Strategies in Aliphatic Polyester Synthesis for Biomaterial and Drug

Chapter 15

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Strategies in Aliphatic Polyester Synthesis for Biomaterial and Drug Delivery Applications Angela L. Silvers, Chia-Chih Chang, Bryan Parrish, and Todd Emrick* Polymer Science & Engineering Department, University of Massachusetts Amherst, Conte Center for Polymer Research, Amherst, MA 01003 *[email protected]

Aliphatic polyesters are among the most important class of synthetic polymers for biomedical applications due to their biodegradability and generally high biocompatibility. However, conventional aliphatic polyesters are semi-crystalline, hydrophobic solids lacking in functionality, such that strategic tailoring of their structure and functionality could expand their application base considerably. Numeorus synthetic methods have been examined for introducing functionality to aliphatic polyesters. This chapter will describe a number of reported methods, focusing on examples of ring-opening polymerization (ROP) of functionalized lactones, and post-polymerization functionalization that affords well-defined materials with high degrees of functionality and narrow polydispersities. In addition, new developments in biocompatible ROP catalysts as well as novel polyester architectures, such as cyclic polymers, will be discussed.

Introduction Early efforts to use synthetic polymers as biomaterials were based on high volume commodity polymers such as polyurethanes, polyacrylates, nylon, and poly(tetrafluoroethylene), each designed initially for conventional materials purposes. Nevertheless, the wide availability and favorable physical properties of these polymers led to their use by surgeons in medical procedures that require durable and generally inert materials (1, 2). However, the use of such polymer © 2012 American Chemical Society In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


materials in surgical and other biological applications has been problematic, leading in some cases to inflammation, due to the immune response of the body to the presence of foreign materials. Notable pioneering examples of polymer materials in biological applications include efforts of DeBakey and coworkers, who as early as the 1950’s used Dacron™ (polyethylene terepthalate) for cardiovascular prostheses (3). These procedures were found to be successful in the repair of large arteries, but unfortunately failed in cases where the internal diameter was less than 5 mm. The breadth of expertise needed to solve such challenging problems in biomaterials, and effectively introduce synthetic materials to the body, includes chemistry, biology, engineering, and medicine, thus generating a challenging interdisciplinary topic that requires collaborative activity among these disciplines. While many different types of polymers are of interest in biomaterial applications, aliphatic polyesters are particularly relevant to consider due to their degradable nature under physiological conditions, thus making them desirable as resorbable materials. Aliphatic polyesters were initially used to fabricate degradable sutures in the 1960’s (4), and have since found use in a wide range of biomaterial applications including drug-delivery systems (5), tissue-engineering scaffolds (6), and temporary tissue/bone replacement (7) as depicted in Figure 1.

Figure 1. Examples of biomaterial applications using aliphatic polyesters

More recent advances include the work of Langer on aliphatic polyesters for tissue-engineering and drug-delivery (8), Fréchet and Grinstaff on drug-delivery (9) and surgical (10–12) applications of dendrimers, and Duncan in the area of drug-delivery systems and polymer therapeutics (13). An effective approach to synthesizing aliphatic polyesters of controlled molecular weight and potential medical importance involves a ring-opening polymerization of monomers shown in Figure 2, such as lactide, glycolide, ε-caprolactone (ε-CL), and δ-valerolactone (δ-VL). The ring-opening homoand copolymerization of lactones and lactides can be performed in the bulk or in solution using organometallic catalysts such as aluminum iso-propoxide (Al(OiPr)3), tin(II) 2-ethylhexanoate, (Sn(Oct)2), tin(II) trifluoromethane sulfonate 238 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


(Sn(OTf)2), as well as organic catalysts based on N-heterocyclic carbenes (14, 15). Primary and secondary alcohols and amines effectively initiate polymerization, and give aliphatic polyesters with control over end-group functionality, overall molecular weight, and polydispersity (PDI, defined as Mw/Mn).

Figure 2. Aliphatic polyesters prepared by ring-opening polymerization

A range of mechanical properties and degradation rates can be achieved by copolymerization (2) of the monomers shown in Figure 2. However, many of these aliphatic polyesters are semi-crystalline, hydrophobic solids, and all lack access to functional groups that could otherwise be used to tailor their properties. Thus, methods to integrate functionality into aliphatic polyesters for fine-tuning their physical and biological properties have been sought. Obtaining water soluble polyesters is of particular interest for injectable applications, as are polyesters functionalized with drug moieties, cell-adhesion promoters, and targeting groups for drug-delivery and tissue-engineering applications. A recent development in the utility of aliphatic polysters includes the formation of cyclic polymers, which are anticipated to exhibit numerous distinct properties that contrast linear polymers due the absence of end groups and topological constraints. Two common strategies for the formation of such polymers are cyclization of reactive chain ends (Figure 3a,b) and ring-expansion polymerization (Figure 3c). Cyclization of linear polymers typically requires high dilution in order to favor unimolecular chain-end coupling over intermolecular reactions. Covalent bond formation between chain ends of a single chain is accomplished by introducing catalysts/reagents to heterotelechelic polymers (such as the azide-alkyne click example of Figure 3a) or by adding a difunctional coupling agent to homotelechelic polymers (such as the thiol-maleimide example of Figure 3b). The cyclic topology offers slower hydrolytic degradation because chain scission into linear fragments must occur before further mass loss can take place. 239 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 3. Schematic representation of strategies for forming cyclic polyesters by (a) ring-closing of a heterotelechelic polymer using CuAAC; (b) ring-closing of homotelechelic polymer using thiol-ene chemistry; (c) ring expansion polymerization with a cyclic tin alkoxide catalyst

Strategies for Functionalization of Aliphatic Polyesters Functionalization of aliphatic polyesters is a delicate challenge from the perspective of organic and polymer synthesis, as their degradable nature that renders them desirable as biomaterials also limits the scope of chemical reactions available for successful modification. Consequently, mild synthetic strategies must be employed for controlled functionalization that can proceed in the absence of substantial ester bond degradation. Methods for functionalizing aliphatic polyesters include end-group functionalization of linear polyesters and non-linear polyesters such as dendritic and hyperbranched polymers that contain multiple functional groups as chain-ends. In addition, the introduction of pendent functionality distributed as grafts along a linear polyester backbone affords functional comb-type structures. End-Group Functionalization The simplest functionalization strategy of aliphatic polyesters is achieved at the chain-ends (Figure 4). This can be accomplished using functional initiators for ring-opening polymerization, and/or through end-capping reactions. For example, initiation of lactone polymerization from the chain-end hydroxyl groups of poly(ethylene glycol) (PEG) -diols and -monomethyl ethers produces tri- and di-block copolymers, respectively, that can assemble into micellar structures in water with a polyester core and a PEG corona (16, 17). Other examples of end-capping include esterification of the polyester hydroxyl chain-end with 4-azidobenzoyl chloride to give UV-photocurable polyesters (18), and 240 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


end-capping with phosphorylcholine residues to give polyesters with phospholipid like moieties that reduce protein adsorption relative to non-functionalized polyesters (19).

Figure 4. End-functionalized polyesters: a) poly(ethylene glycol)-b-polyester, b) phenyl azide terminated polyester, and c) phosphorylcholine terminated polyester Chain-end functionalization limits functional group incorporation to one or two groups per polyester molecule. Thus, during polyester degradation, very little of the degraded material remains bound to the functional group of interest. Methods that increase the level of functionality on polyesters have been pursued by several groups, for example by the synthesis of dendritic, hyperbranched and comb-like polyester architectures. Highly Functionalized Dendritic and Hyperbranched Aliphatic Polyesters Non-linear polymer architectures including dendritic, hyperbranched, and linear-dendritic hybrid materials have been prepared as a means of altering polyester properties and introducing high levels of functionality (Figure 5). In addition to the effect of branching on solid-state and solution properties, the large number of end-groups that result from this branching offer the opportunity to obtain very high levels of functional group loading through end-capping reactions. Dendrimers are especially attractive for polymer-based drug delivery, where high drug loading per delivery vehicle is particularly beneficial. Fréchet, Szoka, and coworkers implemented this concept through the synthesis of aliphatic polyester dendrimers with covalently attached drugs such as the chemotherapy drug doxorubicin (Figure 5a) (6, 20). In vivo evaluation of such conjugates demonstrated the improved effectiveness of the dendritic drug carrier relative to the free small molecule drugs. Hyperbranched polymers also provide considerable branching and chain-end functionality, but can be prepared by conventional polymerization chemistry rather than the step-wise coupling approach to dendrimers. Hyperbranched aliphatic polyesters have been prepared by ring-opening polymerization of lactones bearing hydroxyl groups, as seen for example in reports by Hedrick and coworkers on bis(hydroxymethyl)-substituted ε-CL (Figure 5b) (21), as well as by Fréchet and coworkers on ring-opening polymerization of hydroxyethyl-substituted ε-CL (22). Hybrid copolymers consisting of linear and dendritic segments have also been prepared and evaluated 241 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


as biomaterials, for example by Grinstaff and coworkers on photocross-linkable dendritic-linear-dendritic triblocks (Figure 5c) prepared for opthalmic tissue repair applications (10–12). After methacrylate end-capping, the hybrid copolymers were cross-linked to seal corneal lacerations and were found to perform better than nylon sutures.

Figure 5. a) Polyester dendrimer and drug conjugate; b) hyperbranched aliphatic polyester; and c) dendritic-linear-dendritic triblock copolymer Aliphatic Polyesters with Pendent Functionality Functionalization of linear aliphatic polyesters with grafted moieties placed pendent to the polymer backbone has also been explored for integrating the desired functionality into the polymer material. As the introduction of pendent functionality to commercially available aliphatic polyesters presents few synthetic options and carries the risk of polymer degradation, recent work has focused on ring-opening polymerization (ROP) of functionalized lactones. Many substituents present slow lactone ROP, indicated for example by Jérôme and coworkers, where polymerization of a PEG-1,000-substituted ε-CL proved difficult (23). 242 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Consequently, a stepwise approach may be preferred, starting with the synthesis of lactones possessing small substituents that are compatible with ROP, followed by post-polymerization modification of the functionalized polyester products. By copolymerizing functionalized lactones with unsubstituted lactone monomers, the functional group density can be tailored over a wide range. However, conditions chosen for these post-polymerization reactions must be compatible with the polyester backbone to avoid degradation or cross-linking, while successful modification presents many options for polymer tailoring that are not possible in the case of unsubstituted polyesters. Indeed, several examples have been reported, including polyesters with pendent alkyl bromides (24, 25), ketones (26), alcohols (27–29), alkenes (25, 28, 29), alkynes (30), carboxylic acids (27), acrylates (31), 2-bromo-2-methylpropionates (32), PEG (23, 30, 33), dendrons (34), and oligopeptides (30, 35). The remainder of this chapter provides a brief description of a few such synthetic accomplishments, and potential applications for these pendent functionalized aliphatic polyesters, while also examining new catalytic methods for performing ROP of conventional and functional lactones.

Pendent Functionalization of Aliphatic Polyesters as Degradable Synthetic Polymers for Biology The most commonly employed methods for producing functionalized lactones that are amenable to ring-opening polymerization (ROP) include: 1) Baeyer-Villiger ring-expansion of α-substituted cyclohexanones; 2) mono-substitution of 1,6-cyclohexane diol followed by oxidation with pyridinium chlorochromate (PCC), and subsequent ring-expansion using Baeyer-Villiger chemistry; and 3) substitution α to the carbonyl group of lactones, using for example lithium diisopropylamide (LDA) as a non-nucleophilic base, followed by addition of an appropriate electrophile. Taken together, these routes produce variously substituted ε-CL and δ-VL monomers, each having its own attractive features in terms of synthetic ease and versatility for polymerization and subsequent substitution. Hedrick, Jérôme, and coworkers provided early examples of pendent functionalized poly(ε-CL) by polymerization of allyl-functionalized ε-CL monomer 1 (25), prepared from 2-allyl cyclohexanone by Baeyer-Villiger oxidation using meta-chloroperoxybenzoic acid (m-CPBA), (noting olefin epoxidation as an undesired side-product (Figure 6)).

Figure 6. Allyl-functionalized ε-CL (1) prepared from Baeyer-Villiger oxidation of 2-allylcyclohexanone 243 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Lactone 1 was homopolymerized successfully and copolymerized with both ε-CL and L,L-lactide, using Sn(Oct)2 as the catalyst, to give allyl functionalized polyesters shown as 2 in Figure 6, with good agreement of theoretical and experimental molecular weights (3,000-12,000 g/mol) and narrow polydispersities (1.1-1.4). Chemical transformations performed on the pendent allyl groups of polymer 2 included bromination, epoxidation, and hydrosilation reactions to give polyesters 3-5 in Figure 7. In all cases the transformations were achieved in the absence of degradation or cross-linking, demonstrating the compatibility of alkenes with controlled ROP, and the synthetic diversity of aliphatic polyesters upon post-polymerization modification.

Figure 7. Polymerization of lactone 1 and subsequent functional group transformations: bromination (3), epoxidation (4), and hydrosilation (5) Hedrick and coworkers further expanded the diversity of pendent polyester functionalization by the synthesis of hydroxyl and carboxyl containing polymers (8, 9 in Figure 8) from novel lactones, such as protected hydroxyl and acid ε-CL derivatives 6 and 7, respectively, using Sn(Oct)2 catalysis for ROP, and catalytic hydrogenolysis for removal of the benzylidene groups post polymerization (27). Importantly, this deprotection strategy proved compatible with the aliphatic polyester backbone, such that the functionalized polymers could be prepared and isolated efficiently.

Figure 8. Protected hydroxyl (6) and carboxyl (7) monomers and corresponding deprotected polyesters (8,9) 244 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Emrick and coworkers synthesized and polymerized novel lactone monomers substituted α- to the carbonyl group by treatment of δ-VL and ε-CL with non-nucleophilic bases such as LDA (36) and subsequent addition of an electrophile. This strategy led to novel aliphatic polyesters substituted with allyl (28), cyclopentene (29), alkyne (30, 37), and TMS-protected alkyne groups (38) (Figure 9). Lactone monomers 10 and 11 were prepared by deprotonation of δ-VL with LDA, followed by quenching with allyl bromide or propargyl bromide to give the allyl and alkyne derivatives, respectively. Cyclopentene derivative 13 was prepared by ring-closing metathesis of diallyl lactone 12.

Figure 9. Allyl (10), alkyne (11), diallyl (12), cyclopentene (13), TMS-protected alkyne (14) derivatives of δ-valerolactone, and alkyne-substituted ε-caprolactone (15) Lactones 10 and 13 were homo- and copolymerized using Sn(OTf)2 (14) in conjunction with ε-CL or δ-VL as comonomers to give aliphatic polyesters with a controlled density of pendent allyl groups based on comonomer ratio (28, 29). The cyclopentene-susbstituted structures proved uniquely suitable for oxidation (1,2diol formation) and subsequent esterification, giving the first reported example of aliphatic polyester-graft-PEG copolymers with substantial PEG-grafting densities (greater than 20 mol % for PEG-1100) and narrow polydispersities (29). Emrick and coworkers also demonstrated aliphatic polyester functionalization by “click” chemistry using Cu(I)-catalyzed cycloaddition of azides to alkynes (CuAAC), and thiol-ene addition. CuAAC has proven extremely useful in recent years for connecting small molecules, synthetic polymers, and biologically relevant materials (39–41). Sn(OTf)2-catalyzed homopolymerization and copolymerization of alkyne-functionalized lactone 11 (Figure 9) with ε-CL led to novel aliphatic polyesters with tunable degrees of alkyne substitution along the polyester backbone. These polymers proved to be useful precurors for subsequent “click” coupling of azide-containing compounds (30, 42). Key to the success of this concept is stability of the polyester to the click conditions; the polyesters proved amenable to a variety of click type reactions with organic azides. For example, water-soluble polyester-graft-PEG copolymers and polyester-graft-phosphorylcholine (PC) (16 in Figure 10) could be prepared by reaction with azide-functionalized PEG-1100 monomethyl ether and PC-azide, respectively, to give grafting densities ranging from 10 to 100 mole percent for PEG (30) and 20-100 mole percent for PC (42). 245 In Degradable Polymers and Materials: Principles and Practice (2nd Edition); Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 10. Phosphorylcholine-grafted polyesters (16) by post-polymerization click chemistry of alkyne-substituted polyesters

Click coupling also proved useful on alkyne-functionalized aliphatic polyesters for grafting oligopeptide sequences (30), and in the preparation of a polyester-drug conjugate with the cancer drug camptothecin (CPT). In the latter case, the polyester “prodrugs” were rendered water soluble with grafted PEG units (43). This methodology carries a number of benefits relative to other methods discussed thus far, including the relatively easy (one-step) monomer synthesis, the ability to homopolymerize or copolymerize the alkyne-functionalized lactone, and the single post-polymerization step that enables coupling of a very diverse range of azide-functionalized moieties with little-to-no polymer degredation imparted by the mild click conditions. Emrick and coworkers extended this click cycloaddition concept on alkyne-functionalized aliphatic polyesters by exploring orthogonal click reactions for sequential functionalization of a diblock polyester (17 in Figure 11) possessing blocks differentiated by a trimethylsilyl (TMS) protecting group on the alkynes of one block, free alkynes on the other block (38). TMS-propargyl valerolactone was synthesized following the same sequence performed for lactones 10 and 11, by LDA deprotonation and alkylation with TMS-propargyl bromide. Sn(Oct)2-mediated ring opening polymerization of the TMS-propargyl lactone afforded homopolymers with molecular weights ranging from 5,000 to 15,000 g/mol and low polydispersities (

Strategies in Aliphatic Polyester Synthesis for Biomaterial and Drug

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