Polymeric Modification and Its Implication in Drug Delivery: Poly-Îµ

Review pubs.acs.org/molecularpharmaceutics

Polymeric Modification and Its Implication in Drug Delivery: Poly-εcaprolactone (PCL) as a Model Polymer Tapan K. Dash and V. Badireenath Konkimalla* School of Biological Sciences, National Institute of Science Education and Research, Institute of Physics Campus, Sainik School, Sachivalaya marg, Bhubaneswar-751005, India ABSTRACT: Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery. In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery. However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering. This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope. Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade. Past studies show a significantly higher utility of modified form of PCL in comparison to its native form. From the statistical analysis of these modifications and the formulations prepared, we present a basic understanding of the impact of selective modifications on the formulation design. In conclusion, we remark that a thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications. KEYWORDS: copolymers, polymeric modification, polymer selection, amphiphilization, counterbalancing properties, polymeric prodrugs, responsive polymers, multidrug resistance

1. INTRODUCTION In the latest advancements of formulation development, use of biodegradable polymer based formulations is extending from controlled drug delivery to sophisticated systems such as targeted, environment sensitive, pulsatile and intelligent drug delivery systems.1,2 From investigations so far it has been observed that different pharmaceutical formulations require optimization of different but unique combinations of polymeric properties and architecture to obtain an effective drug delivery system. Moreover demands of fabrication condition and release characteristics vary for different drugs depending on their physicochemical and pharmacological profile. Therefore, the prerequisite properties of biodegradable polymers differ among different formulations as well as drugs, which need a special consideration prior to formulation design.2−4 Physical and chemical properties of polymers like solubility, degradation behavior, chemical composition, crystallinity and hydrophilicity are reported to have great impact on selection of preparation method, polymer drug compatibility, surface morphology, zeta potential (ζ) and drug release from prepared formulations.5,6 In addition to polymeric properties several other factors such as type and objective of formulation, route of administration, drug or polymeric properties etc. also affect selection of polymer (Figure 1). Hence selection of polymer is a crucial step for development of a successful drug delivery system or device. © 2012 American Chemical Society

Figure 1. Factors affecting polymer selection.

1.1. Rationale behind Modifications. To date several biodegradable polymers are reported with suboptimal property for pharmaceutical formulations. Their diversified properties favor their preference to fulfill specific objectives.7,8 However irrespective of the nature of origin (natural or synthetic) biodegradable polymers have their own advantages and Received: Revised: Accepted: Published: 2365

April 10, 2012 July 9, 2012 July 23, 2012 July 23, 2012 dx.doi.org/10.1021/mp3001952 | Mol. Pharmaceutics 2012, 9, 2365−2379

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Figure 2. Various types of polymeric modification applied in drug delivery and tissue engineering.

Table 1. Polymers Used, Approaches Adopted for PCL Modification and Their Application Perspective polymer used starch PEG

meth of prepn [catalyst used] ROP [N-methylimidazole] or blending ROP [SO/SEH]

MPEG

ROP [SO/SEH/Et2O] radical polymerization

chitosan

ROP [SEH or methasulfonic acid] or blending

PEO

ROP[SO] or blending

PEI

ROP [SO/SEH] or Michael addition ROP [SO/SEH]

PLA/ PLGA PU

HA

step 1, isocyanate terminated PCL; step 2, chain extension ROP [SEH] or free radical/atom transfer polymerization blends

PVA/ PVP silica

RAFT, blend, glutaraldehyde cross-linking blend

acrylate

a

properties altered (major)

features

formulations prepd

ref

mechanical property ionic and mechanical property ionic and mechanical property ionic and mechanical property ionic and mechanical property ionic property

↓ crystallinity; ↓ tensile strength; ↓ elongation at break value; ≈hydrophobicity amphiphilic (CMC: 0.2−2.7 nM/mL);a ↑ tensile strength and tenacity; ↓ elongation; thermoresponsive

MS; film

23−25

micelle; hydrogel; NP

26−28

amphiphilic (CMC: 60nM-1.8 μM/mL);a P-gp inhibition

micelle; NP

29, 30

amphiphilic (CMC: 0.89−3.9 μg/mL);a swelling behavior

micelle; MS; scaffold; blend

31−33

amphiphilic (CMC: 10 μg/mL)a

micelle; NP; MS; scaffold; hydrogel

34, 35

amphiphilic (CMC: 44−32 μg/mL);a DNA complexation

micelle; NC; NP

36, 37

mechanical and ionic property mechanical property ionic property

↑ elongation at break value and Young’s modulus

NP; film; scaffold

38, 39

thermo responsive; shape memory effect

implant; fiber

40, 41

amphiphilic; pH and thermo responsive

42, 43

mechanical property mechanical property mechanical property

↑ tensile strength; ↓ yield stress

micelle; hydrogel; blend scaffold; fiber

↓ crystallinity; ↓ tensile strength; ↓ toughness

scaffold; film

47−49

↑ mechanical strength

scaffold; film

50, 51

44−46

Values are obtained from specific references and are liable to change as per the chain length of polymers.

more, intelligent polymer design and modification resulted in polymers with targeting features (passive targeting due to EPR effect), P-gp inhibitory activity, environment sensitivity and enhanced pharmacokinetic profile of many hydrophobic drugs.9 Hence it is likely that polymeric properties act as the determinant for formulation design or development and their selective modification plays a key role to overcome biological (low bioavailability, selectivity, shorter biological half-life etc.) as well as pharmaceutical (physicochemical properties for formulation processing) limitations. In this current assortment we specially emphasize polymeric modifications and their role in drug delivery with special reference to PCL. Figure 4 represents various implications of PCL modification which will be dealt in more detail in the later part of the review (section 3.3). Among biodegradable polymers modified for amelioration of properties, a special focus is made on PCL mainly due to its

disadvantages. For instance, natural polymers for drug delivery and tissue engineering possess good compatibility, but lack of suitable physical properties such as solubility, mechanical strength or stability limits their application. On the other hand, in the case of synthetic polymers, in spite of their felicitous properties for processing of formulations, the absence of biological recognition signal constrains their application in pharmaceutical formulations and devices.4 Therefore, modification approach is adopted in order to obtain a predesigned range of properties without switching among polymers. Figure 2 illustrates various means of modifications of polymeric properties. Polymeric modification is not a very novel approach, but very recently it has been extensively employed to alter polymeric properties that attenuate degradation, drug release pattern or mechanical properties that resulted in a polymer suitable for multiple formulations or increased biocompatibility. Further2366

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polymer is involved, and these are the majorly demonstrated modifications for diverse purposes. This review categorizes PCL modifications according to involvement or noninvolvement of other polymers. 3.1. Modification without Involving Other Polymers. This approach involves alteration of functional groups in PCL that is primarily intended to improve their reactivity. In a study self-cross-linkable PCL-fumarate (PCLF) was prepared by poly condensation of PCL-diol and fumaryl chloride that was later cross-linked in sodium chloride (porogen) containing Nvinylpyrrolidinone medium. This PCLF cross-linked scaffold was reported to be compatible with human fetal osteoblasts and in Sprague−Dawley rats justifying its usefulness as an injectible scaffold material.20 In another study, polypyrrole (PPy) incorporation resulted in decreased melting transition temperature of PCLF films from 34.6 to 30.8 °C and decreased tensile modulus but increased resistivity and protein adsorption of prepared films. Further, peak nerve growth (PC12 cell lines) on electric signal responsive films was recorded upon application of an optimum electric signal of 20 Hz.21 Sabino et al. prepared oxidized-PCL to introduce vinyl and hydroxyl groups using potassium permanganate and reported a much higher physical miscibility with poly(p-dioxanone) without alteration of their thermodynamic miscibility.22 3.2. Modification Involving Other Polymers. PCL based modified polymers demonstrated so far predominantly involve its copolymers with several other polymers in different forms (Figure 3). Nevertheless other modifications (blends and

broad spectrum of compatibility with a wide range of other polymers. Its versatile nature, ease of fabrication and biocompatibility establish it to be the polymer of interest by investigators worldwide for drug delivery and tissue engineering applications. But when we consider properties of unmodified PCL there are considerable restrictions for its use. For example, its hydrophobic nature does not allow facile release of hydrophobic drugs (from prepared formulations) and micelle formation, long-term degradation (ranging from weeks to months) slows down tissue replacement in the case of scaffolds, mechanical property limits its application to hard tissue engineering only, nonreactivity is unsuitable for preparation of NC etc.10−12 Therefore, attempts have been made to overcome these undesirable properties by various types of modification mentioned in Figure 2 for successful application in pharmaceutical formulations. To great excitement, use of modified PCL dominated over the past decade by virtue of which PCL was demonstrated in almost all novel formulations overcoming the above-mentioned restrictions.11 Additionally, functionalization as a result of PCL modifications is a featured advantage and considered as another cause for this typical preference for modified PCL. Hence this review describes various modifications of PCL, resultant alteration in properties and their implications in novel drug delivery.

2. APPROACHES FOR SYNTHESIS OF PCL AND ITS COPOLYMER Detailed description on synthetic approaches of PCL, the mechanisms involved and catalysts used are described in a review by Labet et al.13 Among them, ring-opening polymerization (ROP) is the widely practiced method for synthesis of PCL and its copolymers. Methods of synthesis of various PCL based copolymers are summarized in Table 1. In an exploratory study, Chang et al. described the use of antitumor agent doxifluridin as initiator in the preparation of PCL by ROP.14 In another study on synthesis of PCL by Escherichia coli catalyzed ROP, 70−90 °C was reported to be the optimum temperature for total conversion. This biocatalytic enzymatic activity provided great advantage over conventional enzymatic conversion in terms of efficiency and operational stability.15 Trollsas et al. described preparation of hydroxyl, bishydroxyl, amino, and carboxyl functionalized CL by Bayer Villigers oxidation of corresponding cyclohexanone derivative which can be advantageous in increasing reactivity of PCL for further modifications. But its usefulness and widespread application in producing pharmaceutical biopolymers is yet to be explored.16 Nevertheless in certain instances, the reactivity of PCL is induced by initially enriching PCL with other functional groups such as acrylates, maleate, oxime linkages, etc. followed by further desired modification. For instance, Liu et al. initially synthesized PCL-acrylate to make it suitable for Michael reaction which was later modified to Hy-PEI-g-PCL-bMPEG.17−19

Figure 3. Different demonstrated architecture of PCL modification: (i) graft copolymer; (ii.a) diblock copolymer; (ii.b,c) triblock copolymer; (ii.d) tricomponent triblock copolymer; (iii) star shaped copolymer; (iv) hyperbranched copolymer; (v) molecular brush or comb shaped copolymer; (vi) targeted block copolymer.

composite) were also reported in different formulations. Table 1 summarizes different modifications (arranged based on the other polymers used for PCL modification), properties altered and formulations prepared from respective PCL modification. 3.3. Implications of PCL Modification. Initial investigatory modifications of PCL were subsequently employed to increase its hydrophilicity, degradation and biocompatibility. But sequentially over time implications of PCL modification extended from micellar solubilization to environment sensitivity and P-gp inhibition which turned out to be the major goal in

3. PCL MODIFICATIONS Approaches employed to modify polymeric properties illustrated in Figure 2 are also applicable for PCL. Out of the abovementioned modifications, backbone modifications by alteration or introduction of new functional group have major implications for altering degradation and reactivity. However for other nodes of the modification chart (Figure 2), i.e., for copolymers, blends and composites, another modifying 2367



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Figure 4. continued

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Figure 4. Demonstrated implications of PCL modification.

alkaline media.59 In another study involving a blend of polyanhydride and PCL within 5 days of degradative study, anhydride degraded completely whereas PCL component remained unchanged as pure form.54 Thus PCL modifications induce segmental degradation and decreased degradation half-life from months to days. From several studies it has been evident that degradation controls the release pattern, hence this aspect of PCL modification found its implication in modulating release profile of encapsulated drugs. Interestingly, it was observed that, irrespective of the nature of PCL modification, drug release followed a biphasic pattern.25,60 Further this higher degradation pattern overcomes the disadvantage of slower tissue replacement of scaffolds as in the case of unmodified PCL. Therefore, due to higher hydrophobic nature of PCL, it is obvious to result in increased degradation rate in all trialed modifications irrespective of other polymer used (since other polymers are less hydrophobic except PLA) and this feature can be employed to alter drug release pattern. 3.3.2. Amphiphilization. Amphiphilic molecules found their application in pharmaceutical drug delivery owing to their property of micellar solubilization. CMC is subject to alter depending on both length and polarity difference between interconnected hydrophilic and hydrophobic segments. Nonamphiphilic PCL restricts the formation of micelle, but on the other hand high hydrophobicity along with broad spectrum of compatibility of PCL (flexibility for selection of modifying

the current scenario. The implications of modified PCL and polymers used respectively are illustrated in Figure 4. 3.3.1. Alteration of Degradation Pattern. This is the most imperative modification for PCL to be used successfully in pharmaceutical formulations. Moreover, alteration of degradation pattern is a facile one among modifications and any modification in the backbone or alterations of block as well as physical mixing have been shown to affect the degradation behavior. Expected higher degradation rate after these modifications is attributed to the fact that the modifying polymers are mainly hydrophilic that disturbs the crystalline aggregation of PCL blocks which restricts water permeability and degradation.52−55 Figure 5 illustrates mode of degradation of PCL after different modifications. Furthermore alteration in degradation behavior is highly influenced by the polymeric ratio and chain length of other polymers involved (e.g., PEG, PEO, PGA, starch, acrylates etc.) as these are the determinants of kinetics of mass loss. However, blending PCL with PLA and HA were reported to have little impact on the degradation behavior and initiation of mass loss.39,56,57 Fukushima et al. reported the degradation of PLA and PCL nanocomposite with sepiolite to be more sustained for PLA but remained unaffected for PCL.58 Modified PCL-based network from PCL-diol was prepared by photopolymerization in the presence of methacrylic anhydride. In a degradative study for 60 h, photopolymerized network degraded (bulk degradation, mass loss 70%) faster than linear PCL (surface erosion, mass loss 5%) in 2369



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between drug and copolymer component was observed from a report by Shuai et al. Here there was dependence of fenofibrate encapsulation on PCL chain length, but such dependence was not observed in the case of DOX. 26,29,68 In certain modifications of PCL such as PEG, chitosan, Eudragit, etc. negative value of ζ decreased as the chain length of modifying polymer increased.31,65,69 Many of these modifications produced copolymers with positive ζ value that made it suitable for complexation with negatively charged DNA under suitable conditions. For example PEI-PCL (ζ 10−50 mV), P(CL-co-Py+CL) (ζ 80.3 ± 3.0 mV), MPEG-b-PCL-g-PDEMA (ζ 10−18 mV), hy-PEI-g-PCL-b-mPEG (ζ 12−25 mV), PCL-bPluronic-b-PCL-g-PEI (ζ 31 mV) etc. showed considerable DNA complexation characteristics wherein zeta potential gradually decreased as the DNA to polymer ratio increased.17,37,70−72 Further, PCL upon copolymerization with poly glycidyl methacrylate (PGMA) and oligo(ethylene glycol) monomethyl ether methacrylate-folic acid (P(OEG-MA-FA)) produced self-assembling amphiphilic copolymers in which interaction between PGMA and iron oxide (FeO) facilitated FeO loading. Taking these features into account Hu et al. produced paclitaxel loaded micelles that were able to provide contrast for imaging.42,73 3.3.3. Alteration of Mechanical Property. Mechanical properties of fabrication such as mechanical strength, elongation at break, Young’s modulus and shape rigidity/ flexibility play a decisive role for their application in tissue engineering. Biodegradable polymers are employed in the form of rigid devices for hard tissue (bone repair, regeneration and engineering) and flexible devices for soft tissue (neural, cartilage and vascular tissue engineering). Owing to its easily modifiable nature, PCL and its modified forms have potential to mimic the mechanical properties of various body tissues. Hence altered PCL reserves an application in both rigid and flexible tissue engineering devices. Table 1 illustrates various other polymers that primarily affect mechanical properties of PCL. In this regard, blends of PCL with starch, PU, HA, and silica were shown to have higher impact on mechanical properties. However, the alteration of these properties may not be isotropic as shown by Ashton et al. where polymeric ratio dependent anisotropy for PU-PCL blend was reported.40 From the phenomenal observation it may be worth noting that a PCL blend with PLA in contrast to other modifications has incremental elongation at break in the order PLA (15%) < PCL (120%) < PLA-PCL (160%). Further, Lahiri et al. reported the reinforcement of mechanical properties (increase of elastic modulus by 1370%, tensile strength by 109% and elongation at break by 240%) of PLA-PCL upon incorporation of up to 5% boron nitride nanotubes (BNNT).39,74 Gorna et al. studied PU based on poly(EO-PO-EO) as soft and PCL as hard segment in different combinations and reported their similar mechanical properties to that of commercial products.41 A study involving PCL of different chain length as different soft segment and 1,4-butane diisocyanate as a hard segment confirms the direct and inverse relation of hard segment content with tear strength and stain at the yield point respectively.75 In another study, Ag incorporation into PUPCL fibrous mats was reported to enrich them with antibacterial property but resulted in increased tensile strength/modulus and reduced elongation.76 Importantly, the principle of modification is based on the fact that mechanical demands of tissue engineering devices vary based on application. Fabrications for hard tissue engineering needs

Figure 5. Degradation pattern of devices from modified PCL. (a) Normal autocatalyzed degradation of PCL where degraded fragments unable to escalate leach degradation. Thus, inner core degrades faster than surface. Water permeation into the core is the limiting factor for initiation of autocatalysis. In the case of PCL modified with hydrophilic polymers, sites for surface degradation are provided and water permeation into bulk is facilitated as hydrophilic polymer degrades easily owing to faster breakage of inter- or intrapolymeric bonds. Hence autocatalysis starts at an early stage. Additionally, devices from modified PCL show more prominent degradation features, i.e., blends with surface pores were more prone to breaking (earlier size reduction) whereas copolymeric devices degraded uniformly with autocatalysis at a faster rate. For modified forms such as blends (b) and copolymers (c) the mechanism of degradation is highly inclined to bulk degradation and surface erosion respectively. Initiation of degradation at the amorphous region is evidenced by increased crystallinity upon degradation.

hydrophilic polymers) allows amphiphilization of PCL easily. Hence PCL modification yielded a number of experimental amphiphilic copolymers. Among them water-soluble ones such as PEG, MPEG, PEO and PEI are highly preferred as they produced many functionalized copolymers along with amphiphilization and, thus, rendered PCL suitable for formulation of multimodal micelles and micellar NPs. However, as an exception starch being a hydrophilic polymer was unable to alter the hydrophobicity of PCL after grafting whereas it was reported to be possible with dextran.24,62 PCL amphiphilization is advantageous as micelles carrying drug can be formulated without use of organic solvents.63,64 Owing to hydrophobic interaction between PCL segment and lipophilic drug CMC reduces in the presence of drugs that are lipophilic. It has been noted that increase in PCL length in the copolymer decreases the CMC and micellar size that in turn increases the solubility of hydrophobic drugs.29,31,60,65 In another aspect of drug delivery, the facilitated or restricted interaction between drug and polymeric segments controls the drug loading and release rate followed by polymeric degradation. Hence by strategic manipulation of hydrophobic to hydrophilic segments in the copolymer, drug loading or release can be accordingly modulated effectively.61,66,67 Indication of interaction specificity 2370



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forming gel system.28,55,83 Similarly, pH responsiveness of acrylate-PCL copolymers was found to be largely dependent on the acrylate segments and increase in PCL segment reduced responsiveness.43 Further, this responsiveness can be employed to design targeted formulation for cancer therapy owing to acidic intracellular pH and increased reduction potential of cancer cells.84 Shuai et al. reported faster release of DOX from MPEG-b-PCL micelles at pH 5.0 than at pH 7.4 indicating facilitated release inside cancer cells.68 In another study Wang et al. demonstrated redox responsive release of DOX after PCL modification with PEEP involving a disulfide link. PEEP-SSPCL copolymeric NPs provided selective release of DOX in cancer cells owing to their increased intracellular glutathione concentration.80 In another approach to modulate pH-dependent release pattern, Jin et al. produced oxime linked PCL (OPCL) and further modified it to PEG-b-OPCL-b-PCL. Owing to pH sensitivity of the oxime link, micelles from PEGb-OPCL-b-PEG preferentially released DOX in cancerous cells.19 Environment-responsive PCL modification does have a role in tissue engineering as well. For instance novel shape memory networks and thermoresponsive transformation features of PCL-DMA networks and PCL/PU blends respectively have exciting applications in vascular/soft tissue engineering. In both modifications polymeric composition dependent shape memory and transformation behavior was reported. Ajili et al. demonstrated optimal 70:30 blend of PU-PCL network as cardiovascular implant with shape memory feature, wherein it was reported that PU acts as a physical cross-link and is responsible for its permanent shape whereas the PCL segment brings the temporary shape.40,85,86 3.3.6. Polymeric Drug Conjugates and Prodrugs. Polymerconjugated delivery (PCD) of drugs is being focused in the past decade as a novel approach in controlled as well as targeted therapeutics. PCL in copolymeric form is mainly studied in conjugation with various drugs to evaluate its potential as PCD. The other polymer used to modify must have reactive groups for conjugation and usually are preferred to be hydrophilic in nature, so that prodrugs becomes “drug conjugated amphiphilic carrier”. Shahin et al. synthesized PEO-b-P (CL-PTX) that showed a pH-sensitive cleavage pattern with nonsignificant increase in drug release. Increase in hydrophobic domain resulting upon conjugation with paclitaxel produced PCD with lower CMC and higher micellar size. Resultantly it prevented water permeation into the core and further retarded the rate of paclitaxel release (in comparison to physically loaded paclitaxel in PEO-b-PCL micelles).34 In another similar study, DOX was attached to caprolactone involving different linkages, i.e., hydrazone bond and amide bond in a targeting ligand (RGD4C) attached to PEO-b-PCL producing RGD4C-PEOb-P (CL-Hyd-DOX) and RGD4C-PEO-b-P(CL-Ami-DOX) respectively. The release of DOX from the hydrazone linked conjugate was reported to be much faster than the amide linked form in a pH triggered manner (in pH 5), and their intracellular distribution also varied in resistance and sensitive cells.87 Triblock copolymer MPEG-b-PCL-b-PLL when linked covalently to Pt(IV) acted as a prodrug for cisplatin(II). Under an acidic or reductive environment release of cisplatin from selfassembled Pt(IV) linked copolymeric micelles was escalated enriching delivery system with targeted features.84 From the study involving water-soluble paclitaxel polymeric prodrugs, Li et al. demonstrated the potential of polymeric prodrugs in

careful control of mechanical strength and porosity, but on the other hand crucial factors for soft tissue engineering are different such as elongation at break (elasticity) and tensile strength. Furthermore, mechanical strength has an inverse relation with porosity of scaffold and elasticity. Hence an ideal PCL modification must have sufficient mechanical strength and plasticity to provide good mechanical stability; on the other hand, these systems should have adequate porosity or rate of degradation for a scope of tissue growth/repair. 3.3.4. Enrichment with P-Glycoprotein (P-gp) Inhibitory Activity and Circumvention of MDR. Acquired drug resistance is most commonly caused by prolonged use of therapeutic agents. Among causes of drug resistance, overexpression of Pgp plays a leading role in developing resistance for antibiotics and chemotherapeutic agents. In various studies, nanoformulations circumvented the drug resistance by enhanced permeation and retention effect. Many PCL based copolymeric formulations showed an existent feature to overcome P-gp mediated drug resistance. Devalapally et al. showed that micellar paclitaxel or tamoxifen delivery using PEO-b-PCL copolymer was able to reverse the degree of resistance from 300-fold to 2-fold in P-gp positive SKOV-3 cells.77 In another study Qiu et al. reported the ionic and self-assembly features of PEI-b-PCL that can be used for combinatorial gene (through ionic complexation) and drug delivery (through micellar encapsulation). Thus PEI-g-PCL copolymers provide multifactorial strategy for formulation design to overcome MDR.36 In studies involving paclitaxel/docetaxel encapsulated NPs from blend of PCL and poloxamer-118/68, it was reported to reverse MDR in MCF-7/TXF cell lines.78,79 In a comparative study to find out the efficiency of PEG and PEEP to circumvent drug resistance in MCF-7/ADR cell lines, efficiency of DOX accumulation was reported to be equivalent. However, susceptibility of degradation of disulfide (SS) linked PEEPSS-PCL in cancer cell made them advantageous over diblock copolymer PEG-b-PCL.80 Among the studies to overcome MDR the most promising was done by Elamanchili et al. where the P-gp inhibitory activity of MPEG-b-PCL was reported. This modification resulted in increased intracellular accumulation of DOX and paclitaxel in P-gp overexpressing cell lines.81 3.3.5. Enrichment with Environment Sensitivity. An environment-sensitive delivery system that releases drugs in response to parameters such as alteration of pH or temperature has major implications as targeted drug delivery. This feature is based on the fact that polymers in the delivery system degrade or alter in their arrangement depending on the physiological conditions. PCL as such lacks environment-sensitive properties, but upon modification it has shown its prepatent application in temperature and pH sensitive delivery systems.19,82 Modifications of PCL with PEG, MPEG, PEEP, acrylates, chitosan and Pluronic result in these functional or responsive copolymers. Copolymers such as PEG-b-PCL or MPEG-b-PCL were studied as hydrogels, NPs and micelles for temperature-sensitive drug delivery making it a polymer of major interest. Here, the transition behavior was primarily controlled by the constituent polymeric ratio. In a study by Liu et al. it was observed that the PCL:PEG ratio when ranging between 0.5 and 2.0 produced water-soluble amphiphilic copolymer showing temperature dependent sol−gel transition between 20 and 60 °C, whereas when this ratio was exceeded it produced a water insoluble copolymer with no transition behavior. This temperature dependent transition of PCL based copolymer, MPEG-b(PCL-ran-PLA), was reported to be suitable as injectable in situ 2371


micelles

hydrogels

microspheres

films/membranes or tubes

formulation

metronidazole tissue engineering esophageal tissue engineering TGF-β1 levonorgestrel hydrogels for tissue engineering dexamethasone 5- fluorouracil

PEEA

PMAA-g-PCL poly(LA-co-CL)

2372

PEO-b-P(CL-PTX)

PEI-g-PCL PEO-b-PCL

MPEG-b-PCL- FA MPEG-b-PCL-b-PLL MPEG-b-PCL, PCL-bPDEMA PCL-b-PEG-b-PCL PCL-b-PEO-b-PCL PEEP-b-ssPCL PEG-b-P(CL-TMC) PEG-b-OPCL-b-PEG PEG-b-PCL

chitosan-g-PCL chitosan-g-PCL-g-PEG MPEG-b-PCL

P(CL-MAA-MEG) Au-PCL-b-MPEG

17-β-estradiol paclitaxel

valspodar

honokiol nimodipine paclitaxel paclitaxel DOX paclitaxel fenofibrate rapamycin DNA (gene) DOX DOX ellipticine 125 iodine curcumin

HCN paclitaxel cisplatin indomethacin

EHC paclitaxel, rutin curcumin, etoposide, indomethacin DOX

tissue engineering

PCL dimethacrylate

chitosan-g-PCL PCL-b-PEO-b-PLA pHEMA-co-PCL

paclitaxel

drug used or intended purpose

dextran-g-PCL

copolymer used

sustained release controlled release controlled release reduced toxicity pH sensitivity improved efficacy improved solubilization controlled release carrier targeted delivery, PCD improved compatibility targeted imaging improved solubility and controlled release carrier and improved bioavailability improved solubility improved solubilization and PCD

improved cytoplasmic accumulation EPR effect targeted delivery targeted delivery PCD pH sensitive delivery

sustained release controlled release tunable biodegradation and mechanical property pH responsiveness controlled release, imaging and photo therapy controlled release carrier prolonged release improved efficacy and solubility

improved biocompatibility elastomeric properties

controlled release

shape memory effect

controlled release

objectives achieved

60 34

107

63 67 102 64 19 103 26 66 36 87 104 105 206

65 93 84 101

68

31 92 29, 100

98 99

91 61 97

95 96

94

86

62

ref

starch-PCL

PVP-PCL silica-PCL

poly anhydridePCL PU-PCL

PLA-PCL

blends used

Table 2. Copolymers in Different Drug Delivery/Tissue Engineering Formulations and Their Objectives

dexamethasone

CV implants/polymeric endoaortic paving iodine silver nanorod

ofloxacin

sabeluzole

drugs used or intended purpose objectives achieved

controlled release

improved mechanical property enhanced activity

shape memory effects

controlled release/improved cell growth controlled release

ref

25

47 51

40, 85

54

38

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blends/composites

fibers or scaffolds/ fibrous scaffolds

nanoparticles

nanocomplex

formulation

Table 2. continued

DOX tetrandrine 40- DMEP tamoxifen, paclitaxel docetaxel paclitaxel, iRGD tibolone tissue engineering silver NP

PU-PCL

magnetite indomethacin Taxol DNA BSA honokiol 30, 110 71 52 111

improved efficacy improved gene transfection controlled release improved solubility and to overcome MDR circumvention of MDR localized release improved solubility circumvention of MDR improved efficacy enhanced cellular uptake controlled release improved mechanical and antibacterial property improved mechanical property and functionalization

poloxamer-118/ F68 PCL

blends used

76

cartilage engineering hard tissue engineering doxycycline, ofloxacin tissue engineering

controlled release improved mechanical property

functionalization improved compatibility

tissue engineering

HA-PCL PEOPCL POSSP(CLurea) PVP-PCL wollastonite -PCL chitosan-PCL PLA-PCL

soft tissue engineering

improved mineralization and cell growth compatibility, porosity control and improved cell growth novel nanocomposite

hard tissue engineering

HA-PCL

controlled zeta potential

improved tissue compatibility

reversal of MDR

objectives achieved

tissue engineering

tissue engineering

paclitaxel, docetaxel

drugs used or intended purpose

Eudragit-PCL

80 27 112 77, 113 114 49 115 32, 116 chitosan-PCL

109

37, 53, 72 42

108 17, 70

ref

localized drug delivery

transfection vector; nasal epithelial carrier controlled release and imaging

DNA (gene) paclitaxel, magnetite

sustained release carrier

objectives achieved

indomethacin DNA (gene)

drug used or intended purpose

PEEP-SS-PCL PEG-b-PCL PEG-b-PCL-b-PEG PEO-b-PCL PLGA-b-PLA-b-PCL PVP-b-PCL P(PSu-CL) chitosan-g-PCL

MPEG-b-PCL-g-PDEMA PCL-b-PEG-b-PCL

PGMA-b-PCL; P(OEG -MA-FA)-b-PCL MPEG-b-PCL

N-phthaloyl-chitosan-g-PCL PCL-bromo-CL-Py; hy -PEI-g-PCL-b-mPEG PCL-PEI; PCFC-g-PEI

copolymer used

90, 33 74

48 118

35, 45, 56, 117 50

44, 46

69

89

78, 79

ref

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4.1. Modification That Render PCL Suitable for Diversified Formulation. Modification of PCL produced polymers suitable for many formulations including micelles, NC and scaffolds for soft tissue engineering etc. which cannot be formulated with innate form of PCL. Furthermore their preferences for prepared formulation after modification varied based on nature of modification (blending and copolymerization). From observations on the polymers used for PCL modification and preferred method of modification we remarked that water-soluble polymers such as PEG, MPEG, PEO and PEI are preferably copolymerized whereas hydrophilic polymers that are insoluble under normal conditions such as starch, HA and clay are mostly blended with PCL. But use of polymers for different modification is much randomized to conclude any regular selectivity pattern. However as an overall consensus from experimentation it has been observed that the polymers used for blending with PCL are discrete unlike copolymers where it is mostly limited to certain water-soluble polymers only. This selectivity pattern of polymer further diluted as most of the polymers can overcome the long-term degradation pattern to a different extent. Therefore upon correlating formulations prepared and type of modification (Table 2 and Figure 6) it can be figured out that, although the demonstrations are overlapping, PCL copolymers with watersoluble polymers resulting in a change of ionic properties are preferred for drug or DNA delivery formulations (micelle, MS, NC and NP), but use of PCL based blends with water insoluble polymers mainly resulting in alteration of mechanical properties are highly inclined toward tissue engineering formulations (scaffold, fiber and film). Therefore, the PCL modifications and formulations prepared from them correlated well based on the properties ameliorated. A special consideration is being given to PCL modifications with PEG, PU, PEO, PGA and PLA as their copolymers retained the ability of melt processing which is essentially a useful procedure since the processing does not involve any organic solvent.35,38,85,119 4.2. Modification That Render PCL's Functionalization. Escalation of biodegradation, modulation of mechanical property and amphiphilization of PCL were observed to be the major objectives of its modification. When enriched with functionalization, optimized design involves modification as per the aimed application perspective so that the property of interest does not alter much. For example, when PCL was copolymerized with PEG or GA/PLGA, they individually produced amphiphilic copolymer. However GA/PLGA prevented crystallization of PCL in the fabrication that has a role to play in drug loading as well as degradation of fabrication whereas PEG enriched fabrications with environment responsiveness.28,66,114 Further responsiveness can also be adjusted by suitable chemical modification which was shown in a sequential study by Wang et al. where pH responsiveness of P (CL-bMAA-b-MEG) hydrogels is shown to be much higher than P (CL-b-MAA-b-EG).43,98 Study involving micellar drug delivery was carried out to optimize size, stability, environment responsiveness and tissue compatibility by two PCL based copolymers, mPEG-b-PCL and (PCL-b-PDEMA). mPEG-bPCL in the mixture reduced the size of micelles formed with increased stability and tissue compatibility whereas PCL-bPDEMA enriched with pH responsiveness.101 Micelles obtained from combination can be used as environment responsive carrier system as both of the copolymers were reported to be distributed uniformly around the PCL core. In discrete studies to modify the surface of PCL fabrications,

therapeutics and reported PCL as preferred polymer for drug conjugation.88 Apart from the above-mentioned application of PCL modification, there are many modifications having special features that are advantageous in drug delivery applications. Chitosan upon blending with PCL increased the application perspective of PCL as composite due to its drug loading dependent swelling behavior and pH responsive release pattern. Additionally Sarasam et al. reported improvement in biocompatibility of PCL upon chitosan mixing in terms of tissue growth and surrounding necrosis area.33,89−91 Similar hydrogel behavior was shown by acrylate-PCL copolymer [poly(caprolactone-methacrylic acid-ethylene glycol)] (P(CL-MAAEG)) and is expected to have promising implications in drug delivery.43 Further, hydrogels based on PEG-b-PCL-b-PEG were reported to be suitable for controlled timolol delivery due to increased ocular compatibility.82 In a study by Chen et al., a fluorescent PCL copolymeric micelle was produced where the fluorescent activity of chitosan-g-PCL-g-PEG was activated after cross-linking with glutaraldehyde.92 In some studies, devices from copolymerization protected degradation of the active ingredient. Different studies report the use of PCL copolymers for stabilization of active ingredient. For instance, covalent link of paclitaxel to PEO-b-PCL and ionic loading of DNA to PEI-bPCL system rendered protection from hydrolysis and DNase respectively.34,53 Importantly modifications additively enriched active targeting to tumor when the modifying polymer contains a specific ligand for certain upregulated receptor in cancer cells. Based on this phenomenon, Park et al. formulated folate conjugated MPEG-b-PCL that reported higher selective accumulation of folate in cancer cell.93

4. DISCUSSION PCL is a polymer that has been implicated in almost all novel formulations for drug delivery and tissue engineering with several functionalized features. However innate features of PCL are unsuitable for many pharmaceutical formulations and possess no functionalization. From investigation over the past decade we observed this extended spectrum of application in terms of diversity of formulation and functionalization being mainly attributed to its amiable modification. In this review we focused on two aspects of PCL modification, namely, modifications that render it suitable for diversified formulations and modifications that render it functionalized (section 3.3, Tables 1 and 2). Figure 6 shows a plot on relative frequency of experimentations (over past decade) for a better understanding of correlation between polymeric modification (blend/copolymer) and formulation suitability.

Figure 6. Relative preference of modification those rendered PCL suitable for diversified formulation. 2374



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phobic composition with degradation, porosity with mechanical strength, hydrophilic composition with plasticity and elongation, degradation and surface hydrophilicity with cell adhesion and growth etc. These balanced property needs may differ among different formulations but can be achieved by strategic polymeric modification. Under optimal composition, each of the modifying polymers in the combination complements others to produce suitable application specific modified polymers. Owing to diversity of polymers used in drug delivery, study of their property in combination, their macromolecular engineering and resulting features can be analyzed for reference whose implications will be analogous to response surface method of optimization in formulation design.

polymers like Eudragit, methacrylic acid and PVP are blended and/or grafted. This highly influenced zeta potential (length dependent increase of positive ζ for Eudragit and negative ζ for PVP) and hydrophilic surface modification reported to reduce surface hydriphobicity that in turn increased the cytocompatibility and cellular uptake.49,69,82,95 In another study, Ma et al. demonstrated application specific modification of PCL using PEO where PEO5000-PCL24500 was preferred copolymer for solubilization of curcumin whereas PEO5000-PCL13000 was most efficient for reducing release rate.106 Furthermore such a strategic modification is also applicable for formulations for tissue engineering. For instance, the maleic anhydride-PCL/starch has improved mechanical properties in comparison to normal PCL/starch blend with higher water resistance and, hence, is preferred for selective attenuation of mechanical properties. A similar kind of study was performed by Wu et al. where acrylate modification of PCL compensated the unsuitable mechanical properties resulting from blending of starch with PCL.18,23 Apart from mechanical properties, alteration in surface hydrophilicity and increased compatibility by bioactive materials is the most cardinal consequence of these modifications that increases cell attachment and growth. Most importantly, PCL possesses a poor biological recognition signal (owing to absence of any polar functional groups such as −OH, −NH2, −COOH etc.) especially in soft tissues that can be overcome by this modification approach. Additionally PCL when modified with HA acted as nuclei for biological apatite accumulation, thereby enhancing mineralization. Furthermore porosity inarguably facilitates cell growth by providing higher specific surface area and allows leaching of active ingredient from functional scaffolds that has a crucial role in the development of functionalized scaffolds. This is substantiated in a study by Wei et al. that reported superior compatibility PCL scaffolds when modified with mesoporous wollastonite in comparison to conventional wollastonite.44,47,118

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AUTHOR INFORMATION

Corresponding Author

*NISER, School of Biological Sciences, FC210, Institute of Physics Campus, Sachivalaya marg, Bhubaneswar-751005, India. Phone: 0091-674-2304121. Fax: 0091-674-2304070. Email: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors acknowledge support from Department of Science and Technology, Government of India, for the “Fast Track Scheme For Young Scientists” grant (No. SERC/LS-411/2011).

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ABBREVIATIONS USED CL, ε-caprolactone; EG, ethylene glycol; CMC, critical micelle concentration; DOX, doxorubicin; EHC, 7-ethyl-10-hydroxycamptothecin; EPR, enhanced permeation and retention; FA, folic acid; HA, hydroxyapatite; HCN, hydroxy camptothecin; Hy-PEI, hyperbranched PEI; MEG, methoxy ethylene glycol; MPEG, methoxy PEG; MS, microsphere; NC, nanocomplex; NP, nanoparticle; PCFC, PCL-Pluronic-PCL; PCL, poly-εcaprolactone; PDEMA, poly(diethylamino)ethyl methacrylate; PEEA, poly(ether-ester-amide) (PCL(-OOC-Seb-COCl)); PEEP, poly(ethyl ethylene phosphate); PEG, polyethylene glycol; PEI, polyethylene amine; PEO, polyethylene oxide; pHEMA, poly(2-hydroxyethyl methacrylate); P-gp, P-glycoprotein; PLA, poly-L-lactic acid; PLL, poly-L-lysine; PLGA, poly lactide glycolic acid; POSS, polyhedral oligomeric silsequioxane; PU, polyurethane; PVA, polyvinyl alcohol; PVP, polyvinyl pyrolidone; Py+CL, γ-bromo-ε-caprolactone quaternized by pyridine; RAFT, reverse addition fragment transfer polymerization; SEH, stannous ethyl hexanoate; SO, stannous octate; ssPCL, star shaped PCL; TMC, trimethylene carbonate

5. CONCLUSION AND PERSPECTIVE The versatility of PCL for pharmaceutical formulations along with functionalization features demonstrated over the past decade justifies its immense usefulness.11 This review details the modifications of PCL along with the modification approach applied, formulation prepared and the objectives achieved. Considering its spectrum of application for different functionalization in different drug delivery systems, especially those that are solely resulted from modification, we conclude that (a) polymeric modification is a promising approach that provides an opportunity to custom design polymer for specific formulations as well as functionalization and (b) PCL can be used as a model polymer to study polymeric modification to obtain user defined polymeric properties and functionalization. As a broader prospective, from the above observations it may be concluded that polymeric modifications (Figure 2) have greater scope for producing polymers with diverse cluster of properties. But for its noteworthy application they must possess well optimized counterpoising polymeric properties which may differ for formulations for drug delivery and tissue engineering. Some of the properties to be balanced for drug delivery devices are solubility with degradation, hydrophilic−hydrophobic composition of copolymer with self-assembly or drug encapsulation or drug release, surface texture and functionalization with interaction with water, degradation, environment responsiveness and targeting features; whereas for devices for tissue engineering, the properties to be balanced are hydro-

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