Translatable High Drug Loading Drug Delivery Systems Based on

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Translatable High Drug-Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers WeiZhi Chen, Sensen Zhou, Lei Ge, Wei Wu, and Xiqun Jiang Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b00218 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 24, 2018

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Biomacromolecules

Translatable High Drug-Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers Weizhi Chen, Sensen Zhou, Lei Ge, Wei Wu, Xiqun Jiang* MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P. R. China.

* To whom correspondence should be addressed Email: [email protected]

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ABSTRACT ：

Most nanocarriers possess low drug-loading, resulting frequently repeated administration and thereby high cost and increased side effects. Furthermore, the characteristics of nanocarrier materials, especially the drug loading capacity plays a vital role on the drug delivery efficacy. In this review, we focus on the readily translatable polymeric drug delivery systems with high drugloading, which are comprised of biocompatible polymers such as poly(ethylene glycol), poly(Nvinylpyrrolidone), polyoxazoline, natural proteins like albumin and casein, non-natural proteins such as recombinant elastin-like polypeptides, as well as nucleic acids. In the end of this review, the applications of these polymeric nanocarriers on the delivery of proteins and gene drugs were also briefly discussed.


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1. Introduction Chemotherapy plays a vital role on cancer treatment. However, most chemotherapeutic drugs are hydrophobic and not suitable for in vivo usage. The small molecule weight of most chemotherapeutic drugs is also an obstacle for prolonging blood circulation. To achieve a better therapy efficacy, multiple injection with relatively high dose is needed. On the other hand, chemotherapy drugs have no selectivity and can kill normal cells as well, which means that the side effect is systematic. In turn, the side effects severely limit the injection dose of drugs. Therefore, numerous works have been done for improving the anti-cancer efficiency and reducing the side effect of chemotherapeutic drugs. With the development of medical technology and the improving understanding of tumor pathology, drugs based on proteins, peptides as well as nucleic acids have been developed. However, rapid enzymatic degradation, low stability and undesirable pharmacokinetics hinder the application of these biological medicine in clinic. Nanomaterials are very helpful in cancer treatment for improving the drug accumulation within tumors and decreasing the systemic toxicity of most drugs.1-4 Most solid tumors have special pathophysiology characteristic such as rich blood vessels, increased permeability of the blood vessels and ineffective lymphatic drainage. Nano-sized drug carriers can extravasate via leaky blood vessels and accumulate at tumor site which is known as “enhanced permeability and retention (EPR) effect”.5 EPR effect is also called passive targeting. On the other hand, various targeting agents which are based on the characteristic of tumor micro-environment have been investigated and widely applied for selectively targeting tumors.6 For both passive targeting and active targeting approaches, the carrier materials play a crucial role for improving drug delivery efficacy. To get a satisfactory drug delivery efficacy, the materials should be deliberately designed. Materials used for drug delivery, in our opinion, should 1) be biocompatible and non-


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toxic; 2) allow to load or conjugate diverse drugs with high drug-loading; 3) show a favourable release behavior; 4) have a good pharmacokinetics and an extended circulating half-life; 5) allow to modification and functionalization; 6) be easy to obtain or synthesize in a few steps with high yield. Biocompatibility is the primary requirement for materials used for drug delivery. Secondly, high drug content is necessary. High drug content means low frequency of drug administration which ultimately reduces clinical costs and side effect, and improves the life quality of the patient. In this review, we will discuss about the merits and demerits of most frequently used biocompatible drug nanocarriers with high drug loading that are either natural or synthetic. In the first part of this review, we will discuss the synthetic material-based nanocarriers, for example, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone) (PVP), polyoxazoline (POx), as shown in Figure 1. Then natural biopolymer materials including proteins, peptides and nucleic acids will be introduced. We will also briefly discuss gene therapeutic drugs delivery in the end of this review.


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Figure 1. The biocompatible materials applied for drug delivery systems which we will discuss in this review. 2. Synthetic Polymer-Based Nano Drug Delivery Systems 2.1. PEGylated Nanomedicines Targeted delivery of drug to tumor sites needs a prolonged blood circulation time, slow clearance from body and low nonspecific interaction with proteins in blood. However, not all the hydrophilic polymers can provide the long circulation time. Poly(ethylene glycol) (PEG) is a FDA-approved synthetic polymer which has been widely applied for drug delivery systems due to its great biocompatibility and stealth property. PEGylation can enhance the water solubility of hydrophobic drugs and prolong the body-residence time of drugs, providing a lower kidney/liver clearance rate when compared to the unmodified drugs. Furthermore, PEGylated carriers are also characterized by reduced interaction with serum proteins. The longer blood circulation time gives drugs more opportunities to reach tumor sites before being expelled from body. On the other hand, the end groups of PEG can be easily modified for functionalization since it is also soluble well in organic solvents. Moreover, PEG with various molecular weight and low polydispersity index (PDI) are easily obtained through the anionic polymerization of ethylene oxide.


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Figure 2. The application of biocompatible polymers in drug delivery systems. a) Drugs are directly conjugated to the ends of polymers and then the conjugates self-assemble into nanoparticles; b) Amphipathic polymers self-assemble into micelles and hydrophobic drugs are laoded into the cores; c) Biocompatible polymers are used for coating the surface of nanoparticles to improve biocompatibility.


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As shown in Figure 2, PEG can be directly conjugated with drugs to develop a prodrug.7-9 Hu et al. synthesized polyprodrug amphiphiles with PEG and a reduction-cleavable CPT prodrug monomer.10 These polyprodrug amphiphiles provides >50 wt% CPT loading content with four different self-assembly nanostructures, spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Shen et al. used short PEG with only eight repeating units as hydrophilic block to conjugate with camptothecin (CPT). This amphiphile could self-assemble to a prodrug vesicle with high drug content as high as 58 wt %.11 As shown in Figure 3, the vesicle is not only a CPT prodrug but also can be used as drug carrier to load other drugs such as doxorubicin (DOX) for synergy therapy. When free drug was loaded into the cavity of prodrug-based vesicles, the drug loading could be further enhanced. Huang et al. prepared an PEG-acetal-paclitaxel (PTX) prodrug which access to load free PTX when self-assembly into nanoparticles in water.12 This approach highly improved the drug loading to 60.3 wt%. Gu et al. designed a new graft copolymer which can form a polymeric nanocarrier in a protein folding-like manner with great loading capacity for two drugs (25.1 wt% for CPT and 30 wt% for DOX).13 Wu et al. developed fourth-generation dendrimers with different length PEG as end groups.14 On this bases, gemcitabine (GEM) was conjugated to the fourth-generation dendrimers and obtained drug-conjugated dendrimers with 23-25 drug molecules attaching to one molecule of the dendrimers. In vivo examination in 4T1 tumorbearing mice found that the GEM-conjugated dendrimers with longest PEG end group showed the best tumor accumulation and penetration ability. Liu et al. prepared PEGlated unimolecular micelles served as a novel theranostic platform which showed favourable CPT loading ability (high than 17.3 wt%).15 Alternately, PEG can be introduced as side chains for improving the hydrophilicity of the polymer backbones. For example, Yu et al. used PEG oligomer as the side


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chain of polyrotaxanes (PR) and then linked PTX with a high drug loading content about 29 wt%.16 The PR-PTX conjugate exhibited a unique in vivo fate, significant antitumor response and deep intratumoral penetration. In addition, PEG can be used as hydrophilic block to build nanocarriers with various hydrophobic blocks.17-20 During the self-assembly of amphiphilic copolymers, the premixed hydrophobic drugs can be loaded into the micellar cores. However, most drugs are highly hydrophobic and can self-aggregate when exposed to aqueous solutions, leading to a very low drug loading usually lower than 5 wt%. To overcome drug aggregation, Cheng group prepared a dimeric prodrug of CPT (CPT-SS-CPT) through two carbonate linkage on the 2,6bis(hydroxymethyl)-aniline whose amine group was protected by a disulfide bond.21 Then, they used methoxy poly(ethylene glycol)-block-polylactide (mPEG-PLA) to co-precipitate CPT-SSCPT, as shown in Figure 4, and found that the drug loading of CPT-SS-CPT dimeric drug can be up to 50 wt%. The high drug-loading micelles showed great stability and could steady release drug when the disulfide bond was cleaved. They also extended this strategy to DOX loading and achieved similar high drug payload, suggesting that the dimerizing of drugs is a powerful method to acquire a high drug loading. Instead of coprecipitation, dimeric drug can be conjugated with PEG to form a liposomes-like structure.22 The amphiphilic molecule could self-assembly into vesicles with drug loading as high as 60 wt%. Xu et al. reported an DOX prodrug based on PEG monomethylether-b-poly-(methacrylamide tert-butyl carbazate) (MPEG-MABH).23 DOX was conjugated into MPEG-MABH through a pH-liable hydrazone bond with a high drug loading content about 40 wt%. Further, PEG can be coated onto the surface of nanocarriers, especially inorganic nanocarriers, to lower their interactions with serum proteins and achieve better EPR effect.24-26


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Figure 3. The schematic diagram of the amphiphilic camptothecin (CPT) prodrugs (OEG-CPT and OEG-DiCPT) and their self-Assembly into nanocapsules for loading other drugs. Reprinted with permission from ref 11, Copyright 2010 American Chemical Society. Although PEG has shown great advantages in prolonging the circulation time in vivo and making nanoparticles more “stealthy”, some defects of PEG have also gradually been found. For example, the non-biodegradability of PEG with high molecule weight reminds the use of relative low mass PEGs.27 On the other hand, paradoxically, PEGs with lower molecule weight are much easier to be oxidized.28 Most importantly, some studies demonstrated that PEG might trigger antibody-mediated clearance in animals and human.29,30 When PEGylated nanoparticles were first injected into body, the pharmacokinetics is great. Nevertheless, the great pharmacokinetics would disappear and the body eliminates the PEGylated nanoparticles more rapidly when PEGylated nanoparticles were injected into the body repeatedly. This is the so called accelerated blood clearance (ABC) phenomenon.31-33 Thus, researchers are making efforts to reduce the


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ABC phenomenon by evaluating the effect factors,34-36 and focus on the searching of alternatives to PEG.

Figure 4. Schematic Illustration of Encapsulating Hydrophobic Drugs into Nanoparticles. (a) Hydrophobic drugs are encapsulated in a polymeric micelle with undesired formation of large drug precipitates. (b) Illustration of drug dimer nano-aggregation followed by surface coating and particle stabilization by an amphiphilic polymer via hydrophobic interaction. Reprinted with permission from ref 21, Copyright 2015 American Chemical Society. 2.2. Poly(N-vinylpyrrolidone) (PVP)-Based Nanomedicines


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Poly(N-vinylpyrrolidone) (PVP) is one of the alternatives to PEG which has attracted more and more attention in drug delivery application due to its good biocompatibility.37-41 In World War II, it was used as a plasma expander, or a retarding agent for subcutaneous injection of hormone preparation such as vasopressin.42 PVP can be well synthesized through controlled radical polymerization of vinylpyrrolidone,43,44 and has low PDI below 1.2. The functionalization of end groups is readily accessible.45,46 PVP possess a high solubility in aqueous solution and can be used for improving the hydrophilicity and blood circulation time of drugs. The well-defined molecular structure provides PVP favorable biological properties. Similar to PEG, PVP also has stealth property. PVP-based shell is able to prolong the liposome circulation time in vivo.47 Kamada et al. found PVP modified tumor necrosis factor (TNF)-α had a longer plasma half-life than native TNF-α as well as PEGylate TNF-α.48 Moreover, a distinct advantage of PVP is that PVP has no ABC phenomenon. When repeatedly injected into bodies, the pharmacokinetics of PVP coated nanoparticles remained same as the first time and no anti-PVP IgM antibody was produced.49 Thus, PVP was considered as a promising substitute to PEG. PVP can be used as hydrophilic block to build various block copolymers with different hydrophobic blocks. These various amphiphilic block copolymers are able to self-assemble into nanoparticles in aqueous solution and load drugs when used for drug delivery.


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Figure 5. Schematic diagram of the preparation of PVP−PASP-CDDP nanoparticles. Reprinted with permission from ref 53, Copyright 2015 American Chemical Society. Zhu et al. prepared poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) (PVP-PCL) block copolymer which could self-assemble into micelles in water to load an anticancer drug paclitaxel (PTX).50,51 Different lengths of PVP with 3000, 6000 and 12000 Da molecule weight were used to build various PVP-PCL copolymers with the same length of PCL block. And they found that the biological performance of the resulting micelles is highly influenced by the length of hydrophilic PVP block. As the length of PVP block became longer, the stronger anti-protein adsorption and better tumor accumulation were observed. Regardless of the length of PVP block, the resulting PVP-PCL micelles all possessed high drug loading (15 wt%) and superior anticancer efficacy compare to Taxol® (the commercial PTX formulation). Xie et al. synthesized


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a pseudo-block copolymer PVP-PCL through supermolecular chemistry based on the host-guest recognition between β-cyclodextrin (β-CD) and adamantine (Ada).52 The association constant between β-CD and Ada is around 1х105 M-1 in water indicating that the binding competence is very strong. Cabazitaxel (CBZ) as model drug was loaded into the PVP-PCL micelles with a drug loading content about 14.4 wt%. Similarly, as shown in Figure 5, Yao et al. utilized the supermolecular chemistry to prepare pseudo copolymer poly(N-vinylpyrrolidone)-poly(aspartic acid) block copolymers (PVP-PASP) which could turn into nanoparticles when antitumor agent cisplatin (CDDP) was incorporated.53 The drug payload is as high as 50 wt%. This noncovalently linked PVP-PASP-CDDP superamolecular nanoparticles showed great potential in drug delivery field. Host-guest interaction and supermolecular chemistry provides a facile approach to synthesize a series of desired polymer structure under mild conditions.54-56 In addition, the supermolecular structure can be dissociated under certain conditions which can be designed for stimulus-responsive dissociation and controlled release of drugs.57,58 Leroux group prepared an poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-PDLLA) with 37% DLLA content which was less cytotoxic than Cremophor® EL (CrmEL).59 When treated with water, PVP-PDLLA could self-assemble into polymeric micelles which could efficiently solubilize water-insoluble drugs such as PTX and docetaxel (DCTX). When PTX was loaded, the polymeric micelles showed equipotent cytotoxicity to Taxol®. Moreover, comparing to 20 mg/kg of Taxol®, this PTX-loaded PVP-PDLLA possessed a higher maximum tolerated dose (MTD) even than 100 mg/kg, suggesting the great biocompatibility of PVP. Comparing to Taxotere, PVP-PDLLA nanomedicine showed comparable in vitro cytotoxicity and in vivo toxicity.60 Whereas, blank vehicle PVP-PDLLA was more tolerable than polysorbate 80 even at a 4-fold higher dose.


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2.3. Poly(2-oxazoline) (POx)-Based Nanomedicines Except PVP, poly(2-oxazoline)s (POx) are another class of potential substitute of PEG. POx, also called peptide-like polymers, have been considered as potential biomedical materials due to their good biocompatibility.61-64 POx with low PDI (20 wt%) could improve the pharmacological effectiveness similar to Abraxane®.98 As shown in Figure 7, modification with AS1411 aptamer provided the additional targeting ability and could further enhanced the cellular uptake of HSA nanoparticles.99 When HSA nanoparticles were used for loading DOX, it could significantly reduce the cardiotoxicity of DOX, suggesting that albumin-based nanocarriers is a promising strategy for drug delivery.100 Also, drugs could be conjugated to peptides through covalent linkage and then self-assemble into nanoparticles. For instance, Xu et al. used albumin to conjugate DOX and self-assemble the conjugates into nanoparticles with PEGs as the hydrophilic shell.101 In the nanoparticles, each albumin molecule was associated with an average of 50.6 doxorubicin molecules, including conjugation of DOX and the physically absorption of DOX into the nanoparticles core, suggesting the great drug loading capacity of this nanoformulation. Kuan et al. reported a dendronized HSA (DHSA) with a high density of poly(amido amine) (PAMAM) on the surface of HSA.102 The dendronized HSA showed greater DOX loading capacity (11 DOX molecules per DHSA) than HSA (5 DOX molecule per HSA). Kratz group utilized HSA to conjugated chemical drugs such as DOX, CPT and PTX.103,104 For


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drug controlled release, the linkers between drugs and HSA were precisely designed and can be cleaved respectively by pH, matrix metalloproteinase 2/9, cathepsin B, urokinase-typeplasminogen activator (uPA), prostate-specific antigen (PSA).105-108 3.2. Casein Drug Delivery System Milk proteins are widely used in the food industry due to their nutritional and functional properties. Casein is the major component of milk protein and consists of αs1-, αs2-, β-, and κcasein.109 Casein is considered as a great ingredient for drug delivery systems due to its edibility, biocompatibility and biodegradability.110,111 Huang et al. used a layer-by-layer milk protein casein to coat iron oxide nanoparticles for oral drug delivery.112 The outer casein layer protected and maintained the bioactivity and stability of loading drugs in the acidic gastric condition. These casein-coated nanoparticles effectively transported drugs to pass the stomach and accumulate in the small intestine. Due to its amphiphilicity, casein could self-assemble into spherical micelles from 50 nm to 500 nm in aqueous solution which made casein a kind of natural nanocarrier for drug loading. However, the low stability of these natural micelles is an obstacle for its application in drug delivery. Thus, crosslinking which can stabilize the structure of casein micelles is needed. Casein-based

nanoparticles

can

be

crosslinked

by

1-ethyl-3-(3-dimethylaminopropyl)

carbodiimide (EDC) through promoting the formation of amide bonds between carboxylic and amino groups.113 The amino groups in casein can be crosslinked by glutaraldehyde.114,115 And transglutaminase (TGase) also can be used for improving the stability of casein micelles through catalyzing an acyl transfer reaction between lysine residues and glutamine.116,117 Liu et al. prepared hollow casein nanospheres which showed extraordinary capability to penetrate cell barriers.118 They first prepared casein-poly(acrylic acid) (casein-PAA) spheres in


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the presence of acrylic acid and propionic acid, followed by crosslinking with glutaraldehyde. Due to the non-covalent interactions between the casein, PAA and propionic acid, dialysis was used to remove the PAA and propionic acid components of the nanoparticles and the hollow fullcasein spheres were then generated. This preparation method for protein-based nanoparticles is environment-friendly due to the absence of surfactant and organic solvent. It is noteworthy that these hollow casein nanospheres could largely internalized by HeLa cells via a temperature- or energy-independent fashion. This extraordinary property of casein nanoparticles may be mainly due to its proline-rich structure. Nevertheless, the hydrodynamic diameter of the hollow casein nanospheres is about 479 nm and the toxicity of the cross-linker glutaraldehyde made it not an ideal drug delivery system. Afterwards, Zhen et al. found that the size of casein nanoparticles could be reduced by simply replacing the crosslinker glutaraldehyde with transglutaminase (TGase) which is a food additive.119 Not surprisingly, casein nanoparticles showed great penetration ability both in multicellular spheroids and tumor tissues. In addition, CDDP-loaded casein nanoparticles (with 10 wt% loading content) have significant anti-cancer efficacy in tumor-bearing mice compared to free drug. Genipin extracted from gardenia fruits has also been used for crosslinking casein micelles for drug controlled release.120, 121 3.3. Elastin-like polypeptides (ELPs) Drug Delivery System Although natural proteins are easily available, the limitation of functionalizations with drugs, imaging agents and other functional molecules hinders their development. Therefore, artificial peptides with special structure emerged. Although both chemical and genetic technologies have been used for the synthesis of peptides and proteins, the reaction and purification processes of chemical methods are usually tedious and time-consuming, and thus chemical methods are only suitable for synthesizing peptides with low molecule weight and most


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of the products have no bioactivity. Differently, genetic engineering technology usually could get bioactive peptides with high security and specific conformation through the precise control on the coding gene. With the improvement of genetic engineering technology and molecular biological methods, a variety of recombinant peptides and proteins have been developed, for example, elastin-like polypeptides (ELPs), silk protein and collagen. Also, some bioactive proteins and peptides such as antibody and their fragments, enzymes and other small bioactive peptides have been prepared.122-126 Bioactive proteins and peptides that are usually used as functional sections are beyond the scope of this review and will not be discussed. ELPs, whose structure is similar to native elastin, consist of a repeated pentapeptide sequence VPGXG, where X is a guest residue that can be any amino acid except proline.127 ELPs can be highly expressed from Escherichia Coli and easily purified through inverse transition cycling (ITC) method. Most importantly, ELPs have desirable pharmacokinetics and low immunogenicity.128,129 Similar to POx, ELPs also have a LCST. When temperature is above the LCST, ELP chains would be transferred from random conformation to β-turn conformation followed by coacervation.130 Many factors influence the LCST of ELPs such as molecular weight, concentration, hydrophobicity of X residue, ion strength and pH value.131,132 Precise control of the above factors allows one to adjust the LCST of ELPs to clinical hyperthermia range and the thermo-targeting property can be used for improving tumor therapy.133 The thermos-sensitive ELP copolymers with various hydrophilic blocks and hydrophobic blocks can be acquired by simply changing the X residue with different amino acid. In certain conditions, ELP copolymers can self-assemble into micelles whose interior can further load different drugs. Matthew et al. synthesized a series of ELP block copolymers with various hydrophilic-to-hydrophobic block ratios and molecular weights.134 When the ligand at the


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hydrophilic terminus of ELP block copolymer, the ligand would lay on the surface of assembled micelles at high density for multivalent targeting.134,135 When hydrophobic drugs were conjugated to ELP chain ends, the conjugate could self-assemble into micelles. For example, DOX and PTX were conjugated into the cysteine at the C ends of hydrophilic ELP chains, respectively, and the micelles were formed.136,137 Chilkoti group have made lots of efforts in this field. They found both DOX and PTX conjugated chimeric polypeptide nanoparticles could reduce the side effect of free drugs and exhibited a higher maximum tolerated dose. At the maximum tolerated dose, DOX conjugated chimeric polypeptide nanoparticles could abolish tumors after a single injection. Also, PTX chimeric polypeptide nanoparticles outperform Abraxane® in multiple murine cancer models. In the terms of reducing side effects and improving maximum tolerated dose, peptides and proteins have done exceptionally well and shown great potentials. Nevertheless, micelles which are usually induced by weak hydrophobic effect only possess temporal stability and can disassemble when extensive diluted. In other words, the presence of micelles needs a relative high concentration usually larger than critical micelle concentration (CMC). When injected into body, micelles are heavily diluted by blood and very likely to dissociate. Besides, the conjugation usually involves a lot of complicated chemical synthesis. To solve these problems, ELP nanoparticles with poly(N-3-acrylamidophenylboronic acid) (PAPBA) as cross-linker (Figure 8a) were prepared.138 Phenylboronic acid can interact with the overexpressed sialic acid residues on the surface of cancer cells (Figure 8b).139,140 ELP-PAPBA nanoparticles showed well spherical morphology with a hydrodynamic diameter about 100 nm and great stability in a wide pH range from 3.0 to 8.5. Then, DOX was loaded into the nanoparticles with a loaded content about 10.3 wt% and encapsulation efficiency about 85%.


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DOX-loaded ELP-PAPBA nanoparticles exhibited a concentration-dependent cytotoxicity similar to free DOX. Meanwhile, blank ELP-PAPBA nanoparticles showed no inhibition on the growth of testing cells, illustrating the good cellular compatibility. Further, the cell internalization pathway of ELP-PAPBA nanoparticles by pretreating cells with free phenylboronic acid or sialic acid was investigated and found that ELP-PAPBA nanoparticles were largely internalized into cancer cells mainly through the interaction between phenylboronic acid and sialic acid residues. In vivo experiments revealed that ELP-PAPBA nanoparticles could effectively accumulate in tumor sites, reduce the heart side effect of free DOX and achieve a superior anticancer efficacy.

Figure 8. Schematic representation of (a) Preparation of ELP and PAPBA-ELP nanoparticles; Adapted

from

ref

138

with

permission

of

The

Royal

Society

of

Chemistry.


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http://dx.doi.org/10.1039/C7PY00330G (b) Schematic representation of the interaction between the PBA moieties in the nanoparticles and the sialic acid on the surface of cancer cells. Other proteins were also applied in drug delivery field, such as silk protein and collagen.124,141,142 Tian et al. synthesized a cell penetrating peptide-taxol conjugate (Taxol-CPP) which could self-assembled into nanospheres with a peptide shell.143 The nanospheres with a high loading of taxol about 26.4 wt% could be used for encapsulating a second drug such as DOX. 4. Nucleic Acid-Based Nanomedicines DNA is a biocompatible material which also can be used as carriers for drug delivery.144,145 With DNA nanotechnology, DNA can be served as a useful tool to fabricate various nanostructures, especially after the emergence of DNA origami.144,146 Recently, more and more researchers utilized DNA nanostructures to delivery drugs for cancer therapy. Except the great biocompatibility, DNA nanostructures as excellent drug carriers also possess the ability to target delivery, resist enzymatic degradation and overcome multidrug resistance.147-149 Zhu group synthesized floxuridine-integrated DNA strands by solid-phase synthesis. And these DNA strands could self-assemble into DNA polyhedral with well-defined morphology and displayed great anticancer ability.150 Huang group constructed DNA icosahedra for DOX delivery through a distinct six-point-star motif with aptamer.151 DOX could efficiently intercalate into DNA icosahedra with about 1200 molecules associated with one particle. With DNA origami, Ding group synthesized tubular and triangular DNA nanostructures.152 The loading efficacy of DOX intercalated into DNA origamis was approximately 50-60%, comparing to 30% for double-strand M13 DNA. Gu group designed a cocoon-like DNA


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nanoclew (NCl) with a maximum DOX loading capacity of 66.7 wt%, much higher than that of normal nanosystems (usually 17.3 wt%

15

Polyrotaxanes

PTX, 29 wt%

16

Nanoparticles

CPT, 50 wt%

21

Liposomes-like

DOX, 60 wt%

22

Micelles

DOX, 40 wt%

23

Nanoparticles

PTX, 15 wt% and 25 wt%

50, 51


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Supramolecular micelles

CBZ, 14.4 wt%

52

Supramolecular nanoparticles

CDDP, 50 wt%

53

Supramolecular micelles

CBZ, 17.5 wt%

72

Supramolecular nanoparticles

CDDP, 53 wt%

73

Micelles

PTX, 45 wt% and 3rd generation toxoids, 30-50 wt%

74-76

Micelles

Multidrug, 50 wt%

77

Micelles

DOX, 11 wt%

82

Nanoparticles

PTX, >20 wt%

98

Nanoparticles

PTX, 15 wt%

99

Nanoparticles

DOX, 50.6 molecules per HSA

101

Dendronized HSA

DOX, 11 molecules per DHSA

102

Casein

Nanoparticles

CDDP, 10 wt%

119

ELP

Nanoparticles

DOX, 10.3 wt%

138

CPP

Nanospheres

Taxol, 26.4 wt%

143

DNA icosahedra nanoparticles

DOX, 1200 molecules per particle

151

DNA nanoclew

DOX, 66.7 wt%

153

DNA nanotrains

DOX, 50 molecules per nanotrain

154

POx

HSA

Nucleic acid

6. Conclusions and Future Perspectives In this review, we summarized the biocompatible drug delivery systems with high drug loading content, as shown in Table 1. PEG is the most used biocompatible polymer for drug


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delivery systems based on its hydrophilicity and prolonged blood circulation time. However, ABC phenomenon of PEG reduced the therapy effect of repeated injection. Due to the similar anti-protein adsorption performance of PEG, PVP and POx are considered as promising alternatives of PEG and have attracted much attention for drug delivery. Although PVP and POx prolonged circulation time, they also showed disadvantages in biodegradability. The in vivo fate of these polymers should be severely evaluated and investigated especially after frequently repeated administration. Peptides and proteins are promising carriers for drug delivery due to its great biocompatibility and biodegradability. Since comprised of amino acid, peptides and proteins carriers could become nutrient to the peripheral tissues after biodegradation. Moreover, redundant carriers could be expelled from body through natural metabolism pathway. In contrast to peptides, the molecular weights of proteins usually very large. Preparing high drug loaded nanocarriers with proteins is a challenge. Proteins usually have complicated secondary, tertiary and quaternary structures. They are usually stabilized in water with hydrophilic parts outside and hydrophobic parts inside. Drugs can be loaded into the hydrophobic interior and conjugated on the surface. With rational design, a desired drug loading content can be achieved. In addition, proteins can be programmedly prepared with desired structure, molecular weight and residues through genetic engineering technology. Further, protein-based nanocarriers are especially suitable for protein drugs delivery. Nucleic acid is a class of incoming drug carriers. By virtue of DNA nanotechnology, diverse DNA origamis spring up. With precise control of sequences, drugs can effectively intercalate into the DNA nanostructures. From technology term, it is easy to build various DNA nanostructures with high drug loading capacity. However, the biosafety of DNA nanostructures


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for long term usage still need further investigation since DNA is an important component of the genetic materials and vital for the functionality of proteins. There is still a long way to obtain ideal drug carriers and delivery systems. Biocompatibility is the fundamental demand for drug delivery materials. To improve the therapy index of drug, nanocarriers must be delicately designed with favorable in vivo behaviors. Meanwhile, high drug loading means less frequency of injection. Whereas, every coin has two sides. High drug loading could affect the stability and drug release from nanocarriers. How to obtain a relatively high drug loading and meantime maintain acceptable stability and release kinetics? Maybe structure optimization is a solution. In the future, with the development of technology, different drugs with customized carriers which can maximize the therapy index of drug would be realized.

AUTHOR INFORMATION Corresponding Author * Email: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by National Key R&D Program of China (2017YFA0205400) and Natural Science Foundation of China (No. 51690153, 21474045, 21720102005 and 51422303), and the Program for Changjiang Scholars and Innovative Research Team in University.


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For Table of Contents Use Only

Translatable High Drug-Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers Weizhi Chen, Sensen Zhou, Lei Ge, Wei Wu, Xiqun Jiang*


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Translatable High Drug Loading Drug Delivery Systems Based on

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