Kimura Kotaro, Yamasaki Keishi, Nakamura Hideaki, Haratake Mamoru, Taguchi Kazuaki, Otagiri Masaki
Faculty of Pharmaceutical Sciences, Sojo University.
DDS Research Institute, Sojo University.
Chem Pharm Bull (Tokyo). 2018;66(4):382-390. doi: 10.1248/cpb.c17-00838.
Nanoparticles prepared using human serum albumin (HSA) have emerged as versatile carriers for improving the pharmacokinetic profile of drugs. The desolvation of HSA using ethanol followed by stabilization through crosslinking with glutaraldehyde is a common technique for preparing HSA nanoparticles, but our knowledge concerning the characteristics (or functions) of HSA nanoparticles and their efficiency when loaded with drugs is limited. To address this issue in more detail, we prepared anthracycline-loaded HSA nanoparticles. Doxorubicin-loaded HSA nanoparticles with a size similar to doxorubicin-unloaded particles could be prepared by desolvating at a higher pH (8-9), and the size (100-150 nm) was optimum for delivery to tumor tissues. Using this procedure, HSA nanoparticles were loaded with other anthracycline derivatives, and all showed cytotoxicity in cancer cells. However, the efficiency of drug loading and dissolution rate were different among them possibly due to the differences in the type of association of the drugs on nanoparticles (doxorubicin and daunorubicin; covalently bound to nanoparticles, pirarubicin; both covalently bound to and adsorbed on nanoparticles, aclarubicin; adsorbed on nanoparticles). Since the formulation of such drug-loaded HSA nanoparticles should be modified for efficient delivery to tumors, the findings reported herein provide the useful information for optimizing the formulation and the production process for the HSA nanoparticles using a desolvation technique.
用人血清白蛋白（HSA）制备的纳米颗粒已成为改善药物药代动力学特征的通用载体。用乙醇使HSA去溶剂化，然后通过与戊二醛交联进行稳定化处理，是制备HSA纳米颗粒的常用技术，但我们对HSA纳米颗粒的特性（或功能）及其载药时的效率了解有限。为了更详细地解决这个问题，我们制备了载有蒽环类药物的HSA纳米颗粒。可以通过在较高pH值（8-9）下去溶剂化来制备尺寸与未载阿霉素颗粒相似的载阿霉素HSA纳米颗粒，且该尺寸（100-150nm）最适合递送至肿瘤组织。使用此方法，HSA纳米颗粒负载了其他蒽环类衍生物，并且所有这些衍生物在癌细胞中均显示出细胞毒性。然而，它们之间的载药效率和溶解速率不同，这可能是由于纳米颗粒上药物结合类型的差异（阿霉素和柔红霉素；与纳米颗粒共价结合，吡柔比星；既与纳米颗粒共价结合又吸附在纳米颗粒上，阿克拉霉素；吸附在纳米颗粒上）。由于此类载药HSA纳米颗粒的制剂应进行改进以有效递送至肿瘤，因此本文报道的研究结果为使用去溶剂化技术优化HSA纳米颗粒的制剂和生产工艺提供了有用的信息。
