Lages Maëlle, Pesenti Théo, Zhu Chen, Le Dao, Mougin Julie, Guillaneuf Yohann, Nicolas Julien
Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay 17 Avenue des Sciences 91400 Orsay France
Aix-Marseille-Univ., CNRS, Institut de Chimie Radicalaire UMR 7273 F-13397 Marseille France.
Chem Sci. 2023 Mar 6;14(12):3311-3325. doi: 10.1039/d2sc05316k. eCollection 2023 Mar 22.
Radical ring-opening polymerization (rROP) has received renewed attention to incorporate cleavable linkages into the backbones of vinyl polymers, especially from cyclic ketene acetals (CKAs). Among the monomers that hardly copolymerize with CKAs are (1,3)-dienes such as isoprene (I). This is unfortunate since synthetic polyisoprene (PI) and its derivatives are the materials of choice for many applications, in particular as elastomers in the automotive, sport, footwear, and medical industries, but also in nanomedicine. Thionolactones have been recently proposed as a new class of rROP-compatible monomers for insertion of thioester units in the main chain. Herein, we report the synthesis of degradable PI by rROP the copolymerization of I and dibenzo[,]oxepane-5-thione (DOT). Free-radical polymerization as well as two reversible deactivation radical polymerization techniques were successfully used for the synthesis of (well-defined) P(I--DOT) copolymers with adjustable molecular weights and DOT contents (2.7-9.7 mol%). Reactivity ratios of = 4.29 and = 0.14 were determined, suggesting preferential incorporation of DOT in comparison to I. The resulting P(I--DOT) copolymers were successfully degraded (from -47% to -84% decrease in ) under basic conditions. As a proof of concept, the P(I--DOT) copolymers were formulated into stable and narrowly dispersed nanoparticles, showing similar cytocompatibility on J774.A1 and HUVEC cells compared to their PI counterparts. Furthermore, Gem-P(I--DOT) prodrug nanoparticles were synthesized by the "drug-initiated" method and exhibited significant cytotoxicity on A549 cancer cells. P(I--DOT) and Gem-P(I--DOT) nanoparticles were degraded under basic/oxidative conditions by bleach and under physiological conditions in the presence of cysteine or glutathione.
自由基开环聚合（rROP）已重新受到关注，旨在将可裂解键引入乙烯基聚合物主链中，尤其是通过环状乙烯酮缩醛（CKA）来实现。在难以与CKA共聚的单体中，包括异戊二烯（I）等（1,3）-二烯。这很遗憾，因为合成聚异戊二烯（PI）及其衍生物是许多应用的首选材料，特别是在汽车、体育、鞋类和医疗行业用作弹性体，在纳米医学中也有应用。硫代内酯最近被提议作为一类新的与rROP兼容的单体，用于在主链中插入硫酯单元。在此，我们报告了通过rROP合成可降解PI，即I与二苯并[，]氧杂环庚烷-5-硫酮（DOT）的共聚。自由基聚合以及两种可逆失活自由基聚合技术成功用于合成具有可调分子量和DOT含量（2.7-9.7 mol%）的（结构明确的）P（I-DOT）共聚物。测定了竞聚率r1=4.29和r2=0.14，表明与I相比，DOT优先插入。所得的P（I-DOT）共聚物在碱性条件下成功降解（特性粘度从-47%降至-84%）。作为概念验证，P（I-DOT）共聚物被制成稳定且分散窄的纳米颗粒，与PI对应物相比，在J774.A1和人脐静脉内皮细胞（HUVEC）上显示出相似的细胞相容性。此外，通过“药物引发”方法合成了吉西他滨-P（I-DOT）前药纳米颗粒，对A549癌细胞表现出显著的细胞毒性。P（I-DOT）和吉西他滨-P（I-DOT）纳米颗粒在碱性/氧化条件下可被漂白剂降解，在生理条件下，在半胱氨酸或谷胱甘肽存在时也可降解。
