Читать книгу Poly(lactic acid) - Группа авторов - Страница 99

As mentioned earlier, the macromolecular design of a polymer regulates its physico‐chemical properties. Advanced structures such as combs, brushes, ladders, and so on were synthesized to meet the vast demands from different targeted applications of such polymers. Several graft copolymers based on LA are prepared to modify the properties such as degradability, transition temperatures (T _g and T _m), morphology, mechanical properties, and solubility. Surface characteristics of PLA films were modified by grafting. Micelle structures, having a multifunctional core and hydrophobic shell, were developed with higher drug activity and lower material toxicity. Some of these modifications are described in the following text. The star‐shaped highly branched polymers are discussed separately in Section 4.4.1.

To prepare degradable polymers, graft copolymers of LA acting as macromonomer and t‐butylacrylate were prepared by free radical polymerization. An increase in LA units resulted in an increase in the degradation rate [156]. ATRP of MMA (96.5%) and (meth)acrylate‐terminated LA‐based macromonomer (M _n 2800 g/mol, 3.5%) yielded a homogeneously branched poly(MMA‐g‐LA) of low dispersity (Đ = 1.15) [157]. The reactivity ratio of MMA for conventional radical polymerization is 1.09 while with ATRP is 0.57. This accounted for the lower dispersity of ATRP‐synthesized poly(MMA‐g‐LA).

Degradable comb‐like polymer can be prepared by free radical copolymerization of LA‐based macromonomer with vinyl (N‐vinylpyrrolidone) and acrylic [MMA, methacrylic acid (MA)] monomers [158]. ROP to form PLA is not limited to synthesis of polymer and then fabricate or apply for specific purpose. Even PLA growth can be initiated at the surface via surface‐anchored poly(2‐hydroxyethyl methacrylate) (HEMA), which can then initiate ROP of LA using Sn(Oct)₂ as a catalyst. An overall “bottle‐brush” structure of the polymer was obtained due to the formation of surface‐anchored poly(hydroxyethyl methacrylate‐g‐LA) [159].

PLA and its random copolymer with GA are grafted onto poly(vinyl alcohol) to increase hydrophilicity and manipulate the structure [160]. A novel comb‐type PLA was prepared using a depsipeptide–lactide random copolymer having pendant hydroxyl groups as macroinitiator for graft polymerization of LA. The comb‐type polymer had a lower T _g, T _m, and crystallinity than linear PLA [161].

A graft copolymer of poly(NIPAAm‐co‐methacrylic acid)‐g‐DLLA, [poly((NIPAAm‐co‐MAAc)‐g‐LA)], along with diblock copolymers of DLLA and EG and poly(2‐ethyl‐2‐oxazoline) was used for the formation of mixed micelles with a multifunctional core and core/shell morphology. These micelles exhibited higher drug activity and lower material cytotoxicity than micelles based on formulation without the inclusion of diblock copolymers [162]. This formation of nanostructure allowed screening of the highly negative charges (due to the carboxylic groups) in the pristine graft copolymer.

New thermoresponsive, pH‐responsive, and degradable nanoparticles comprising poly[DLA‐g‐(NIPAAm‐co‐methacrylic acid)] were prepared by grafting PDLA onto NIPAAm‐co‐methacrylic acid copolymer. A core–shell structure was formed with a hydrophilic outer shell and a hydrophobic inner core that exhibited a phase transition temperature above 37°C. The drug loading level of 5‐fluorouracil (5‐FU) as encapsulated nanoparticles from these copolymers could be as high as 20%. The release of 5‐FU was controlled by the pH in the aqueous medium. These studies indicated that these nanoparticles can be used as a drug carrier for intracellular delivery of anticancer drugs [163].

In biological systems, an organism can create the proper organic matrix as a substrate for the nucleation and growth of inorganic crystals due to the interfacial interaction between inorganic and organic phases. In analogy, in vitro fabrication of novel inorganic/organic composites holds special relevance in several biomedical fields more specifically in implants/bone regeneration. Such applications demand appreciable interactions at the interface of the two; demanding appreciable biocompatibility and favourable bioactivity to induce growth of bone cells. To provide abovementioned benefits, ceramics (hydroxyapatite) along with PLA modified with other functionalities such as carboxyl groups found to mediate the process. This interaction assisted the nucleation sites of HA crystals and may be used as a template to manipulate and control the growth and size of HA crystals necessary for bone growth. To affect the surface characteristics, photoinduced grafting appeared as a useful technique due to its usual advantages. Solvent cast PLA films were modified by grafting with vinyl acetate, acrylic acid, and acrylamide by a UV‐induced photopolymerization process [164]. For the same purpose, PLA surfaces have also been modified by grafting poly(methacrylic acid) via photooxidation followed by UV‐mediated polymerization. Thus, the introduced carboxyl groups due to MMA onto PLA surfaces acted as the nucleation sites of hydroxyapatite crystals. Nanohydroxyapatite/PLA composites with interfacial interaction between the two phases were prepared using these graft copolymers [165]. FTIR, XRD, and SEM studies supported that the modified PLA could act as a template to control the nucleation, growth, morphology, size, and distribution of hydroxyapatite crystals over the organic phase.

A thermoplastic polyolefin (TPO), more specifically TPO‐g‐PLA was prepared by grafting PLA onto maleic anhydride‐functionalized TPO in the presence of 4‐dimethyl aminopyridine (DMAP). A high reaction temperature and a high DMAP concentration resulted in the polymerization of LA. These copolymers were used as a compatibilizer for PLA/TPO blends. An increase in concentration of this copolymer from 0 to 2.5% resulted in an increase in elongation at break and tensile toughness of the blends [166].

Butanediamine (BDA)‐g‐PDLLA was synthesized by grafting maleic anhydride onto the side chains of PDLLA via melt‐free radical polymerization using benzoyl peroxide as initiator. BDA was then grafted via an N‐acylation reaction. The degradation behavior of these graft copolymers could be controlled by the content of BDA. Grafting of BDA onto PDLLA reduced or neutralized the acidity of PDLLA degradation products due to dangling amine component. Also a uniform degradation of these copolymers was observed in comparison with an acidity‐induced auto‐accelerating degradation featured by PDLLA [167].

New amphiphilic graft copolymers of hyaluronic acid (HA) were prepared by grafting both hydrophobic (PLA) and hydrophilic branches (PEG) on the PLA backbone. The copolymers (PLA‐g‐HA‐g‐PEG) were characterized by spectroscopic techniques. Branched PLA with various lengths of graft chains were synthesized by ROP of L‐ or D‐lactide with polyglycidol as an initiator [168]. The branched PLLA revealed a lower T _g, T _m, crystallinity, and Young’s modulus and higher strain at break than the corresponding linear PLLA or PDLA film.

The PLA surface was chemically modified by a single‐step, nondestructive grafting technique using vinyl monomers such as acrylamide, maleic anhydride, and N‐vinylpyrrolidone in the vapor phase. Benzophenone was used as a photo‐initiator under solvent‐free conditions. The modified surfaces exhibit higher wettability, and the grafting was verified by X‐ray photoelectron spectroscopy, attenuated total reflection, FTIR, contact‐angle measurements, and scanning electron microscopy. The graft chain pendant groups remain functional and can subsequently be modified so that a tailor‐made surface with desired properties may be achieved [169].

Acrylic‐acid‐grafted PLA (PLA‐g‐AA) and multi‐hydroxyl‐functionalized multiwalled carbon nanotubes are melt blended to improve thermal stability and mechanical properties of the composite. The formation of a covalent bond (ester linkage) resulted in a significant improvement in compatibility [170]. Alternatively, carboxylic acid‐functionalized multiwalled carbon nanotubes were grafted onto PLLA by a one‐step in situ polycondensation reaction [171]. Acrylic‐acid‐grafted PLA, titanium tetraisopropylate, and starch blends were prepared by an in‐situ sol–gel and melt blending processes. The carboxylic acid groups of acrylic acid act as a coordination site for the titania phase to form a Ti—O—C chemical bond. This resulted in a nano‐scale dispersion of TiO₂ in the polymer matrix [172].

PLA‐g‐dextran having various lengths and number of grafted chains and sugar units were synthesized using the trimethylsilyl protection method. The surface of these films is believed to be covered with hydrophilic dextran segments, which led to the suppression of cell attachment and protein absorption onto the film [173–175]. In another study, PLA‐g‐dextran copolymers were synthesized by a three‐step process: partial silylation of the dextran hydroxyl groups, ROP of DLA initiated by the remaining hydroxyl groups of dextran, followed by silyl ether deprotection under mild conditions. The emulsifying properties of these glycopolymers depend on the PLA/dextran ratio [176]. PLA‐g‐dextran and PLA‐g‐silylated dextran adopt a core–shell conformation in various solvents [177]. Studies on encapsulation and release behavior of bovine serum albumin from PLA‐g‐dextran revealed a higher loading than in PLLA microspheres [178].

Studies on gelatin‐g‐PLA were extensively reported in the literature. These degradable, in general, amphiphilic polymers are useful for parenteral drug delivery systems and tissue engineering. These copolymers were prepared by the ROP of LLA onto functionalized gelatin using bulk copolymerization at 140°C or solution copolymerization at 80°C with Sn(Oct)₂ as the catalyst. The number of grafting sites on the gelatin chain could be adjusted by partial trimethyl silylation of pendant hydroxyl, amino, and carboxylic acid groups [179].

Novel triblock copolymer PLGA‐PEG‐PLGA showed a pH‐dependent hydrolytic degradation with itaconic acid (ITA), obtained from renewable resources, delivers a reactive double bond and carboxylic functional group to the end of PLGA‐PEG‐PLGA. The so obtained carboxylic groups containing copolymer (ITA/PLGA‐PEG‐PLGA was found to be more susceptible to hydrolytic degradation than the unmodified copolymer as reflected with nearly 45% decrease in M _n value (in initial 10 days) when kept at pH 7.4 [180].

PLA lacks reactive functional groups and the presence of the polyester backbone limits further modification to alter its chemical and physical properties and advocate its applicability to vast domain. To overcome this limitation, PLA bearing functional side chains such as alkenes, alkynes, hydroxyl, amino, carboxylic acid, thiol, and azido groups have been prepared [105,181–185]. Among these, azide or alkyne groups are valuable addition in its structure as it allows a facile coupling azide–alkyne [3 + 2] cycloaddition “click” chemistry under mild conditions. For example, pendant azide groups in PLA were reduced to amine to assist further modification to quaternary ammonium groups using copper‐catalyzed [3 + 2] cycloaddition reaction. The resultant polymer showed an enhanced antimicrobial activity both in suspension and as a film [186]. Amphiphilic brush‐grafted copolymers of PLA‐g‐POEGMA [POEGMA, poly[(oligoethylene glycol) methacrylate] revealed a molecular architecture upon assembly, which increase their potential as drug delivery carriers. The copolymer was prepared by ATRP of oligo(ethylene glycol) methacrylate (OEGMA) macromer using brominated PLA (Br‐PLA) as a macroinitiator [187].