Biomedical Engineering Department, Northwestern University, Evanston, Illinois 60208, USA.
J Am Chem Soc. 2011 Aug 10;133(31):11850-3. doi: 10.1021/ja203077x. Epub 2011 Jul 19.
A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.
本研究采用了一种新型的细胞靶向、pH 敏感的聚合物载体，用于将抗癌药物硼替佐米（BTZ）递送到癌细胞中。我们的策略是基于将 BTZ 简便地共轭到含有儿茶酚的聚合物载体上，这些载体旨在通过细胞表面受体介导的机制被癌细胞选择性摄取。在这项研究中用作构建块的聚合物是聚乙二醇（PEG），它因其能够减少与蛋白质和细胞的非特异性相互作用而被选择。儿茶酚部分被利用其能够结合和释放硼酸酯类治疗药物，如 BTZ，这是一种 pH 依赖性的方式。在酸性环境中，如在癌症组织或亚细胞内体中，BTZ 从聚合物结合的儿茶酚基团上解离出来，释放出游离药物，从而抑制蛋白酶体的功能。将生物素作为一种癌细胞靶向配体呈现在聚合物载体上，以促进载药聚合物载体靶向进入癌细胞。我们的研究表明，与非靶向药物-聚合物缀合物相比，癌细胞靶向药物-聚合物缀合物显著增强了对乳腺癌细胞的细胞摄取、蛋白酶体抑制和细胞毒性。pH 敏感的儿茶酚硼酸结合机制为控制靶向癌细胞中 BTZ 的释放提供了一种化学选择性方法，为将来应用于其他含硼酸的治疗药物治疗广泛的疾病建立了一个概念。
