State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China.
Int J Pharm. 2021 Nov 20;609:121142. doi: 10.1016/j.ijpharm.2021.121142. Epub 2021 Sep 29.
Polyprodrugs, in which drug was used as the structural unit by linking with each other via the dynamic covalent bonds in the main chain, are expected to endow excellent drug delivery performance. Here, acid-triggered degradable diblock polyprodrug, poly(doxorubicin)-polyethylene glycol (PDOX-PEG), was designed with DOX as structural unit alternately linked with acid-labile hydrazone and maleic amide groups, by the polycondensation of DOX-based dimers (D-DOX or D-DOX) with PEGylated dimer (DOX-ADH-DOX-PEG) as end capping agent. The optimized PDOX-PEG, which was synthesized with D-DOX and the PEGylated dimer at a feeding ratio of 10%, possessed a high M of 3.1 × 10 g/mol with a high DOX content of 75.42%. It could easily self-assemble into near spherical nanoparticles with average hydrodynamic diameter of 135 nm. They showed excellent pH-triggered sustained drug release owing to the acid-triggered degradation of the polyprodrug block in the tumor intracellular microenvironment, with low premature drug leakage of 4.39 % within 60 h. The MTT results indicated the enhanced antitumor efficacy of the proposed PDOX-PEG nanoparticles than free DOX. The results demonstrated the promising potential of the proposed acid-triggered degradable diblock PDOX-PEG polyprodrug for tumor treatment.
聚前药是指药物通过动态共价键在主链上相互连接作为结构单元，预期能赋予优异的药物递送性能。在这里，设计了一种酸响应性可降解嵌段聚前药聚（多柔比星）-聚乙二醇（PDOX-PEG），其中 DOX 作为结构单元通过基于 DOX 的二聚体（D-DOX 或 D-DOX）与聚乙二醇化二聚体（DOX-ADH-DOX-PEG）的缩聚反应，交替连接酸不稳定腙和马来酰亚胺基团，后者作为端封试剂。通过 D-DOX 和聚乙二醇化二聚体以 10%的进料比合成的优化 PDOX-PEG 具有 3.1×10g/mol 的高 M 值和 75.42%的高 DOX 含量。它可以很容易地自组装成平均水动力直径为 135nm 的近球形纳米粒子。由于肿瘤细胞内微环境中聚前药嵌段的酸触发降解，它们表现出优异的 pH 触发持续药物释放，在 60h 内提前药物泄漏率低至 4.39%。MTT 结果表明，与游离 DOX 相比，所提出的 PDOX-PEG 纳米粒子具有增强的抗肿瘤功效。结果表明，所提出的酸响应性可降解嵌段 PDOX-PEG 聚前药具有治疗肿瘤的巨大潜力。
