Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance

• Published in: Oncotarget 2015-02, Vol.6 (5), p.2827-2842
• Main Authors: Wang, He, Yin, Henghui, Yan, Fengjiao, Sun, Mingna, Du, Lingran, Peng, Wei, Li, Qiuli, Feng, Yinghong, Zhou, Yi
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation - drug effects; Chemistry, Pharmaceutical; Cyclodextrins - chemistry; Dose-Response Relationship, Drug; Doxorubicin - chemistry; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Carriers; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Female; Folic Acid - metabolism; Humans; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Mitochondria - drug effects; Mitochondria - metabolism; Nanoparticles; Poloxamer - chemistry; Research Paper; Rotaxanes - chemistry; Signal Transduction - drug effects; Solubility; Time Factors; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3090

Resistance to treatment with anticancer drugs is a significant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efficacy in vitro and in the drug-resistant MCF-7/Adr (DOX) xenograft tumor model. More specifically, the nanoparticles significantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers.