Hyaluronic acid conjugated nanoparticle delivery of siRNA against TWIST reduces tumor burden and enhances sensitivity to cisplatin in ovarian cancer

Sophia A Shahin; Ruining Wang; Shirleen I Simargi; Altagracia Contreras; Liliana Parra Echavarria; Louise Qu; Wei Wen; Thanh Dellinger; Juli Unternaehrer; Fuyuhiko Tamanoi; Jeffrey I Zink; Carlotta A Glackin

doi:10.1016/j.nano.2018.04.008

Hyaluronic acid conjugated nanoparticle delivery of siRNA against TWIST reduces tumor burden and enhances sensitivity to cisplatin in ovarian cancer

Nanomedicine. 2018 Jun;14(4):1381-1394. doi: 10.1016/j.nano.2018.04.008. Epub 2018 Apr 14.

Authors

Affiliations

¹ Irell & Manella Graduate School of Biological Sciences, City of Hope - Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope - Beckman Research Institute, Duarte, California, USA.
² Department of Chemistry and Biochemistry, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA.
³ Department of Stem Cell and Developmental Biology, City of Hope - Beckman Research Institute, Duarte, California, USA; Department of Biological Sciences, California State University, Pomona, CA.
⁴ Department of Stem Cell and Developmental Biology, City of Hope - Beckman Research Institute, Duarte, California, USA; Department of Biological Sciences, California State University, Long Beach, CA.
⁵ Department of Stem Cell and Developmental Biology, City of Hope - Beckman Research Institute, Duarte, California, USA.
⁶ Department of Surgery, City of Hope - Beckman Research Institute, Duarte, California, USA.
⁷ Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA.
⁸ Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA.
⁹ Irell & Manella Graduate School of Biological Sciences, City of Hope - Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope - Beckman Research Institute, Duarte, California, USA. Electronic address: cglackin@coh.org.

Abstract

TWIST protein is critical to development and is activated in many cancers. TWIST regulates epithelial-mesenchymal transition, and is linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance. The majority of epithelial ovarian cancer (EOC) patients with metastatic disease respond well to first-line chemotherapy but most relapse with disease that is both metastatic and drug resistant, leading to a five-year survival rate under 20%. We are investigating the role of TWIST in mediating these relapses. We demonstrate TWIST-siRNA (siTWIST) and a novel nanoparticle delivery platform to reverse chemoresistance in an EOC model. Hyaluronic-acid conjugated mesoporous silica nanoparticles (MSN-HAs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with siTWIST-MSN-HA and cisplatin exhibited specific tumor targeting and reduction of tumor burden. This platform has potential application for overcoming clinical challenges of tumor cell targeting, metastasis and chemoresistance in ovarian and other TWIST overexpressing cancers.

Keywords: Hyaluronic acid; Mesoporous silica nanoparticle; Ovarian cancer; TWIST; siRNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Cell Line, Tumor
Cisplatin / therapeutic use*
Female
Humans
Hyaluronic Acid / chemistry*
Mice
Microscopy, Confocal
Microscopy, Fluorescence
Nanoparticles / chemistry*
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / chemistry*
Tumor Burden / drug effects
Twist Transcription Factors / genetics
Twist Transcription Factors / metabolism

Substances

RNA, Small Interfering
Twist Transcription Factors
Hyaluronic Acid
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding