Original Article A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin Phei Er Saw, PhD a,b , Jinho Park, PhD b , Sangyong Jon, PhD b, ⁎ , Omid C. Farokhzad, MD a, ⁎⁎ a Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA b KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Received 12 August 2016; accepted 6 October 2016 Abstract A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-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 decorated with 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) and Dox to drug-resistant breast cancer cells. APT EDB -LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/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 drug- resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy. © 2016 Elsevier Inc. All rights reserved. Key words: Aptide; Multi-drug resistance; Extra-domain B (EDB) of fibronectin; siRNA; Drug delivery; Liposomes Multidrug resistance (MDR) is one of the biggest challenges in chemotherapy and a major impediment to current cancer therapy modalities. 1 A key characteristic of drug-resistant cancer cells is overexpression of P-glycoprotein (P-gp), a cellular membrane protein that actively pumps out a diverse class of drugs to the cell exterior, rendering treatment ineffective. 2 MDR-1 belongs to P-glycoprotein superfamily, in which overexpression of P-gp family members often results in active pump-out of drugs from the cytoplasm to cell exterior, a phenomenon known as drug resistance. 2,3 Drug resistance can also be acquired during the course of treatment, due to various adaptive responses of cells; i.e. activation of alternative compensatory signaling pathways for survival. 4 In addition to the presence of drug-resistance machinery, the lack of appropriate overexpressed surface biomarkers in these cells has limited the targeted drug delivery and treatment of drug-resistant cancers. 1 As proven by many others, nanoparticle- based drug delivery system could overcome drug resistance in cells using a Trojan horse approach, where drugs were carried into the cell cytoplasm, unrecognized by P-gp as a substrate. 5–13 In this regard, a drug-delivery carrier decorated with a targeting ligand for a surface marker protein specific to drug-resistant cancer cells could provide a new therapeutic option for hard-to-treat cancers. Recently combinations of RNAi and chemotherapy have pre-clinically demonstrated synergistic effects in inhibiting tumor growth 7,9–11,14–18 . Generally, the purpose of the combination should determine the therapeutic regime. If the focus is to inhibit the expression of a Pgp protein to enhance drug uptake, a BASIC SCIENCE Nanomedicine: Nanotechnology, Biology, and Medicine 13 (2017) 713 – 722 nanomedjournal.com Abbreviations: P-gp, P-glycoprotein; MDR, multidrug resistance; siRNA, small interfering RNA; siMDR1, siRNA specific to the MDR1 gene; EDB, extra-domain B of fibronectin; APT, aptide; Dox, doxorubicin; 9R, nona-arginine peptide; RT-PCR, reverse transcription-polymerase chain reaction; LS, liposome; APT EDB -LS, EDB aptide-conjugated liposome. Conflict of Interest: The author declares no conflict of interest. This work was supported by a Global Research Laboratory grant (2015045887) through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning and the David H. Koch-PCF Program in Cancer Nanotherapeutics. ⁎ Correspondence to: O.C. Farokhzad, Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ⁎⁎ Correspondence to: S. Jon, KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. E-mail addresses: syjon@kaist.ac.kr (S. Jon), ofarokhzad@bwh.harvard.edu (O.C. Farokhzad). http://dx.doi.org/10.1016/j.nano.2016.10.005 1549-9634/© 2016 Elsevier Inc. All rights reserved. Please cite this article as: Saw PE, et al, A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin. Nanomedicine: NBM 2017;13:713-722, http://dx.doi.org/10.1016/j.nano.2016.10.005