Institut des Biomolécules Max Mousseron (IBMM - UMR 5247), CNRS, Université Montpellier , ENSCM, Faculté de Pharmacie , 15, Avenue Charles Flahault BP14491 , Montpellier Cedex 5 , France.
Biomacromolecules. 2018 Oct 8;19(10):4003-4013. doi: 10.1021/acs.biomac.8b00973. Epub 2018 Sep 19.
We developed a new simplified method for the synthesis of well-defined linear, diblock, or starlike N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer drug carriers using controlled reversible addition-fragmentation chain transfer polymerization. The prepared monodispersed polymers are after the drug attachment intended for enhanced anticancer therapy. This new approach significantly reduces the number of required synthetic steps and minimizes the consumption of organic solvents during the synthesis. As a result, highly defined linear, diblock, and starlike copolymers designed for pH-triggered drug activation/release in tumor tissue were formed in sufficient amounts for further physicochemical and biological studies. Within the synthesis, we also developed a new procedure for the selective deprotection of tert-butoxycarbonyl hydrazide and amine groups on hydrophilic HPMA copolymers, including the one-pot removal of polymer end groups. We studied and described in detail the kinetics and efficacy of the deprotection reaction. We believe the simplified synthetic approach facilitates the preparation of polymer conjugates bound by the pH-sensitive hydrazone bond and their application in tumor treatment.
我们开发了一种新的简化方法，用于使用可控可逆加成-断裂链转移聚合合成具有明确结构的线性、二嵌段或星型 N-(2-羟丙基)甲基丙烯酰胺（HPMA）基聚合物药物载体。所制备的单分散聚合物在药物附着后，旨在增强抗癌治疗效果。这种新方法显著减少了所需的合成步骤的数量，并在合成过程中最小化了有机溶剂的消耗。结果，形成了大量数量的设计用于在肿瘤组织中 pH 触发药物激活/释放的高度明确的线性、二嵌段和星型共聚物，以便进行进一步的物理化学和生物学研究。在合成过程中，我们还开发了一种新的程序，用于选择性脱保护叔丁氧基羰基腙和亲水性 HPMA 共聚物上的胺基团，包括聚合物端基的一锅法去除。我们详细研究和描述了脱保护反应的动力学和效率。我们相信简化的合成方法促进了通过 pH 敏感腙键结合的聚合物缀合物的制备及其在肿瘤治疗中的应用。
