Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.
Bioconjug Chem. 2011 May 18;22(5):870-8. doi: 10.1021/bc1002295. Epub 2011 Apr 19.
We report the preparation and physical and biological characterization of human serum albumin-based micelles of approximately 30 nm diameter for the delivery of amphipathic drugs, represented by doxorubicin. The micelles were surface conjugated with cyclic RGD peptides to guide selective delivery to cells expressing the α(v)β(3) integrin. Multiple poly(ethylene glycol)s (PEGs) with molecular weight of 3400 Da were used to form a hydrophilic outer layer, with the inner core formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity, where each albumin was associated with about 50 doxorubicin molecules. The formed micelles were stable in serum but continuously released doxorubicin when incubated with free thiols at concentrations mimicking the intracellular environment. When incubated with human melanoma cells (M21+) that express the α(v)β(3) integrin, higher uptake and longer retention of doxorubicin was observed with the RGD-targeted micelles than in the case of untargeted control micelles or free doxorubicin. Consequently, the RGD-targeted micelles manifested cytotoxicity at lower doses of drug than control micelles or free drug.
我们报告了大约 30nm 直径的人血清白蛋白为基础的胶束的制备和物理生物学特性，以作为两亲性药物（以阿霉素为例）的递药载体。胶束表面共轭有环肽 RGD 以指导对表达α(v)β(3)整合素的细胞的选择性递药。使用多种分子量为 3400Da 的聚乙二醇（PEG）形成亲水外壳，由通过二硫键与阿霉素共轭的白蛋白形成内核。额外的阿霉素通过物理吸附进入该内核以达到高载药量，每个白蛋白与大约 50 个阿霉素分子结合。形成的胶束在血清中稳定，但当与浓度模拟细胞内环境的游离巯基孵育时，持续释放阿霉素。当与表达α(v)β(3)整合素的人黑色素瘤细胞（M21+）孵育时，与未靶向对照胶束或游离阿霉素相比，靶向 RGD 的胶束显示出更高的摄取和更长的阿霉素滞留。因此，与对照胶束或游离药物相比，RGD 靶向胶束以较低的药物剂量表现出细胞毒性。
