Abstract

pH-responsive drug delivery systems that are bearing with acid-sensitive linkages between therapeutic molecules and polymers have been extensively explored in cancer treatment. But there is no systematic study to choose the best acid-sensitive linker in literature. In this report, three polymer-drug conjugates were synthesized with different pH-sensitive linkers such as ester, amide, and hydrazone with the anticancer drug doxorubicin with the same polymer backbone and the same molecular weights. We believe that this study will provide useful decision-making information to choose the best linker for the stimuli-responsive delivery system. First, we synthesized three different norbornene monomers with ester linker (mono 1), amide linker (mono 2), and hydrazone linker (mono 3). Next, the homopolymerization of mono 1 (HP-DOXE), mono 2 (HP-DOXA), and mono 3 (HP-DOXH) were carried out to obtain same molecular weight of homopolymers by using second generation Grubbs’ catalyst. In vitro drug release profile indicated the importance of having the hydrazone linker that helps the drug at the mildly acidic conditions resembling the pH of the cancerous cells, compared to amide and ester linkers with the same polymer backbone and the same molecular weights of polymers. The cell viability experiments in cancerous cell lines demonstrate that the hydrazone linker kills more cells compared to ester and amide linkers up to 500 µg/mL concentration.

摘要

在癌症治疗中已广泛探索了在治疗分子和聚合物之间带有酸敏感键的pH响应药物传递系统。但是，没有系统的研究来选择文献中最佳的酸敏感性连接基。在该报告中，合成了三种具有不同pH敏感连接基（例如酯，酰胺和）的三聚体-药物共轭物，以及具有相同聚合物主链和相同分子量的抗癌药阿霉素。我们相信，这项研究将提供有用的决策信息，以选择最佳的刺激响应传递系统的连接器。首先，我们合成了三种不同的降冰片烯单体，分别带有酯连接基（单1），酰胺连接基（单2）和连接基（单3）。接下来，对mono 1（HP-DOXE），mono 2（HP-DOXA）进行均聚，与具有相同聚合物主链和相同分子量聚合物的酰胺和酯连接基相比，体外药物释放曲线表明，具有link连接基的重要性，该连接基可在类似于癌细胞的pH的弱酸性条件下帮助药物。在癌细胞系中进行的细胞活力实验表明，与浓度高达500 µg / mL的酯和酰胺连接体相比，hydr连接体杀死了更多的细胞。