A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin

Amajor problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulatemulti-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decoratedwith a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB-specific aptide (APT(EDB))-conjugated liposome to simultaneously deliver siRNA(siMDR1) andDox to drug-resistant breast cancer cells. APT(EDB)-LS(Dox, siMDR1) led to enhanced delivery of payloads intoMCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APT(EDB)-LS(Dox) or APT(EDB)-LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APT(EDB)-LS(Dox, siMDR1) treatment resulted in significant reduction of the drugresistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy. (C)2016 Elsevier Inc. All rights reserved.