification with active agents (Dox as drug, folic acid as targeting group, and fluorescein (FITC) fluorophore as imaging agent), methacryloylglycyl-glycine (MAGG), Boc-hydrazide methacryloylglycyl-glycine (BHMAGG), and FITC-modified aminopropyl methacrylamide (MAFITC) were used along with HMPA in the polymerization process (Figure 84, Table 17).16 The amount of Fol or Dox in prodrug structure could be easily tuned by changing the molar ratio of Fol or Dox. All the conjugates produced nanoparticles in aqueous media. As shown in Table 17, the increase of folate content induced an increase of the size of the polymer conjugates. This effect was attributed to the hydrophobic feature of folate molecules. The release of Dox from the conjugate 5 (Table 17) showed that the release behavior was pH-dependent. After 120 h, around 15, 25, and 60% of Dox was released at pH ∼ 7.4, 6.5, and 5.0, respectively. Finally, the cytotoxicity of the conjugates for T24 cells showed that the targeted prodrug was highly toxic. Indeed, the cell viability after 3 days was decreased to around 3, 15, and 33% for

Figure 124. Synthesis of hyperbranched polyglycerol amine (PG) and conjugation with Dox and PEG.41 AU


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Figure 125. Synthesis of mPEGylated peptide dendrimer and conjugation with Dox.42

10−30 nm in water. After 3 days, around 65% of Ptx was released at pH 7.4 due to the presence of hydrolyzable acetal bond between the polymer and Ptx. Moreover, this prodrug at high concentrations (>0.1 μg/mL) showed more cytoxicity for MCF-7 cells in comparison to free Ptx. To create a carrier for proteins, two cholesterol (Chol) derivatives containing ester or vinyl ether bond were conjugated to pullulan by click chemistry. Acid-stable cholesteryl-modified pullulan (acS-CHP) and acid-labile cholesteryl-modified pullulan (acL-CHP) containing around 1.7 Chol units per 100 pullulan glucose units were obtained (Figure 90).294 These polymeric conjugates self-assembled at neutral pH (∼7.4) to produce stable nanogels with sizes around 18 nm (PDI ∼ 0.22) and 27 nm (PDI ∼ 0.25) for acS-CHP and acL-CHP, respectively. The swelling properties of asS-CHP was independent of the pH value. However, around 135% enhancement of the swelling was observed at pH 4.0 after 8 h for acL-CHP. In fact, around 80%, Chol chains were degraded in acL-CHP nanogels at pH ∼ 4.0 after 24 h. Its amphiphilic property and ability to form nanogels was significantly reduced while no degradation occurred in acS-CHP nanogels. The acLCHP nanogels were found to be a good candidate for protein delivery because they formed stable complexes with proteins at neutral pH that could be released upon acidification. Methoxypolyethylene glycol-block-poly(L-lysine) (mPEG-bPLL, Mn ∼ 6700 g·mol−1) comb copolymers were prepared, and the NH2 pendant groups of lysine were conjugated with various amounts of cholesterol via acid-labile boronate ester bonds (Figure 91).154 The assembly of these copolymers at pH ∼ 7.4 produced micelles with sizes in the range of 167−197 nm. By changing the pH to 5.0, the particle size increased to around 955 nm due to the cleavage of the boronate ester bond in acidic medium. These micelles could encapsulate around 2− 14 wt % of Dox. The release rate was quite fast at the beginning: micelles with 7.5 wt % of encapsulated Dox released 55% Dox at pH ∼ 5.0 after during 20 min. Afterward, a sustained release was observed and after 160 h around 38% and 85% of Dox was released at pH ∼ 7.4 and 5.0, respectively. An acrylate monomer containing naproxen (Nap) with an oxidation-labile boronate ester group was prepared and polymerized from the PEG macroinitiator by means of RAFT polymerization to produce comb amphiphilic block copolymers

around 35 nm. However, the aggregation behavior of this copolymer in NaCl aqueous solution was temperature-dependent. At temperatures higher than 47 °C, the micelles aggregated to larger particles. This aggregation prevented releasing of the lilial so that at pH ∼ 3 the amount of released lilial after 93 h at 50 °C was negligible while around 29% of lilial was released at 40 °C. An exonorbornene (NB) monomer was connected to Ptx through acid-sensitive cycloacetal-based linkage and then copolymerized by ROMP with another NB monomer containing PEG to increase the water solubility and decrease the toxicity (Figure 88).82 By changing the feed ratio of A:B:I (for A and B, see Figure 88) from 25:25:1 to 100:100:1 statistical copolymers with Mn ∼ 90000 g·mol−1 (PDI = 1.11) and 360000 g·mol−1 (PDI = 1.09) were prepared and selfassembled into nanoparticles with sizes of ∼12 and ∼29 nm, respectively. The polymers contained 24 wt % Ptx. After 24 h, less than 20% of Ptx was released at pH ∼ 7.4 while more than 90% of drug was released at pH ∼ 5.5. In another work, similar block copolymers were synthesized with 24 wt % of Ptx.83 The self-assembly of the block copolymers with a feed ratio of A:B:I of 25:25:1 and 100:100:1 produced polymers with sizes around 100.2 and 149.2 nm, respectively, which were larger than nanoparticles of statistical copolymers. Profile release from diblock prodrugs was quite different from the statistical prodrugs. For the diblock copolymers after 24 h, only around 18% and 24% of Ptx were released at pH ∼ 7.4 and 5.5, respectively. After 240 h, the same amount (around 90%) of Ptx was released at both pH values. These results revealed the importance of the polymer structure in the release profile. Indeed, diblock copolymers displayed slower release than statistical copolymers due to the fact that the diffusion pathway to and from the conjugated bond was larger for the assemblies of diblock copolymers than for the assemblies with statistical copolymers. The reason was the slower cleavage of acetal bond as well as a retarded diffusion of the released Ptx from the assembly. Polylactide with pendant alkyne groups was prepared and then these alkyne groups were simultaneously reacted to N3-Ptx and N3-PEG (Mw ∼ 2000 g·mol−1) by click chemistry to produce degradable brush prodrugs with 23.2 wt % Ptx (Figure 89).84 These prodrugs formed nanoparticles with sizes around AV


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Indeed, around 7.3 and 29.3% of Dox was released after 4 days at pH ∼ 7 and 4, respectively. A water-soluble biodegradable polymer prodrug was prepared by reaction between poly(L-succinimide) (PSI) with mPEG-SS-NH2 and 2-(pyridyldithio)-ethylamine (PDA). The polymer was then conjugated to 6-mercaptopurine (6-MP) through a disulfide bond (Figure 94).139 This prodrug formed core−shell micelles with a size of 160 nm in water. Only about 35% 6-MP was released upon hydrolysis after 85 h at 37 °C, while in the same condition in the presence of 10 and 40 mM of DTT, around 72 and 91% of 6-MP was released. Lv et al. prepared methoxyploy(ethylene glycol)-blockpoly(L-lysine) mPEG-b-PLL and conjugated it with Ptx through 3,3′-dithiodipropionic acid (SS) as reduction-responsive or succinic acid (SA) as a nonreduction linker (see Figure 95).85 The amount of Ptx was ∼16−17 wt % in the prodrugs containing SS and SA. Micelles with sizes around 15 nm were prepared from these prodrugs in aqueous medium. Release of Ptx from the prodrugs with a dithiodipropionic acid (SS) linker was both pH- and reduction-sensitive. In extracellular conditions (pH 7.4, GSH 20 μM), only around 8% Ptx was released after 5 days from the prodrug micelles with disulfide linkage. At the same pH (∼7.4) and in the presence of higher concentration of GSH (10 mM), around 75% of drug was released in the same period. Moreover, at pH ∼ 5.0 and even in the absence of GSH, around 50% Ptx was released due to the hydrolysis of the acid labile 3-thiopropionate linkage. In contrast, release from micelle prodrugs with a succinic acid linker (which is neither pH- nor reduction-sensitive) was not much affected much by the change of pH or GSH concentration. A biodegradable Dox prodrug was prepared by conjugation of oligomers of stearyl chitosan (CSO-SA) with doxorubicin via disulfide bonds (Figure 96).65 The prepared prodrugs with 5.5 wt % Dox could form micelles with sizes of ∼60 nm in aqueous medium. The release behavior of Dox was studied for 48 h in the presence of 10 mM or 10 μM of DTT at pH ∼ 7.4 to mimick the intracellular or extracellular thiol concentration, respectively. Around 38% and 81% of Dox was released in the presence of 10 μM and 10 mM of DTT, respectively. High IC50 (307−488 μg/mL) of stearyl chitosan micelles for various cell lines revealed the low cytotoxicity of the polymer backbone, whereas the Dox prodrug had a lower IC50 than free Dox for BEL-7402 and MCF-7 cells. Hydrophilic PEG-b-PHEMA copolymers were prepared by ATRP of 2-(trimethylsilyloxyl)ethyl methacrylate (HEMATMS) using a PEG macroinitiator and subsequent deprotection of trimethylsilyl groups. Then the copolymers were conjugated with a Ptx derivative containing a disulfide bond by esterification of pendant OH groups (Figure 97).86 The prepared prodrugs with ∼18 wt % of Ptx were self-assembled in core−shell micelles with size ∼200 nm. After 60 h at pH ∼ 7.4, around 21 and 72% of Ptx was released from these micelles in the absence and presence of cysteamine as reducing agent, respectively. In vitro cytotoxicity experiments indicate that PEG-b-PHEMA copolymer was fairly safe with low toxicity, whereas the Ptx prodrug had good toxicity for HeLa cells (IC50 ∼ 0.49 μg/mL). In the presence of GSH-OEt (10 mM) as reducing agent, the copolymers were more toxic with an IC50 of ∼0.26 μg/mL. 4.2.3. Postmodification with Nonlabile Linkages. In addition to the aforementioned labile bonds, various kinds of other bonds that are less labile such as amide, ester, and

Figure 126. PEGylation and Dox-conjugation with peptide dendrimer containing malonate end groups.308

as new prodrugs (Figure 92).126 By changing the feed ratio of PEG and Nap-containing monomer, prodrugs with Mn ∼ 43800−60300 g·mol−1 and Nap content 23−42 wt % were synthesized. Because some of the prodrugs were not soluble in water, the solvent-displacement method was used to form nanosized micelles (151−322 nm). However, it was revealed that around 4−33% of boronate esters were degraded during the fabrication of the nanoparticles. In all prodrug micelles, more than 92% of conjugated Nap was released upon the oxidation of a boronate ester group after 24 h at 37 °C in the presence of H2O2 (40 mM). Glycol chitosan was conjugated with different amounts of Dox through acid-labile cis-aconityl linkage to yield prodrugs containing 2.0−5.0 wt % Dox (Figure 93).52 These prodrugs self-aggregated in aqueous medium and formed particles with sizes in the range of 238−304 nm. The prepared prodrugs displayed a slow release behavior even in acidic medium. AW


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the HA-Ptx prodrug was due to the remaining carboxylate groups in the structure of HA. In fact, HA-tosyl derivative with various degrees of substitutions (DSTs = 7−27%) was prepared through tosylation of primary hydroxyl groups and used for the conjugation with Ptx. In this way, HA-Ptx prodrugs with 22 wt % of Ptx were prepared easily in which the drug was bonded to the polysaccharide structure via succinate ester groups. Because of the conjugation by ester bonds, the release of Ptx was slow so that only around 12 and 20% of Ptx were released after 4 days at pH ∼ 6.0 and 7.4. The release of Ptx increased significantly in the presence of hyaluronidase, which induces the degaradation of the HA backbone so that after 4 days at pH ∼ 6 around 42% of Ptx was released. In another report, HA was conjugated to Ptx by the modification of its carboxylate groups (see Figure 101).94 To obtain a water-soluble product, the content of Ptx was adjusted to be low (3 mol % Ptx). Then polyelectrolyte multilayers were constructed from chitosan (CH) and HA-Ptx using the layer-by-layer technique. Cells cultured in polyelectrolyte multilayers from CH/HA-Ptx showed 95% decreasing in viability, whereas cells cultured in CH/HA polyelectrolyte multilayers remained healthy after 4 days. Highly water-soluble poly(L-γ-glutamyl-L-carbocysteine)-paclitaxel (PGSC-Ptx) (solubility ∼60 mg·ml−1) was prepared from the parent polymer with pendant carboxylic acid groups through the conjugation with Ptx using carbodiimide chemistry (Figure 102).106,107 In this conjugation, prodrugs with 36 wt % of Ptx were prepared. Because of the hydrophobic structure of Ptx, the prodrug self-assembled into 15−20 nm nanoparticles in aqueous media. The slow release of Ptx was due to its conjugation via stable ester bonds. After 100 h, only around 15 and 22% of Ptx were released, respectively, at pH ∼ 7.3 and 5.0. In a similar strategy, poly(ethylene oxide)-block-poly(εcaprolactone) copolymers with pendant carboxylic acid groups were conjugated to Ptx to obtain amphiphilic prodrugs with 20 wt % Ptx (Figure 103).109 Stable nanoparticles with sizes around 120 nm were formed with sizes unchanged after 1 week. Only around 5.0 and 6.7% of Ptx was released after 3 days at pH ∼ 7.4 and 5.0, respectively. The main reason for the very slow release was the fact that the conjugated ester linkage was buried in the hydrophobic core of the nanoparticles, which makes it less accessible to water for hydrolysis. In the same way, ring opening copolymerization of L-lactide (LLA) with (3s)benzoxylcarbonylethyl-morpholine-2,5-dione (BEMD) using a PEG macroinitiator (Mn = 4000 g·mol−1) followed by a hydrogenation yielded an amphiphilic copolymer with pendant carboxylic acid groups (Figure 103). The conjugation of Ptx to these carboxylic acid groups using carbodiimide chemistry produced prodrugs containing 16.5 wt % Ptx.98 Because the ester bond is less cleavable than other bonds discussed before, the release of Ptx from micelles of the prodrug was relatively slow: 9% at pH 7.4 and 29% at pH 4.2 after 51 h. Poly(ethylene oxide)-block-polyphosphoester (PEO-b-PPE) with pendant alkyne groups was prepared and conjugated by click chemistry to an azido-ester functionalized Ptx (Figure 104).87 High amounts of Ptx, up to 65 wt %, were loaded in the prodrug. Its solubility in water could reach 6.2 mg/mL in water, whereas free Ptx has only a very poor solubility in water. The polyphosphoester was degraded upon hydrolysis at acidic or basic pH values to release the Ptx but was quite stable at neutral pH. The degradation and release of Ptx was however very slow: after 4 days only ∼5% Ptx was released at pH ∼ 6.0.

carbamate groups have been used for the conjugation of drugs to polymer backbones. Poly(styrene-alt-maleic anhydride) was used as a reactive polymer for the conjugation with secondary amine, hydroxyl, or thiol groups of six different drugs: captopril, metformin, metroniazole, nortriptyline, fluoxetine, and betahistin (Figure 98).295 Amide, ester, or thioester linkages were formed. Between 22 and 78% of anhydride groups were conjugated with these drugs. Because these drugs are used orally, the drug release was studied at pH ∼ 1.3, similar to the gastric environment, at 37 °C. Approximately all the drugs were released by hydrolysis of the conjugated bonds in 300 h. Azido-terminated epoxy-functionalized copolymers were prepared by ATRP copolymerization of glycidyl methacrylate (GMA) with oligo(ethylene glycol) methyl ether methacrylate (Mn ∼ 500 g·mol−1). Then the epoxy groups were reacted with the secondary amino group of ciprofloxacin (Cipro) to produce polymer−drug conjugates (Figure 99). The terminal azido group were conjugated with alkyne groups of dibenzocyclooctyne-Cy5 (DBCO-Cy5) dye by Cu-free click chemistry as labeling group.131 The conjugation bond between the drug and the polymer in this work was not cleavable, and release of the drug or other biological activity of the polymer conjugate was not studied. In fact, the aim of this research was to introduce trifluoroethanol (TFE) as a novel and effective solvent for ring opening of epoxy groups using of amines. There are many reports related to the conjugation of Ptx via ester bonds as a less cleavable linkage to the side chains of various polymers.87,88,92−105,296 Chitosan was conjugated with succinate ester modified-Ptx using carbodiimide coupling chemistry to produce prodrugs with 12 wt % Ptx and solubility around 1 mg·mL−1, which is higher than pure Ptx (Figure 100).99 Because this prodrug was used for oral delivery of Ptx, cleavability of linkage between Ptx and chitosan was studied in PBS (pH 7.4), simulated gastric fluid (SGF, pH 1.2), simulated intestinal fluid (SIF, pH 7.5), rat plasma, and cell culture medium (fetal bovine serum (FBS) 10%). The amount of releaed Ptx in PBS and SGF after 4 h was only around 2 and 9%, respectively. In the same time interval, around 17, 25, and 51% of Ptx was released in SIF, rat plasma, and cell culture medium, respectively. This release behavior showed that the prodrug could pass through the gastric environment without leakage, a key property in oral delivery of drugs. Amphiphilic trimethylchitosan−paclitaxel (TMC-Ptx) conjugate was prepared with a succinate ester linker, and at the same time some of the TMC amino groups were conjugated to folic acid (FA) (Figure 100) to target the prodrugs for cancer cells.105 All conjugation reactions were performed via carbodiimide chemistry to produce a prodrug with 11 wt % of Ptx. NPs with sizes around 100−200 nm were prepared from TMC-Ptx prodrugs. Three factors increased the accumulation of TMCPtx nanoparticles in tumor cells. These factors were (1) the small size of nanoparticles that was proven to enhance the EPR effect,297 (2) positive charges of TMC created strong interaction with negative charges of the cell membrane, and (3) finally the presence of the folic acid moieties in the nanoparticles. All these features led to a selective biodistribution of prodrug NPs, mainly in tumor cells. The accumulation of FA-TMC-Ptx in tumor cells was around 5.0 and 11 times higher than free Ptx for oral and intravenounsly administration, respectively. The release of Ptx was pH-dependent. Around 20 and 41% of Ptx was released after 2 days at pH 5.0 and 7.4. HA was conjugated with Ptx to produce a water-soluble prodrug as depicted in Figure 101.104 High water solubility of AX


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Ptx was conjugated to poly(L-glutamic acid) (PGA)88,89 and its derivative (poly(L-γ-glutamyl-glutamine, PGG)89 through ester bonds to prepare water-soluble prodrugs of Ptx (Figure 105). The content of Ptx in these prodrugs was 21%88 or 32%89 in PGA-Ptx and ∼36% in PGG-Ptx. Although PGG-Ptx displayed a higher water solubility and was able to selfassemble into micelles with sizes around 15 nm, its toxicity for human lung cancer H460 cell line was lower than PGA-Ptx. The effect of molecular weight of PGG-Ptx prodrugs on their performance was investigated by Yang et al.90 They prepared prodrugs with four different molecular weights between 12300 and 81000 g·mol−1 containing 35 wt % Ptx. Their self-assembly in aqueous medium formed nanoparticles with sizes in the range of 13−22 nm. Interestingly, they found that with increasing the molecular weight of the prodrugs, the rate of Ptx release was decreased. This effect was attributed due to the tighter hydrophobic cores in nanoparticles resulting from higher molecular weight prodrugs, which make them less accessible for their hydrolysis by enzymes or water. Poly(ethylene glycol)-block-poly(ε-caprolactone)-block-poly(L-lysine) (mPEG-b-PCL-b-PLL) with pendant catechol groups were prepared and then conjugated with the anticancer drug bortezomib (BTZ) via an acid-cleavable boronate ester (Figure 106).132 UV−vis spectroscopy revealed that ∼13 wt % BTZ was loaded in the prodrug. Micelles of 95 nm with PCL-b-PLLBTZ segment as core and mPEG as shell could be formed. The results showed that at 37 °C after 1 day around 23, and 68% of BTZ was released at pH ∼ 7.4, and 5.5, respectively. In vivo results also showed that the prodrugs were effective for MCF-7 breast cancer cells. A series of poly(ethylene oxide)-block-poly(glycerol monomethacrylate) (PEO-b-PG2MA) drug conjugates (Mn ∼ 11400−18600 g·mol−1, PDI ∼ 1.10−1.16) were synthesized by ATRP of glycerol monomethacrylate with a mPEG macroinitiator followed by conjugation with indomethacin (IND) via ester bonds (Figure 107).122 The drug contents in these polymer conjugates were in the range of 15−49 wt %. Whereas PEO-b-PG2MA copolymers were completely hydrophilic, their conjugation with the hydrophobic drug IND yielded amphiphilic prodrugs that formed nanoparticles with sizes in the size range of 24−100 nm in aqueous medium. These amphiphilic nanoparticles further entrapped physically around 13−20 wt % of IND, which led to an increase the overall amount of IND (conjugated and entrapped) in the prodrugs to reach about 58 wt %. The release behavior of free and conjugated IND from these prodrugs was studied at pH ∼ 2.1 and 7.4. Because free IND possesses a carboxylic acid group in its structure, its solubility in water is dependent on pH. The release of free IND was therefore faster at pH ∼ 7.4. On the contrary, the ester bond between the conjugated IND and the polymer backbone was stable at neutral pH whereas the bond was hydrolyzed at acidic pH, yielding a faster release. Ptx was bridged between mPEG (Mn ∼ 2000 g·mol−1) and an azido-acetal linker through its secondary −OH groups and then grafted to a polylactide derivative containing pendant alkyne groups via click chemistry (Figure 108).91 The prepared prodrug contained around 23 wt % of Ptx and were processed into nanoparticles with sizes in the range of 8−40 nm. The release of Ptx occurred owing to multiple hydrolysis reactions of cycloacetal and ester bonds in the prodrug structure. Cisplatin as an efficient anticancer drug has been used for preparing many polymer−drug conjugates. A degradable terpolymer poly(ethylene glycol)-block-poly(ε-caprolactone)-

block-polylysine (mPEG-b-PCL-b-PLL) with pendant NH2 groups was used for the conjugation with succinate derivatives of oxidized cisplatin through carbodiimide coupling chemistry (see Figure 109).298 Prodrugs containing 13.6 wt % of platinum were synthesized, which corresponds to a conjugation of 92% of the amino groups in the polymer. Nanoprecipitation of mPEG-b-PCL-b-PLL/Pt prodrug created homogeneous spherical 200−220 nm micelles. The conjugated cisplatin drug acted as a cancer drug when it was reduced to the active cisplatin in the presence of a reducing agent. The release of active or inactive forms of cisplatin occurred as a result of reduction or hydrolysis. Hydrolysis resulted in the cleavage of several ester bonds in the prodrug structure, including the ester linkages of the polymer backbone or the conjugate ester linkage. The hydrolysis is faster at pH ∼ 5.0, so that around 35 and 55% of inactive cisplatin species were released after 2 days at pH ∼ 7.4 and 5.0. The active cisplatin was produced only after reduction with ascorbate. Around 80% of active cisplatin was released only after 10 h. Amphiphilic polyphosphazene−platinum conjugates (Mn ∼ 24000−115000 g·mol−1) containing small mPEG (Mn = 350 g· mol−1) moieties were prepared according to the procedure depicted in Figure 110.299,300 The small size of prodrug nanoparticles (15−30 nm) enhanced the EPR effect of the prodrugs so that accumulation of this prodrugs in tumor cells was more than 4 times higher than accumulation in normal cells. 4.3. Self-Immolative Polymers

In 2008, Shabat research group synthesized self-immolative polyurethane with 4-nitroaniline as a reporter group in the side chain on each repeating unit (Figure 111). 4-Hydroxy-2butanone and 4-methyl benzylalcohol were used, respectively, as base-labile and nonlabile triggers at the head of the polymer structure.301 The cleavage of the trigger yielded an initiation of polymer disassembly through azaquinone−methide rearrangement which subsequently resulted in the release of reporter groups. To simulate the degradation and release behavior of the polymer, first a low molecular weight conjugate with selfimmolative bonds was prepared and its degradation was studied (see Figure 112). After a triggered cleavage induced by piperidine, the release of the reporter group in the paraposition, i.e., 1-naphthylamine, was completed in less than 1 h while the reporter group in the vinylogous ortho-benzyl position (4-nitroaniline) needed more than 20 h to be completed. The release of the reporter groups from the synthesized self-immolative polyurethane with a 4-hydroxy-2butanone capping agent in the presence of piperidine in acetic acid required around 2 days to reach around 90% of release. On the contrary, no release of 4-nitroaniline was detected from the polyurethane with 4-methylbenzylalcohol as a capping agent because it could not be cleaved by piperidine. A similar polymer with higher water solubility was prepared according to Figure 111 to evaluate the potential of this polymer conjugate as a drug delivery system. N-(4-(Hydroxymethyl) phenyl) phenyl acetamide was used as capping agent due to its cleavability by PGA enzyme. The incubation of this polymer in PBS (pH ∼ 7.4) revealed that a complete release of 4-nitroaniline was achieved in only 6 h in the presence of PGA. Without PGA, only ∼ 20% of 4-nitroaniline was released due to the hydrolysis of carbamate bonds. The structure of panobinostat (PANO), an anticancer drug that acts as a histone deacetylase inhibitor, does not allow for AY


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Figure 127. Synthesis of PEGylated lysine−aspartic acid dendrimer−Cpt prodrug.73

Figure 128. Preparative route for amphiphilic prodrugs of CA4.134

5. DENDRITIC PRODRUGS

direct conjugation to polymer backbones via labile bonds. Therefore, Zuwala et al. used a disulfide containing selfimmolative linker (SIL) for the synthesis of polymer conjugates of PANO.140 PANO was conjugated to PHPMA via a selfimmolative spacer containing a disulfide redox-responsive linkage according to the process depicted in Figure 113. First, a methacrylate monomer with a 4-nitrophenyl activated carbonate group was prepared and used for copolymerization with HPMA by RAFT polymerization. Because of some release of 4-nitrophenol during the polymerization and its inhibiting effect on the polymerization, low conversions (18−46%) for polymerization reactions were obtained. In a next step, the active carbonate ester groups were reacted with PANO to obtain a water-soluble prodrug. Prodrugs with a molecular weight in the range of 6000−13000 g·mol−1 (with PDI < 1.3) and PANO contents of 6−11 mol % were obtained. The authors proved in previous reports that the SIL containing disulfde could be easily degraded in the presence of DTT or glutathione.302,303 Therefore, the release of PANO was studied in the presence/absence of DTT (5 mM) at pH ∼ 7.4. In the absence of DTT, negligible amount of PANO was released whereas a fast release of PANO was observed upon addition of DTT.

5.1. Dendrimers with Labile Bonds

Dendrimers are a category of molecules with macromolecular architectures that are highly branched.304 Dendrimers have very

Figure 129. Synthesis of dendron−glutaric acid−MP prodrugs.68

well-defined and monodisperse structures with very narrow polydispersities (Mw/Mn ∼ 1.00−1.05).305 The three-dimensional shape of the dendrimers is mainly dominated by the core, while the interior controls their host−guest properties. The interior is composed of several layers called generations. Most of the functional groups are located at the peripheral layer or shell. Polyamidoamine (PAMAM) (Figure 114) and poly(propyleneimine) (PEI) are two types of well-known dendrimers. G2 of PAMAM was targeted for cancer cells with αfetoprotein (rAFP3D) and was conjugated to Dox via a cisaconityl linkage (Figure 115).53 The release behavior at 37 °C AZ


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with PAMAM followed by PEGylation. Only about 3.3 equiv of NH2 groups in PAMAM were present after conjugation. The prodrug then became water-insoluble and more conjugation was not achievable. To increase the amount of loaded Dox, PAMAM was first partially PEGylated using PEG with a molecular weight of 1000 g·mol−1. The presence of PEG chains increased the hydrophilicity of the dendrimer, and therefore more Dox could be conjugated in aqueous medium. Then 8.8 equiv of NH2 groups could be reacted with Dox. In the twostep PEGylation method, a second PEGylation was needed to obtain the desired PEG density (21 equiv of PEG per each PAMAM macromolecule) in the prodrug. The hydrodynamic diameter of PAMAM dendrimer was increased by PEGylation or conjugation with Dox, and the size of the prepared prodrugs was in the range of 4−11 nm. After about 190 h, less than 4% of the conjugated Dox was released from prodrugs with succinic linkage at neutral or acidic medium. In the case of cis-aconityl linkage, around 9% of Dox was released at pH ∼ 7.4 and around 80−85% Dox was released at pH ∼ 4.5. The water solubility of the acid-labile prodrugs as well as the rate and total amount of released Dox from prodrug containing cis-aconityl groups were adjusted by PEGylation density. In a similar work, PAMAM (G4) was prepared with three different PEGylated degrees and conjugated with various amounts of Dox through cis-aconityl as an acid-labile or succinic acid as acid-nonlabile linkage to prodrugs named as PPCD and PPSD, respectively (Figure 117).55 The PEGPAMAM conjugates displayed a lower zeta potential and particle size than the nonmodified dendrimers. The charge of the PPCD prodrugs was lower than the charge of PPSD due to the presence of a carboxylic acid group. The PPCD and PPSD prodrugs were self-assembled into particles with sizes in the range of 15−83 nm in aqueous medium. PPSD released negligible amounts of drug at different pH values, and therefore their toxicity was low. Conversely, the PPCD prodrugs were toxic for murine B16 melanoma cells. The release of Dox from PPCD was pH dependent so that after 96 h at pH ∼ 7.4 or 6.5 only about 5% of Dox was released from all PPCD prodrugs. At more acidic pH, higher amount of Dox was released from PPCD prodrugs. A series of multifunctional targeted Dox-prodrugs based on PEG5000-PAMAM(G4) with different contents of folic acid (FA) were prepared by Cheng et al. according to Figure 118.37 The number of FA was adjusted to be 3.3, 5.8, or 10.1 per PAMAM, while the number of Dox molecules remained constant at 10.1 molecule per PAMAM. The targeted prodrugs produced nanoparticles with sizes in the range of 23−30 nm in

Figure 130. Synthesis of tumor-targeting PEGylated-H40-Dox prodrugs. Picture of the dendrimer reprinted with permission from ref 43. Coypright 2010 American Chemical Society.

showed that only 8% Dox was released at pH ∼ 7.4 after 24 h. Around 75 and 90% Dox was released at pH ∼ 6.0 and 5.5, respectively, at the same time. Moreover, the presence of recombinant receptor-binding fragment of the α-fetoprotein (rAFP3D) targeting agent yielded an effective and selective accumulation of released Dox in SKOV3 tumor cells. Furthermore, the uptake of the prodrug by normal cells was around 50-fold lower than for tumor cells. In another work, G3 of PAMAM was PEGylated and conjugated with Dox through cis-aconityl (as an acid-labile) or succinic acid (as acid-nonlabile) linkages (Figure 116).54 Two strategies were used to prepare prodrugs with different amounts of Dox. In the direct PEGylation strategy, Dox was conjugated

Figure 131. Synthesis of Y-shaped and dumbbell-shaped poly(ethylene glycol)-poly(lactic acid-co-glycolic acid).56 BA


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Figure 132. Synthesis of first and second generation of self-immolative benzyl ether dendrimers.311

mPEG2000 and Dox through glutamic acid as linkers (see Figure 121).39 The Dox conjugation was performed via acid-labile (hydrazone) or acid-nonlabile (amide) bonds. Between 18 and 20 molecules of Dox were conjugated to each dendrimer molecules. The release behavior of Dox from the prodrug with an amide linkage was not sensitive to pH and less than 5% Dox was released at pH ∼ 7.4 or 5.5. Conversely, the prodrug with hydrazone linkage released less than 10% and around 80% Dox at pH ∼ 7.4 and 5.5, respectively. Both dendrimer prodrugs displayed less cytotoxicity for HeLa cells in comparison with free Dox. The dendrimer with hydrazone linkage had an IC50 around 2.5 μM, which was about 7 times more toxic than the dendrimer with the amide linkage. Similarly to an aforementioned procedure in which PAMAM was PEGylated [39], PAMAM was linked to acetylated collagen for metastasis-associated drug delivery (Figure 122). First, primary amino groups of PAMAM-G4 were reacted with tbutyloxycarbonyl-L-glutamic acid γ-benzyl ester and then the Boc groups were deprotected. Afterward, the deprotected amino groups of glutamic acid residues were reacted with carboxylic acid groups of acetylated collagens and remaining unreacted amino groups were blocked by acetylation with acetic anhydride. Finally, the benzyl esters were converted to hydrazide groups by a reaction with hydrazine. The conjugation of Dox with the hydrazide groups of the dendrimer via hydrazone bonds resulted in dendritic prodrugs with 27 molecules of Dox conjugated to each dendrimer. The in vitro cytotoxicity of pure Dox and the Dox-prodrug against MCF-7 (poorly invasive breast cancer cells) and MDA-MB-231 (highly invasive breast cancer cells) was investigated. The IC50 of free Dox were around 2.5 and 33.1 μM for MDA-MB-231 and MCF-7, respectively. The IC50 values for dendrimer Doxprodrug were very close to each other, i.e. ∼4−5 μM.40 Hyperbranched polymers with hydroxyl groups such as polyglycerol and polyol were conjugated with ibuprofen (Ibu) via an ester linkage (Figure 123).125 The prodrugs contained a high payload of Ibu (∼42% in the polyol) and polyglycerol (∼70% in the polyglycerol) that was conjugated via dicyclohexylcarbodiimide (DCC) chemistry. Because of the high drug loading, the prodrugs were hydrophobic and insoluble in water. For this reason, the release behavior was investigated in methanol. Only about 4% Ibu was released after 27 h at room temperature, which confirmed the stability of the

aqueous media. Because of the presence of hydrazone bonds, the release of Dox was pH-dependent. Indeed, around 8, 28, and 42% Dox is released at pH ∼ 7.4, 5.5, and 4.5 after 48 h, respectively. The targeted prodrugs showed lower IC50 values than nontargeted ones and had significantly higher cytotoxicity for KB cells. Dendrimer structures based on mPEG-PAMAM were prepared and conjugated to Dox trough acid-labile hydrazone bonds (Figure 119).38 Amphiphilic prodrugs containing ∼53 and 31 wt % Dox were prepared, and their self-assembly by the solvent replacement method produced micelles with sizes around 49 and 59 nm, respectively. These prodrugs were used for the encapsulation of the hydrophobic anticancer drug 10hydroxycamptothecin (HCPT) at pH ∼ 6.5 in deionized water. Around 19 and 22 wt % HCPT were loaded in mPEG2000PAMAM-Dox and mPEG5000-PAMAM-Dox prodrugs, respectively. A slight amount (10 μM for free Cpt, AB3PHPMA, and the PHPMA conjugate containing the carbonate bond after 24 h, respectively. However, these values reached 200, 300, and 350 nM after 48 h, respectively. In another attempt for the preparation of SIDs with higher water solubility, G1 and G2 dendrons containing 5-amino-2BJ


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of hSIP2 and hSIP3 for 30 min at 460 nm (same condition as hSIP1) yielded a slower depolymerization of the polymer backbone: between 89 and 95% of polymer degradation occurred after 6 h. The slower degradation of hSIP2 and hSIP3 compared to hSIP1 was due to an 1,6-elimination faster than 1,4-elimination (see section 2). The Dox release from polymers with a disulfide capping agent was sensitive to the presence of reducing agent. In the presence of GSH, a complete release of Dox occurred in ∼15 h, whereas almost no release was detected in the absence of GSH. Three enzymatically degradable dendrimeric prodrugs of naproxen (Nap), based on a polyester, a polylysine polypeptide, and a polyamide-ester, were prepared by a convergent method (see Figure 144). The hydrolytic stability of these prodrugs at 37 °C in 0.02 M phosphate buffer at pH ∼ 2, 7, and 8 were investigated for 10 days. At pH ∼ 7, no release was detected from all prodrugs. At pH ∼ 2 and 8, these prodrugs were relatively stable: More than 70% of the conjugated bonds reamined. The release of Nap from these prodrugs at pH ∼ 7 in the presence of two enzymes including cathepsin B or 50% human plasma at 37 °C revealed that the Nap release is faster in the presence of human plasma than with cathepsin B. 80% release from the polyamide-ester prodrug was achieved in the presence of human plasma after 5 days. Only around 16% of drug was released during the same period in the presence of cathepsin B. The releases from the polyester and polyamide prodrugs were slower than for polyamide-ester.

small molecules upon degradation are not active molecules that are needed for the application. As discussed in this review, a variety of drugs were conjugated to various polymers through different conjugation linkages and spacers. Several structural factors affect the release behavior of conjugated drug from the polymer−drug conjugates. One of the key factors is the hydrolytic stability of the conjugated linkage.323 Generally, the hydrolysis of acidlabile linkages, including acetal, imine, hydrazone, and to some extent β-thiopropionate, are relatively fast and conjugated drug can be complelety released in the range of several hours to a few days. The release time depends on environmental conditions such as pH value, temperature, and the presence of enzymes and on the prodrug structural factors. The cleavage of ester linkages are usually slow, which is beneficial for continuous and prolonged release (up to several weeks). Another key structural factor is the water solubility of polymer−drug conjugate. Generally, the release rate from prodrugs with higher water solubility is faster due to more accessibility of conjugated linkages. In prodrugs with large hydrophobic segments, the hydrophobic drugs are usually located in the hydrophobic core of micelles and nanoparticles, which limits the access to the water, hence lowering significantly the hydrolysis rate.

AUTHOR INFORMATION Corresponding Author

6. CONCLUSIONS AND OUTLOOK Polymer chemistry is a very dynamic field and has strongly evolved along its history. One hundred years ago, the main concern for producing polymers was their mechanical and thermal resistance such as for the phenol-formaldehyde resins developed by Baekaland. 317 Nowadays, many synthetic approaches have been unraveled to fabricate polymeric materials that can respond to specific stimuli to produce an action or a signal. Incorporating labile bonds inside a polymer backbone and side chains have proved to yield interesting polymeric materials that are responsive to change of environmental pH value or redox conditions. This field has been largely explored for biomedical applications but deserves to be further applied in agriculture for the controlled release of phytosanitary products or for anticorrosion318 and self-healing materials.319 In the latter fields, the payloads, either corrosion inhibitors or selfhealing agents, are usually physically entrapped and released on demand. However, the release is normally relatively fast once the capsules that entrap the active payloads are triggered. We envision an interesting convergence of materials based on smart nanocontainers that can encapsulate and release active payloads 320,321 and macromolecular design of polymer materials containing labile bonds or based on self-immolative architecture. The interplay between the hierarchical structure of the nanocontainers and the chemistry for cleaving the bond between the supporting macromolecule and the payload to be delivered shall yield a sustained release profile that can be accurately programmed. This feature could be further coupled with payloads that display change of properties once they are activated by a trigger322 so that the payload would experience first a release from the conjugate followed by a change of its properties that shall therefore impart its release profile. Finally, self-immolative polymers are also an intriguing new class of materials. However, new synthetic pathways are needed to overcome the major issue, which is that much of the produced

*E-mail: [email protected]. ORCID

Daniel Crespy: 0000-0002-6023-703X Notes

The authors declare no competing financial interest. Biographies Farzad Seidi received his Ph.D. from the Polymer Chemistry Laboratory at the Sharif University of Technology in August 2011. During his Ph.D. study, he joined Professor Wolfgang Meier’s group at Basel University (Switzerland) in 2010 for a sabbatical for nine months and worked under the supervision of Dr. Nico Bruns. His expertise is in the design and synthesis of new polymer conjugates. In 2016, he joined the group of Professor Crespy at the Vidyasirimedhi Institute of Science and Technology (VISTEC) in Thailand. Ratchapol Jenjob received his Ph.D. in Polymer Science and Technology from Mahidol University. After Ph.D. graduation in 2012, he moved to South Korea to work at Utah-Inha DDS & Advanced Therapeutics Research Center as a postdoctoral fellow. In 2014−2015, he joined Dr. Su-Geun Yang’s group at the Inha Hospital, South Korea. He has been working since June 2016 in the laboratory of Professor Crespy at the Vidyasirimedhi Institute of Science and Technology in Thailand. Daniel Crespy studied chemistry at the University of Strasbourg and completed his Ph.D. under the supervision of Professor Katharina Landfester from the University of Ulm. In 2006, he became a project leader at EMPA (Swiss Federal laboratories for Materials Research and Technology). He joined the department of Professor K. Landfester in July 2009 as a group leader. Daniel Crespy is now an Associate Professor in the Vidyasirimedhi Institute of Science and Technology in Rayong, Thailand. He has published more than 100 peer-reviewed papers in the field of polymer and colloid chemistry. BK


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