Читать книгу Poly(lactic acid) - Группа авторов - Страница 89

The unique properties of PEG, such as solubility in water and polar organic solvents and its insolubility in nonpolar solvents such as ethyl ether and heptane, lack of toxicity, rapid clearance from the body [32], high mobility, and FDA approval of PEG based medical device or formulation for internal consumption, make it a suitable polymer for the preparation of block copolymers of LA or LA–GA. Copolymers of LLA with hydrophilic poly(ethylene oxide) and/or poly(propylene oxide) are vastly reported [25, 43, 44]. Several triblock copolymers of LLA, D,L‐lactide (DLLA), and PEO, with PEO as the central block are reported in the literature [24]. These copolymers are more hydrophilic, flexible, and revealed a higher tendency to degrade than PLLA homopolymer [40]. The hydrophilic domains generated by the EO‐based blocks act as surface modifier of hydrophobic LA‐based domains of the microspheres and thus promote the stability of water‐soluble molecules (e.g., λ‐DNA) with efficient loading within these microspheres. The degradability and biocompatibility of these copolymers make them suitable candidates for controlled delivery of water‐soluble molecules [39]. Diblock and triblock polymers were prepared by bulk or solution polymerization using stannous chloride [39], Sn(Oct)₂ [28, 35, 36], potassium tert‐butoxide [91], sodium hydride [29], calcium hydride/Zn [34], or zinc metal [38] as catalysts. Block copolymers were also prepared in the absence of added catalyst [31].

High polymerization temperatures generally reduce the molar mass of the PLLA [35]. A wide range of copolymers were prepared by varying the molar mass of PEG (1000–30,000 g/mol) and LLA/PEG ratio in the initial feed. A representative structure of such triblock copolymers is depicted in Figure 4.4. The resultant triblock copolymers showed phase separation, due to the hydrophobic and hydrophilic nature of the segments in the polymer backbone, as shown by differential scanning calorimetry (DSC) and wide‐angle X‐ray scattering analysis (WAXS) studies.

Synthesis and applications of copolymers obtained by adding LA to PEG is widely reported in the literature [92–96]. Transesterification reaction of PLA (M _w 5000–400,000 g/mol) with poly(alkylene ethers) (M _w 500–50,000 g/mol) having ≥1 OH per polymer unit was carried out under melt conditions in the presence of Ti(OBu)₄ as a catalyst at 200°C to obtain a high molar mass PLA copolymer. The obtained copolymer showed better flexibility, transparency than that obtained by ROP of lactide in the absence of the above‐mentioned polyalkylene glycol [97]. A synthetic strategy for the preparation of ABA triblock copolymers, consisting of poly(LLA‐co‐GA) and PEG synthesized under bulk conditions, is shown in Figure 4.5 [27].

FIGURE 4.4 Representative structure of triblock copolymer based on LLA and PEG [35].

LA has also been reacted to poly(propylene glycol)diglycidyl ether (PPGDGE₃₈₀) using Sn(Oct)₂ as catalyst. The resultant copolymers showed a range of properties, from weak elastomeric property to tougher thermoplastics, and it was tuned by the feed ratio of LLA and PPGDGE₃₈₀. The obtained copolymers were found to be more hydrophilic than neat PLA [98].

FIGURE 4.5 Schematic diagram of the synthesis of ABA triblock copolymer using aluminum triisopropoxide as a catalyst [27].

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].