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Cancer Res. 2018 Nov 1;78(21):6247-6256. doi: 10.1158/0008-5472.CAN-17-3871. Epub 2018 Aug 16.

CD44-Targeting PLGA Nanoparticles Incorporating Paclitaxel and FAK siRNA Overcome Chemoresistance in Epithelial Ovarian Cancer.

Author information

1
Department of Immunology, School of Medicine, Konkuk University, Chungju, South Korea.
2
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
3
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
4
Bio/Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
5
Department of Bioscience and Biotechnology, Sejong University, Seoul, South Korea.
6
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Center for RNAi and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Immunology, School of Medicine, Konkuk University, Chungju, South Korea. hanhd@kku.ac.kr immun3023@kku.ac.kr.
#
Contributed equally

Abstract

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma.Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. Cancer Res; 78(21); 6247-56. ©2018 AACR.

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