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Mol Cancer Ther. 2019 Oct;18(10):1755-1764. doi: 10.1158/1535-7163.MCT-18-0873. Epub 2019 Jul 15.

Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination Nanotherapy.

Sulaiman A1,2,3,4, McGarry S1, El-Sahli S1, Li L1, Chambers J1, Phan A1, Côté M1,2, Cron GO1,5,6, Alain T1,7, Le Y1,8, Lee SH1, Liu S9, Figeys D1,2,3,4, Gadde S10, Wang L10,2,3,4,11.

Author information

1
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
2
Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
3
China-Canada Centre of Research for Digestive Diseases, University of Ottawa, Ottawa, Ontario, Canada.
4
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
5
Department of Radiology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
6
Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
7
Children Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
8
Radiobiology and Health, Canadian Nuclear Laboratories, Ontario, Canada.
9
Institute of Chinese Traditional Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
10
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Sgadde@uottawa.ca Lisheng.Wang@uottawa.ca.
11
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Abstract

Triple-negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer-related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC), as well as appropriate animal models to accurately evaluate treatment efficacy for clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. We developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NP) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and accumulation of NPs. NF-κB, Wnt, and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls, and tumors progression and CSC subpopulations were analyzed. MRI imaging indicated high vascularization of PDX tumors. IVIS imaging showed accumulation of NPs in PDX tumors. In comparison with control-NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-κB, Wnt, and YAP that have been shown to be crucial for cancer growth, CSC development, and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-κB, Wnt, and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of patients with TNBC.

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