Poly(asymmetrical glycolide)s: The Mechanisms and Thermosensitive Properties Duygu C ̧ etin, Mehmet Onur Arıcan, Halime Kenar, Serap Mert, and Olcay Mert* Cite This: https://dx.doi.org/10.1021/acs.macromol.0c01893 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: A new highly reactive isobutyl lactide monomer (IBL) was synthesized with the ring closing of halogenated carboxylic acid acquired by the reaction of (S)-2-hydroxy-4-methylpentanoic acid with 2-bromopro- pionyl bromide. A desired thermosensitive and injectable PEG-based poly(isobutyl lactide) di- and triblock copolymers (MePEG-PIBL and PIBL-PEG-PIBL), a promising alternative to customary PEG-based PLA and PLGA block copolymers, have been synthesized with narrow polydispersities as low as 1.08, high conversions up to 99%, and suitable hydrophilic/ hydrophobic balances for gel-sol applications by ring-opening polymer- ization at 120 °C. The polymerization rate of MePEG-PIBL was found to be the highest among other PEG-based substituted glycolides (MePEG- PDIBG, MePEG-PIPL, and MePEG-PDIPG) due to having a single and less hindered secondary β-carbon atom (R 2 CH 2 ) in IBL. The mechanism of poly(asymmetrical glycolide)s was also illuminated by single-frequency decoupled 1 H NMR, 13 C NMR, and optical rotation analyses by taking into account the effect of substituents on symmetrical and asymmetrical glycolides. PIBL units of the block copolymers showed an amorphous phase, critical for desired drug release rate, in thermal analyses. Thus, PIBL-based copolymer gels displayed a more effective release profile of paclitaxel (up to 57%) than semi-crystalline PLLA-PEG gels (up to 5.7%) in 2 weeks. The location of PEG, present as an internal or lateral component in copolymers, also affected the rate of hydrolitic degradation (34.6% vs 23.7% degradation of PIBL units in di- and triblock copolymers, respectively). According to the results of cell viability assays (WST-1 test and live/dead assay), where L929 and human primary dermal fibroblasts were tested, the triblock copolymer did not cause any cell damages or cell morphological changes in all concentration ranges tested (0.1-3.0 mg mL -1 ). The aqueous solutions of these copolymers exhibited very well temperature-dependent reversible gel-sol transitions for use in a localized drug delivery system. ■ INTRODUCTION Chemotherapy aims the obstruction of proliferation of cancer cells, the prevention of invasion of tumor cells into other locations in the body, and lastly, the elimination of the tumor. 1 Cytotoxic effects of many anti-cancer drugs in common chemotherapy are not only confined to tumor cells but also unwanted toxicity is usually observed in healthy tissues. 2,3 On the contrary, local drug delivery systems provide desired local drug concentrations at the tumor site with no significant systemic toxicity. 4 Especially, thermosensitive biodegradable hydrogels composed of hydrophobic (i.e., PLGA, PLA) and hydrophilic (i.e., PEG) blocks have been extensively used as drug carriers for these systems. 5-14 PEG-PLGA-PEG and PLA- PEG-PLA triblock copolymers can be preferred in a long-term local drug delivery because the aqueous solution of these copolymers forms a gel in situ when subcutaneously injected into rats and mice, 15,16 and these transparent gels displayed a good integrity for over 1 month 15 with no significant cytotoxic effects on the surrounding connective and muscular tissues. 16 However, PLA-based copolymers are not perfectly suitable for use in a short-term local drug delivery applications due to the characteristics of PLA segments like crystallinity, 17 leading to subsequent precipitation in solution 18 and a slow rate of degradation. 17,19 In addition, because of the sticky paste morphology of thermosensitive PLGA-based materials, weigh or transfer processes of these polymers are quite difficult. 20 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. 21,22 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. 23-30 On the other Received: August 14, 2020 Revised: November 18, 2020 Article pubs.acs.org/Macromolecules © XXXX American Chemical Society A https://dx.doi.org/10.1021/acs.macromol.0c01893 Macromolecules XXXX, XXX, XXX-XXX Downloaded via AUCKLAND UNIV OF TECHNOLOGY on December 15, 2020 at 11:35:55 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.