Synthesis and properties of novel diisopropyl-functionalized polyglycolide–PEG copolymers

Abstract

Because of the importance of glycolide-based polymers in materials and medical applications, we synthesized alternative novel thermosensitive biomaterials to be possible candidates to those well-known polymers. After the synthesis of ldiisopropyl glycolide monomer was performed in two steps, novel PEG based poly(diisopropyl glycolide) diblock and triblock copolymers (MePEG-PDIPG, PDIPG-PEG-PDIPG) were synthesized with high conversions by ring opening polymerization. The molar mass distributions of copolymers were very narrow, and NMR measurements confirmed no racemization in polymer synthesis even at 180 °C. Gel-sol experiments were studied after each component's length in MePEG-PDIPGand PDIPG-PEG-PDIPG was adjusted with care during the synthesis. The polymer showed a sol property at 42-45 °C, which is suitable for the injection and a gel property at body temperature. After loading paclitaxel into gels effectively, the anticancer drug showed prolonged release (60 days). SEM analysis confirmed that when release time proceeded, gels turned into more porous structure due to drug release.

Poly(asymmetrical glycolide)s: The Mechanisms and Thermosensitive Properties

“…This is where poly­(substituted glycolide)­s (PSG) come into play. PSG, prepared from either symmetrical or asymmetrical glycolide monomers, can be utilized to reveal demanded properties such as morphology and drug release for thermogelling applications. , Symmetrical glycolides can be prepared from the dimerization of functional α-hydroxy acids in the presence of p -toluenesulphonic acid under reflux temperature. However, longer reaction times (up to 20 days) and lack of monomer diversity to be synthesized are major disadvantages of the symmetrical glycolides. − On the other hand, asymmetrical glycolide monomers can be synthesized in two basic steps: (i) condensation of functional α-hydroxy acids with α-haloacyl halides (or α-halocarboxylic acids) and then (ii) the ring cyclization reaction of halogenated acid in the presence of sodium carbonate/bicarbonate.…”

“…The copolymerizations of substituted glycolides with PEG have attracted considerable interest in recent years due to providing notable characteristics like forming injectable hydrogels or stable micelles by controlling hydrophobicity and crystallinity. ,,− d , l -3-methyl glycolide, an asymmetrical glycolide monomer, was copolymerized with PEG in the presence of Ca­[N­(SiMe 3 ) 2 ] 2 (THF) 2 catalyst to obtain thermoresponsive poly­( d , l -3-methyl glycolide)- block -poly­(ethylene glycol)- block -poly­( d , l -3-methyl glycolide) (PMG-PEG-PMG) copolymers . These copolymers showed sol to gel transition property or an increase in viscosity without gel formation with increasing temperature.…”

“…These copolymers showed sol to gel transition property or an increase in viscosity without gel formation with increasing temperature. However, the copolymers having low molecular weights (less than 5000 g/mol) were synthesized in a glove-box system in the presence of high loadings of catalyst where its synthesis requires a couple of steps. ,− Symmetrical diisopropyl glycolide monomer (DIPG) was also prepared from l -valine in two steps and used for the synthesis of MePEG-PDIPG diblock and PDIPG-PEG-PDIPG triblock copolymers via ring-opening polymerization (ROP) in the presence of Sn­(Oct) 2 catalyst in order to examine gel to sol characteristics . The polymerization needs much more energy because of having a very high melting point of DIPG monomer around 160 °C.…”

“…The polymerization needs much more energy because of having a very high melting point of DIPG monomer around 160 °C. The prepared paclitaxel-loaded thermosensitive copolymer gels displayed a slow drug release (up to 57% in 2 months) due to the semi-crystalline structure of PDIPG units, which forms a barrier for the diffusion of drug. , There is also an interest in poly­(hexyl-substituted glycolide)-PEG (MePEG-hexPLA) micelles as drug delivery carriers as well. − ,, These micelles have a good stability in aqueous solution at room temperature, and they showed a higher drug loading capacity with hydrophobic drugs like griseofulvin and photosensitizers like meso -tetra­( p -hydroxyphenyl)­porphine (THPP) , due to the more hydrophobic nature of hexyl-substituted glycolide compared to standard MePEG-PLA micelles. However, the long hexyl group as the side chain slows the polymerization compared to the methyl group (lactide) and causes to synthesize low-molecular-weight block copolymers (<10 kDa). , …”

“…The existence and number of a secondary β-carbon atom on the alkyl side chain play a critical role in the polymerization of substituted glycolides. Thanks to having a less hindered secondary β-carbon atom (R 2 CH 2 ) at only one side of the ring, IBL 4 displayed the highest reactivity in the copolymerization with PEG among other glycolide derivatives such as diisobutyl glycolide (DIBG), diisopropyl glycolide, and isopropyl lactide monomer. We recently reported symmetrical DIBG copolymers exploring its nanoparticle formulations .…”