Fn14-Directed DART Nanoparticles Selectively Target Neoplastic Cells in Preclinical Models of Triple-Negative Breast Cancer Brain Metastasis

• DOI: 10.1021/acs.molpharmaceut.2c00663
• Publication Date: 2022-11-14T17:10:56Z
• Authors: Christine P. Carney; Anshika Kapur; Pavlos Anastasiadis; Rodney M. Ritzel; Chixiang Chen; Graeme F. Woodworth; Jeffrey A. Winkles; Anthony J. Kim
• Keywords: Triple-negative breast cancer

Triple-negative breast cancer (TNBC) patients with brain metastasis (BM) face dismal prognosis due to the limited therapeutic efficacy of currently available treatment options. We previously demonstrated that paclitaxel-loaded PLGA–PEG nanoparticles (NPs) directed Fn14 receptor, termed "DARTs", are more efficacious than Abraxane─an FDA-approved paclitaxel nanoformulation─following intravenous delivery in a mouse model TNBC BM. However, precise basis for this difference was not investigated. Here, we further examine utility DART drug platform complementary xenograft and syngeneic BM models. First, that, comparison nontargeted NPs, NPs exhibit preferential association Fn14-positive human murine cell lines cultured vitro. next identified tumor cells as predominant source expression BM-immune microenvironment minimal by microglia, infiltrating macrophages, monocytes, or lymphocytes. then show despite similar accumulation brains harboring tumors, Fn14-targeted DARTs significant specific compared Abraxane. Together, these results indicate primarily BMs enables selective NP cells, likely driving significantly improved observed our prior work.