FIGURE 4.6 Synthetic route for the preparation of cholesterol–PEG–PDLA [37].

      Triblock comb‐like copolymer containing fluorophilic, lipophilic, and hydrophilic units was obtained by first ROP of LA with polyethylene glycol methyl ether to form diblock copolymer, which was subsequently converted to macroinitiator to promote atom transfer radical polymerization (ATRP) of heptadecafluorodecyl methacrylate (FMA). Small‐angle neutron scattering of poly(PEG‐b‐LA‐b‐FMA) bearing distinct numbers of perfluorinated pendant chains (5–20) confirmed existence of an outer shell of fluorinated polymer, which led to the formation of a nanocapsule morphology [99].

Cholesterol‐tethered polymers found utility for attachment of cells. Cholesterol‐linked PEG–PDLA copolymer was reported to promote osteoblast attachment and proliferation [37]. The existence of 5 and 15 ethylene glycol units in the copolymer promoted osteoblast attachment and growth, while incorporation of 30 ethylene glycol units prevented adhesion and proliferation. The strategy adopted for the synthesis of above copolymer is presented in Figure 4.6.

      Stupp et al. [100] synthesized low molar mass oligomers of cholesterol‐(L‐lactide) _n with n ≤ 20 in bulk conditions at 150°C. The cholesterol end group induced liquid crystalline properties and ensured self‐assembly of the oligomers, which may be beneficial for interaction with the cells and provide opportunities to introduce additional bioactive substituents.

In general, additional ring‐substitution on lactide affects polymerization behavior detrimentally. For example, trimethyl GA requires a very higher temperature (180°C) and longer reaction time (24 h) than GA [101]. While tetramethyl GA due to high degree of substitution did not polymerize in the presence of Sn(Oct)₂ [102]. However, existence of different functional groups as a side chain in poly(α‐hydroxy acid)s is interesting and provide avenues for further structural modification and exploration in various application. Certain groups such as alkene [103], allyl [104], alkyne [105, 106], carboxylic acid [107–110], hydroxyl [111], and amine [112, 113] is of profound interest as it allows further structural modifications. Mert et al. [114] reported a viable methodology for the formation of amine‐functionalized PLA‐PEG copolymers as shown in Figure 4.7.

      PEG‐grafted PLA is usually obtained by post‐polymerization modification process via typical Huisgen cycloaddition reaction [105], initially D,L‐lactide is polymerized in the presence of allyl glycidyl ether followed by subsequent PEG functionalization [115]. PEG‐grafted PLA can be synthesized either based on the condensation of hydroxy acids with PEG side chains [116], or by typical ROP reaction of PEG‐grafted lactide analogues [117].

Recently, ROP‐induced crystallization‐driven self‐assembly (CDSA) of block copolymer, PLLA‐b‐PEG, prepared by ROP of LLA using a monofunctionalized PEG initiator in toluene, and triazabicyclodecene (TBD) as a catalyst is reported. The polymerization time observed was much shorter than the self‐assembly relaxation time, which resulted in a nonequilibrium self‐assembly process. Traditionally, such self‐assembly by CDSA typically occurred in dilute solutions (~1% solids w/w); however, above method allowed realization of such architectural growth at an extremely high solid (5–20% w/w) content [118].

FIGURE 4.7 Synthesis of protected and deprotected block copolymers. Polymerization mechanism of asymmetrical monomer with methylated PEG [114].

FIGURE 4.8 Star‐shaped copolymers of LA [119].

      4.2.3 δ‐Valerolactone and β‐Butyrolactone

      There has not been much research considering copolymerization of LA with δ‐valerolactone (VL) and β‐butyrolactone (BL). Anionic block copolymerization of VL and LLA in the presence of potassium methoxide in THF at 20°C gave diblock copolymers with expected compositions and molar mass [49]. Slight racemization of LLA was observed during polymerization due to transesterification reactions.

      Block copolymers of LA and BL have been prepared by first preparing a hydroxyl‐terminated poly(β‐butyrolactone) (PBL). The ROP of (R)‐BL or (RS)‐BL with distannoxanes as catalyst in the presence of 1,4‐butanediol as initiator gave optically active poly[(R)‐BL] or atactic poly[(RS)‐BL] with secondary hydroxyl chain ends and oxytetramethylene units in the backbone. These polymers may be used to initiate the copolymerization of LA at the chain ends and form block copolymers. The optically active poly[(R)‐BL] was found to be brittle, whereas atactic poly[(RS)‐BL] showed elastomeric properties. Thus, ROP of [RS]‐βBL with LLA could be used to prepare elastomeric copolymers, which may alleviate brittle behavior of pristine PLLA. However, utility of Sn(IV) compounds is known as active transesterification catalysts and may cause scrambling of monomer units when LLA is used as a comonomer. Therefore, a two‐stage polymerization was carried out. In the first step, telechelic poly[(RS)‐BL] in the molar mass range of 5000–12,000 g/mol was prepared at 100°C by maintaining the desired molar ratios of (RS)‐BL and 1,4‐butanediol and using Sn(IV) as catalyst. In the second stage, the desired ratio of hydroxyl‐terminated poly[(RS)‐BL] and LLA monomer was added and Sn(Oct)₂ was used as a catalyst and polymerization is carried out at 160°C [47]. Hori et al. [45] have also presented research about the synthesis of random copolymers using LLA and (R)‐BL.

Various mono and bisbenzylalkoxy‐bridged dinuclear indium complexes were explored as catalysts to form poly(hydroxybutyrate) (PHB) and star‐shaped block copolymer, PHB‐b‐PLA, in the presence of branched alcohols suggests nature of catalyst governs the formation of macromolecular architecture (Figure 4.8) [119].

      4.2.4 ε‐Caprolactone

      Copolymerization of LA and CL has been extensively established [51–58]. Random copolymers of DLLA (r ₁ = 10.8) and CL (r ₂ = 0.37) were prepared by using lanthanide halides as initiators [55]. High molar mass copolymers

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