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

He Wang,Qiuli Li,Lingran Du,Fengjiao Yan,Mingna Sun,Yi Zhou,Wei Peng,Yinghong Feng,Henghui Yin

doi:10.18632/oncotarget.3090

Abstract

Resistance to treatment with anticancer drugs is a signiï¬cant 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 efï¬cacy in vitro and in the drug-resistant MCF-7/Adr (DOX) xenograft tumor model. More specifically, the nanoparticles signiï¬cantly 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.

Highlights

The clinical failure of chemotherapy in cancer could be associated with the conventional administration of anticancer drugs as ‘free’ drugs
The self-assembly method appears to be suitable for the incorporation of DOX and DQA into BPRor folate-terminated polyrotaxanes (FPRs)-based nanoparticles; in the present study, DOX nanoparticles, targeted DOX nanoparticles, and functional DOX nanoparticles were formed
The results show that DOX hydrochloride (DOX·HCL), he DOX nanoparticles, and the targeted DOX nanoparticles had a minimal inhibitory effect on the MCF-7 (Fig. 9A) and MCF-7/Adr (Fig. 9B) xenografts when administered by intravenous injection (30.2±14.3%/18.2±12.34%, 52.2±10.12%/58.8±15.5%, and 75.6±15.25%/78.23±24.5%, respectively, at day 34)

Summary

Introduction

The clinical failure of chemotherapy in cancer could be associated with the conventional administration of anticancer drugs as ‘free’ drugs. Such administration leads to a limited drug concentration at tumor sites due to non-targeted distribution throughout the body tissues [1]. Targeted drug delivery offers a potential alternative strategy for chemotherapy. Another major problem in the clinical treatment of cancer with chemotherapeutic drugs is multidrug resistance (MDR) in tumor cells. Acquired resistance in cancer may derive from a drug stimulus, leading to the overexpression of ATP-binding cassette (ABC) transporters and the subsequent efflux of anticancer drugs from within cancer cells [2]. Intrinsic resistance is mainly associated with mitochondria, which are considered the major powerhouses of cells, playing central roles in energy metabolism and in apoptosis [3]

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