In vivo antitumor activity of the folate-conjugated pH-Sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments
In vivo antitumor activity of the folate-conjugated pH-Sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments
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DOI：
10.1021/bc060401p
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发表时间：
2007-07-01
影响因子：
4.7
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Bae, Younsoo;Nishiyama, Nobuhiro;Kataoka, Kazunori
通过优化表面配体的数目，环境敏感的聚合物胶束药物载体的癌症治疗功效和安全性显著提高。这些胶束被设计成通过叶酸与其在癌细胞膜上过表达的受体之间的相互作用靶向癌性肿瘤，同时在细胞内酸性隔室（例如内体和溶酶体）中实现pH控制的药物释放。为了阐明叶酸对细胞毒性、生物分布、抗癌活性和药理学性质的影响，通过精确合成两种不同的自组装成球形胶束的两亲性嵌段共聚物来控制胶束表面上的叶酸浓度，聚叶酸聚乙二醇（酒石酸-腙-阿霉素）与γ-羧酸活化的叶酸和甲氧基-聚（乙二醇）-聚（酒石酸-腙-阿霉素）不含叶酸。重要的是，尽管叶酸缀合物诱导胶束的肿瘤蓄积的极小变化，但叶酸缀合物胶束在7.50至26.21 mg/kg的宽剂量范围内显示出较低的体内毒性和较高的抗肿瘤活性，这比游离药物宽5倍。
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.