Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Department of Pharmacy, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, PR China.
Nanomedicine (Lond). 2016 Nov;11(22):2917-2934. doi: 10.2217/nnm-2016-0252. Epub 2016 Oct 26.
To design pluronic F68 (PF68)-conjugated polyamidoamine (PAMAM) dendrimer conjugates for doxorubicin (DOX) delivery for overcoming multidrug resistance, and clarify the reversal mechanism.
MATERIALS & METHODS: A series of PAMAM-PF68 conjugates were designed. The antitumor activity of the DOX-loaded conjugates was evaluated against MCF-7/ADR cells, tumor spheroids and tumors. Several bioinformatics were detected to characterize the reversal mechanism.
Increased antitumor activity of the DOX-loaded conjugates was achieved in vitro and in vivo. The complexes induced more DOX accumulation via caveolae-mediated endocytosis. After escaping from the endosome/lysosome, the nuclear trafficking of DOX was achieved. Apoptosis was significantly increased by regulating mitochondrial function and gene expression.
With optimized PF68 modification, PAMAM-PF68 conjugates can significantly overcome multidrug resistance in vitro and in vivo.
设计阿霉素（DOX）传递用的泊洛沙姆 F68（PF68）-接枝聚酰胺-胺（PAMAM）树枝状大分子缀合物，以克服多药耐药性，并阐明逆转机制。
设计了一系列 PAMAM-PF68 缀合物。用载 DOX 的缀合物对 MCF-7/ADR 细胞、肿瘤球体和肿瘤进行抗肿瘤活性评估。通过几种生物信息学检测来表征逆转机制。
在体外和体内均实现了载 DOX 缀合物的抗肿瘤活性增加。这些复合物通过穴样内陷介导的内吞作用诱导更多 DOX 蓄积。从内涵体/溶酶体逃逸后，实现了 DOX 的核转运。通过调节线粒体功能和基因表达，显著增加了细胞凋亡。
通过优化的 PF68 修饰，PAMAM-PF68 缀合物可以显著克服体外和体内的多药耐药性。
