4.2.9 Polypeptide
Hybrid copolymers constituted by short L‐phenylalanine (Phe) n blocks (n ranging from 2 to 25) and LLA blocks of different length have been synthesized by ROP of LA using a Phe‐oligopeptide as macroinitiator. A variable morphology from lozenge, flower‐like, fibrillar structures, spheres, ringed spherulites, dendritic, microfibers, to braid‐like microstructures was observed due to self‐assembly of Phe‐oligopeptides in the copolymer [131].
Recently amino‐acid‐based morpholine‐2,5‐diones (MD copolymerized with lactide using DBU : thiourea (TU) catalyst : co‐catalyst system to form an interesting class of bio‐based degradable polymers with low dispersity (8.1–25.2 kDa and Đ = 1.13−1.18) in short periods (5–10 min.) [132]. Ring‐strain in monomer was found to affect the rate of homo‐ vs hetero‐propagation of monomer units and dictated the nature and richness of units in the polymer backbone. As noticed, LLA exhibited a higher ring‐strain compared with 3S,6S‐dimethylmorpholine‐2,5‐dione (DMMD) monomer and thus LLA rapidly homopropagated at a higher rate, resulted in the formation of longer LLA block. This provided a platform for the selective incorporation of α‐amino acids along a hydrolyzable polymer backbone, mimicking peptide that holds significant potential in biological applications. On the contrary, reverse behavior was observed in case of DMMD as it favored heteropropagation with LLA units [133]. In another work comparing “grafting to” versus “grafting from” strategies, the former appeared to be more successful at covalently linking the peptide to thiol functionalized PLA using thiol‐ene click chemistry mediated by AIBN initiator [134]. Core‐shell molecular bottlebrushes with a wormlike conformation related to the retention of the α‐helical conformation of poly(L‐glutamate) backbone obtained as side chains through the “grafting to” strategy on PLA‐b‐PEG copolymer was obtained using azide‐alkyne cyclo‐addition reaction [135]. Degradable poly[LA‐b‐(N‐ɛ‐carbobenzyloxy‐L‐lysine)] copolymers were obtained using LLA macroinitiators and led to controlled polymerizations with low dispersity [136]. Star‐PLA bearing triethoxysilyl propyl groups and bifunctional silylated peptides found to react via sol‐gel process to form cross‐linked networks [117].
4.3 FUNCTIONALIZED PLA
PLAs having amino, carboxyl, or other functional (pendant or chain end) groups are well reported in the literature. These functional groups can be utilized for chemical modification or as binding sites for biomolecules to impart selective binding and adhesion. ROP of LLA or DLA using bis(hydroxymethyl) butyric acid (BHMBA) as an initiator and Sn(Oct)2 as a catalyst at 130°C yielded PLA with pendant carboxyl groups. The chain extension of this polymer with diisocyanate yielded poly(ester–urethane) containing carboxyl groups as pendant functional groups [137].
Thiol‐functionalized PEG‐b‐PLA was prepared by ROP of DLA using PEG disulfide as the macroinitiator. The disulfide bond was cleaved using tributylphosphine to generate a block copolymer having a thiol unit at the PEG end [138]. Finne‐Wistrand and coworkers [139] utilized thiol chemistry to form redox responsive PLA‐b‐PEG nanoparticles. In addition, peptide‐functionalized porous scaffolds were prepared by disulfide exchange reaction of pendant thiol groups in poly(LLA‐co‐CL) [140].
Functionalization of PLA by grafting of maleic anhydride (MAn) has been carried out in the presence of free radical initiators (tert‐butyl peroxide and dicumyl peroxide) [141]. The presence of high succinic anhydride units in the grafts was confirmed by FTIR and NMR. Low percentage grafting was observed in PLA due to the presence of limited free radical sites [142].
Finne and Albertsson introduced a double bond in PLA by using 1,1‐di‐n‐butyl‐stanna‐2,7‐dixacyclo‐4‐heptene as initiator [143, 144]. The presence of a double bond in the LA macromonomer provided a variety of opportunities for further modification. For example, epoxidation was carried out with m‐chloroperoxybenzoic acid (mCPBA) and a quantitative conversion of the double bond to epoxide was observed.
PLA‐functionalized polyoxanorbornenes with one or two exo‐PLA chains, as well as two endo‐, exo‐chains were prepared using Sn(Oct)2 as a catalyst in the presence of mono‐ or di‐alcohol derivatives of oxanorbornenes [145]. These macromonomers were then subjected to ring‐opening metathesis polymerization (ROMP) to yield graft copolymers as shown in Figure 4.12.
A sequential ROP and ROMP reaction was carried out in the same pot to yield well‐defined bottlebrush polymers. The process involved the synthesis of an LA‐based macromonomer via ROP of DLA initiated by an alcohol‐functionalized norbornene. This was followed by ROMP grafting‐through process in the same pot to produce the bottlebrush polymer architecture [146]. Simple one‐pot synthesis of block copolymers of norbornene and LA using a bifunctional initiator based on a ruthenium complex for the ROMP of norbornenes and an alcohol to initiate ROP of LLA using 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) as a catalyst is also reported [147]. Low molar mass oligoLAs end capped with fumarate groups were used for in situ cross‐linkable scaffolds for tissue engineering [148]. Side‐chain functionalized diastereomeric LAs were synthesized from commercially available amino acids and their subsequent polymerization or copolymerization [108]. This approach allows the incorporation of any protected amino acid for the preparation of functionalized cyclic monomers. The quantitative deprotection of amino acids lead to the formation of new functionalized LA‐based polymers.
Protected functional LA copolymers can be synthesized by copolymerization of dibenzyloxy‐substituted monomers with LA. Deprotection followed by modification with succinic anhydride with carboxyl side chains was shown to be suitable for peptide coupling. Such a modification can control the attachment of cells in tissue engineering and other biomedical applications [109].
FIGURE 4.12 Synthesis of oxanorbornenes and LA‐based copolymers [145].
4.4 MACROMOLECULAR DESIGN OF LACTIDE‐BASED COPOLYMERS
Studies on copolymers with LA having a core of LA (or another comonomer) and branches of another monomer (or LA comonomer) have been extensively reported in the literature. Graft copolymers having different architectures (linear branches, hyperbranched, star‐like, brush‐like, and comb‐like) were synthesized to modify the properties of PLA. The hydrophilicity or crystallinity of these copolymers can be varied and controlled by preparing such architectures. A general reaction for the preparation of such copolymers is depicted in Figure 4.13.
Branched PLA is different from linear PLA in physical, thermal, and mechanical properties. Such polymers were prepared by using multifunctional alcohols, for example, inositol, pentaerythritol, glycerol, and so on [149–154]. Finne and Albertsson prepared four‐arm star‐shaped PLLA using novel spirocyclic tin initiators [149]. Kricheldorf et al. [150] polymerized LLA using bismuth triacetate and pentaerythritol as initiator and co‐initiator, respectively. Kim et al. [151] and Arvanitoyannis et al. [152] used Sn(Oct)2, tetraphenyl tin and pentaerythritol, respectively, as the initiator and co‐initiator system for LLA polymerization. Similarly, Korhonen et al. [153] reported star‐shaped polymers using co‐initiators containing multiple hydroxyl groups.
As can be seen, many types of branched PLA are prepared by using organometallic catalysts and multifunctional alcohols. Figure 4.14 shows