Development of bioerodible, short-term controlled-release microcapsules for cancer chemotherapy

本文报道了一种具有短期延迟释药和生物溶蚀特性的动脉化疗栓塞微囊（LMC）。采用空气悬浮包衣法将药物、大豆卵磷脂（SL）、胆固醇（CH）、硬脂酸（SA）和聚乙烯吡咯烷酮（PVP）包埋在乳糖核芯中，再将SL、CH、SA和PVP包埋在乳糖核芯的包衣层中。由此制备的LMCs的粒径药物含量可分别在30-200 μm和几至30%的范围内变化。通过改变LMCs涂层的四种组分的重量比，生物侵蚀和短期药物释放特性也被发现是广泛变化的。对含42%PVP的SL-CH-SA体系的相图进行了估算，结果表明，该体系的释药和生物溶蚀机理与涂层中各组分的相分离行为密切相关。基于一种新的稀释方法，考虑到临床前使用中需要各种类型的具有多功能的微胶囊的个体患者的量身定制治疗，还建立了通过空气悬浮包衣工艺的LMC的小规模生产。该方法仅使用1g抗癌药物（阿霉素（ADR））就提供了尺寸为106-149 μm且药物含量为30%的微胶囊。含ADR的LMCs也表现出短期延迟释放ADR，滞后时间为几到十分钟，而在体外人血浆中，它们可以在30分钟内完全被侵蚀。这些特性甚至在将ADR-LMCs动脉内注射到大鼠肝动脉的体内研究中也实现，表明ADR-LMCs可诱导短暂的动脉栓塞，从而增强栓塞动脉中释放的ADR的药理作用。这些结果表明，在本研究中开发的LMCs将是一类有前途的药物载体动脉化疗栓塞治疗癌症。

Lecithin microcapsules (LMCs) specified by short-term delayed drug-release and bioerosion were developed for intraarteial chemoembolization therapy of cancer. An air suspension coating process was employed to microencapsulate a lactose core with a layer of drug, soybean lecithin (SL), cholesterol (CH), stearic acid (SA) and polyvinylpyrrolidone (PVP) and a coat of SL, CH, SA and PVP. The particle size drug content of the LMCs thus prepared could be varied in the range of 30-200 μm and few to 30%, respectively. By changing the weight rations of four components of the LMCs coat, bioerosion and short-term drug-release properties were also found to be widely changeable. The estimated phase diagram of the SL-CH-SA system incorporating 42% PVP indicated that the mechanisms of drug-release and bioerosion were closely related to the phase-separation behavior of each component in the coat. Small-scale production of the LMCs by the air suspension coating process was also established based on a novel dilution method, taking into consideration of the tailor-made treatment for individual patients in preclinical use where various types of microcapsules with versatile functions were required. This method provided microcapsules with 106-149 μm in size and 30% in drug content by using only 1 g of an anticancer drug (adriamycin (ADR)). The ADR-containing LMCs also demonstrated short-term delayed release of ADR with a lagtime of few to ten minutes while they could be completely eroded within 30 min in human plasma in vitro. These properties were achieved even in vivo studies where the ADR-LMCs were intraarterially injected to hepatic artery of rats, suggesting that the ADR-LMCs may induce transient arterial-embolization and thereby enhance the pharmacological effect of ADR released in the embolic arteries. These results demonstrate that the LMCs developed in this study will be a promising class of drug carriers for intraarterial chemoembolization therapy of cancer.