title: A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin.
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 (APTEDB)-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APTEDB-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 APTEDB-LS(Dox) or APTEDB-LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APTEDB-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.
authors: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Phei Er
authors: PE
authors: Saw
authors: KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Jinho
authors: J
authors: Park
authors: KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Electronic address: syjon@kaist.ac.kr.
authors: Sangyong
authors: S
authors: Jon
authors: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: ofarokhzad@bwh.harvard.edu.
authors: Omid C
authors: OC
authors: Farokhzad
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; D008081:Liposomes; C121542:oncofetal fibronectin; D004317:Doxorubicin
keywords: Aptide; Drug delivery; Extra-domain B (EDB) of fibronectin; Liposomes; Multi-drug resistance; siRNA