College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis , Soochow University , Suzhou 215123 , People's Republic of China.
Institute of Functional Nano and Soft Materials (FUNSOM) , Soochow University , Suzhou , 215123 , People's Republic of China.
Bioconjug Chem. 2018 Aug 15;29(8):2806-2817. doi: 10.1021/acs.bioconjchem.8b00421. Epub 2018 Jul 30.
Shell cross-linked (SCL) polymeric prodrug micelles have the advantages of good blood circulation stability and high drug content. Herein, we report on a new kind of pH/redox responsive dynamic covalent SCL micelle, which was fabricated by self-assembly of a multifunctional polymeric prodrug. At first, a macroinitiator PBYP- ss- iBuBr was prepared via ring-opening polymerization (ROP), wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, PBYP- hyd-DOX- ss-P(DMAEMA- co-FBEMA) prodrug was synthesized by a one-pot method with a combination of atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a doxorubicin (DOX) derivative containing an azide group to react with the alkynyl group of the side chain in the PBYP block, while DMAEMA and FBEMA are the abbriviations of N, N-(2-dimethylamino)ethyl methacrylate and 2-(4-formylbenzoyloxy)ethyl methacrylate, respectively. The chemical structures of the polymer precursors and the prodrugs have been fully characterized. The SCL prodrug micelles were obtained by self-assembly of the prodrug and adding cross-linker dithiol bis(propanoic dihydrazide) (DTP). Compared with the shell un-cross-linked prodrug micelles, the SCL prodrug micelles can enhance the stability and prevent the drug from leaking in the body during blood circulation. The average size and morphology of the SCL prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The SCL micelles can be dissociated under a moderately acidic and/or reductive microenvironment, that is, endosomal/lysosomal pH medium or high GSH level in the tumorous cytosol. The results of DOX release also confirmed that the SCL prodrug micelles possessed pH/reduction responsive properties. Cytotoxicity and cellular uptake analyses further revealed that the SCL prodrug micelles could be rapidly internalized into tumor cells through endocytosis and efficiently release DOX into the HeLa and HepG2 cells, which could efficiently inhibit the cell proliferation. This study provides a fast and precise synthesis method for preparing multifunctional polymer prodrugs, which hold great potential for optimal antitumor therapy.
壳交联（SCL）聚合物体胶束具有血液循环稳定性好和药物含量高的优点。在此，我们报告了一种新型的 pH/氧化还原响应动态共价 SCL 胶束，它是通过自组装多功能聚合前药制备的。首先，通过开环聚合（ROP）制备了大分子引发剂 PBYP-ss-iBuBr，其中 PBYP 代表聚[2-(丁-3-炔-1-氧基)-2-氧-1,3,2-二氧杂磷杂环戊烷]。随后，通过原子转移自由基聚合（ATRP）和铜（I）催化的叠氮-炔环加成（CuAAC）反应的一锅法合成了 PBYP-hyd-DOX-ss-P(DMAEMA-co-FBEMA)前药，其中 DOX 衍生物含有叠氮基团与 PBYP 嵌段中的炔基反应，而 DMAEMA 和 FBEMA 分别是 N, N-(2-二甲基氨基)乙基甲基丙烯酸酯和 2-(4-甲酰基苯甲酰氧基)乙基甲基丙烯酸酯的缩写。聚合物前体和前药的化学结构已得到充分表征。通过前药自组装并加入交联剂二硫代双（丙烷二酰肼）（DTP）得到 SCL 前药胶束。与壳未交联前药胶束相比，SCL 前药胶束可以提高稳定性并防止药物在血液循环过程中漏出。通过动态光散射（DLS）和透射电子显微镜（TEM）分别测量 SCL 前药胶束的平均粒径和形态。SCL 胶束可以在适度酸性和/或还原性微环境下解聚，即内体/溶酶体 pH 介质或肿瘤细胞质中高 GSH 水平。DOX 释放的结果也证实了 SCL 前药胶束具有 pH/还原响应特性。细胞毒性和细胞摄取分析进一步表明，SCL 前药胶束可以通过内吞作用迅速进入肿瘤细胞，并有效地将 DOX 释放到 HeLa 和 HepG2 细胞中，从而有效地抑制细胞增殖。这项研究为制备多功能聚合物前药提供了一种快速、精确的合成方法，为优化肿瘤治疗提供了巨大潜力。
