Copoly(styrene-maleic acid) - Pirarubicin micelles: High tumor-targeting efficiency with little toxicity
Copoly(styrene-maleic acid) - Pirarubicin micelles: High tumor-targeting efficiency with little toxicity
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DOI：
10.1021/bc040297g
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Maeda, H
中科院分区：
文献类型：
--
作者：
Greish, K;Nagamitsu, A;Maeda, H
利用苯乙烯-马来酸共聚物（SMA）构建了一种新型抗癌药物吡拉西坦（4 '-O-四氢吡喃阿霉素，THP）胶束。胶束的制备程序很简单，该组件仅由SMA和piraradine在非共价缔合，可能是由SMA和piraradine发色团的苯乙烯部分之间的疏水相互作用。该方法确保了超过80重量%的吡拉罗肽回收率，并且实现了60重量%的载药量。所得胶束（SMA-THP）在水中显示出高溶解度，并且在体外具有约3-4%/天的恒定的吡拉罗肽释放速率。根据凝胶色谱法，SMA-THP胶束具有约34 kDa的平均分子大小;该大小比游离THP的627.6 Da显著增加，这表明形成了胶束结构。当加入白蛋白时，胶束的分子大小增加到约94 kDa，这表明与白蛋白结合，这是SMA的独特特征。SMA-THP胶束制剂在体外对MCF-7乳腺癌细胞和SW 480人结肠癌细胞具有与游离THP相当的细胞毒性效应（93-101%）。在携带S-180肿瘤的ddY小鼠中以20 mg/kg的剂量进行的SMA-THP体内测定显示，在100%的测试动物中完全根除肿瘤。小鼠在用高达100 mg/kg吡拉西坦当量的胶束药物剂量治疗后存活超过1年。这种显著的抗肿瘤活性可以归因于在实体瘤中观察到的大分子药物的增强的渗透性和保留（EPR）效应，这使得能够选择性地将药物递送到肿瘤，从而减少副作用。全血细胞计数、肝功能检查和心脏组织学检查显示静脉注射胶束制剂无不良反应迹象。因此，这些数据表明，静脉内施用SMA-THP胶束制剂可使吡拉韦的治疗效果增强50倍以上。
The copolymer of styrene-maleic acid (SMA) was used to construct micelles containing pirarubicin (4'-O-tetrahydropyranyladriamycin, or THP) as a new anticancer drug formulation. The procedure for the preparation of the micelles was simple, the component consisting of only SMA and pirarubicin in a noncovalent association, possibly by hydrophobic interaction between the styrene portion of SMA and pirarubicin chromophore. This method ensures more than 80% recovery of pirarubicin by weight, and 60% of drug loading (by weight) was achieved. The micelles obtained (SMA-THP) showed high solubility in water and a constant pirarubicin release rate of about 3-4%/day in vitro. SMA-THP micelles had an average molecular size of about 34 kDa according to gel chromatography; this size is a marked increase from the 627.6 Da of free THP, which suggests the formation of a micellar structure. When albumin was added, the molecular size of the micelles increased to about 94 kDa, which indicates binding to albumin, a unique characteristic of SMA. SMA-THP micelle preparation had a cytotoxic effect (93-101%) on MCF-7 breast cancer cells and SW480 human colon cancer cells in vitro that was comparable to that of free THP. An in vivo assay of SMA-THP at doses of 20 mg/kg in ddY mice bearing S-180 tumor revealed complete tumor eradication in 100% of tested animals. Mice survived for more than 1 year after treatment with micellar drug doses as high as 100 mg/kg pirarubicin equivalent. This marked antitumor activity can be attributed to the enhanced permeability and retention (EPR) effect of macromolecular drugs seen in solid tumors, which enables selective delivery of drugs to tumor and thus much fewer side effects. Complete blood counts, liver function test, and cardiac histology showed no sign of adverse effects for intravenous doses of the micellar preparation. These data thus suggest that intravenous administration of the SMA-THP micellar formulation can enhance the therapeutic effect of pirarubicin more than 50-fold.