Feng Chan, Wang Kun, Lin Yun, Song Zhiwang, Lu Yonglin, Liu Jie, Zhu Donglei, Li Yongyong, Dong Chunyan
Cancer Center, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China.
J Mater Chem B. 2018 Mar 28;6(12):1834-1843. doi: 10.1039/c7tb02777j. Epub 2018 Mar 12.
Compared with intracellular drug delivery, drugs with extracellular targeting sites are rarely considered. As one of these drugs, cyclopamine (CYC) is a promising anticancer drug that functions by targeting the cell membrane receptor. For improving therapeutic effect, an albumin-based nano-system (ABN) with the capacity for extracellular retention was developed. The ABN was formulated by incorporating bovine serum albumin (BSA) into nanoparticles at the denaturing temperature of BSA, with CYC acting as a hydrophobic nucleation site, followed by stabilization upon heat-induced disulfide cross-linking. The resultant ABNs are negatively charged with a nanoparticle size that can be delicately regulated by varying the reaction time. In MDA-MB-231 cells, the size and charge of ABNs significantly affected the extracellular retention capacity, with ABN-300 nm exhibiting an enhanced cytotoxic effect. In vivo fluorescence imaging revealed obvious and persistent tumor accumulation of ABNs. A therapeutic study in an orthotopic mammary fat pad tumor model shows that ABN-300 nm possesses the most remarkable antitumor effect compared with the control groups. These results provide a new strategy for improving the efficacy of drug targeting at extracellular sites.
与细胞内药物递送相比，具有细胞外靶向位点的药物很少被考虑。环杷明（CYC）作为这类药物之一，是一种有前景的抗癌药物，其作用机制是靶向细胞膜受体。为了提高治疗效果，开发了一种具有细胞外滞留能力的白蛋白基纳米系统（ABN）。ABN是通过在牛血清白蛋白（BSA）的变性温度下将BSA掺入纳米颗粒中制备而成，CYC作为疏水成核位点，随后通过热诱导二硫键交联实现稳定化。所得的ABN带负电荷，其纳米颗粒大小可通过改变反应时间进行精细调节。在MDA-MB-231细胞中，ABN的大小和电荷显著影响细胞外滞留能力，300 nm的ABN表现出增强的细胞毒性作用。体内荧光成像显示ABN在肿瘤部位有明显且持久的蓄积。在原位乳腺脂肪垫肿瘤模型中的治疗研究表明，与对照组相比，300 nm的ABN具有最显著的抗肿瘤效果。这些结果为提高细胞外位点药物靶向疗效提供了一种新策略。
