Bae Younsoo, Nishiyama Nobuhiro, Kataoka Kazunori
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bioconjug Chem. 2007 Jul-Aug;18(4):1131-9. doi: 10.1021/bc060401p. Epub 2007 May 9.
Cancer treatment efficacy and safety of the environmentally sensitive polymeric micelle drug carriers were significantly increased by optimizing the number of ligands on their surface. These micelles were designed to target the cancerous tumors through the interaction between folate and its receptors that overexpress on the cancer cell membrane while achieving pH-controlled drug release in the intracellular acidic compartments such as endosomes and lysosomes. In order to elucidate the effects of folate on cytotoxicity, biodistribution, anticancer activity, and pharmacological properties, folate concentration on the surface of the micelles was controlled by precise synthesis of two different amphiphilic block copolymers that self-assemble into spherical micelles, folate-poly(ethylene glycol)-poly(aspartate-hydrazone-adriamycin) with gamma-carboxylic acid activated folate and methoxy-poly(ethylene glycol)-poly(aspartate-hydrazone-adriamycin) without folate. It is of significance that, although folate conjugation induced an extremely small change in tumor accumulation of the micelles, folate-conjugated micelles showed lower in vivo toxicity and higher antitumor activity over a broad range of the dosage from 7.50 to 26.21 mg/kg, which was 5-fold broader than free drugs.
通过优化环境敏感型聚合物胶束药物载体表面配体的数量，其癌症治疗效果和安全性得到显著提高。这些胶束旨在通过叶酸与其在癌细胞膜上过度表达的受体之间的相互作用靶向癌性肿瘤，同时在细胞内酸性区室（如内体和溶酶体）实现pH控制的药物释放。为了阐明叶酸对细胞毒性、生物分布、抗癌活性和药理特性的影响，通过精确合成两种不同的两亲性嵌段共聚物来控制胶束表面的叶酸浓度，这两种共聚物自组装成球形胶束，即带有γ-羧酸活化叶酸的叶酸-聚（乙二醇）-聚（天冬氨酸-腙-阿霉素）和不含叶酸的甲氧基-聚（乙二醇）-聚（天冬氨酸-腙-阿霉素）。重要的是，尽管叶酸偶联导致胶束在肿瘤中的积累变化极小，但在7.50至26.21 mg/kg的广泛剂量范围内，叶酸偶联的胶束显示出较低的体内毒性和较高的抗肿瘤活性，其活性范围比游离药物宽5倍。
