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

Abstract

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

Impact of Targeting Moiety Type and Protein Corona Formation on the Uptake of Fn14-Targeted Nanoparticles by Cancer Cells

“…Furthermore, we have shown that paclitaxel-loaded, Fn14-targeted DART NPs exhibit significantly enhanced therapeutic efficacy compared to Abraxane, an FDA-approved paclitaxel nanoformulation, in murine models of primary TNBC and TNBC brain metastases . More recently, we have reported specific and significant targeting of Fn14-positive human and murine TNBC cells after systemic delivery into mice harboring intracranial tumors, further supporting the development of Fn14-directed nanotherapeutics for brain cancer treatment.…”

“…The latter condition was included for maximal PC formation. We used mouse serum in these studies to enable direct comparisons to our previous , and planned in vivo preclinical studies performed in mice. We quantified both the magnitude of NP cellular uptake (Figure A, B; Figure S5A) and the relative uptake of targeted NPs compared to control nontargeted NPs (Figure C, D; Figure S5B).…”

Epidemiological trends, prognostic factors, and survival outcomes of synchronous brain metastases from 2015 to 2019: a population-based study

“…For example, recent preclinical models have demonstrated some efficacy in the use of paclitaxel-loaded polylactide-co-glycolide polyethylene glycol nanoparticles to target triple-negative breast cancer BM. 35 …”

Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends

“…Moreover, mice treated with the hybrid NP had more than a 50% increase in median survival compared to mice treated with the free form of the drugs. In a study conducted by Dancy et al, a PLGA‐PEG polymer NP was formulated with a targeting moiety against the cell surface receptor, fibroblast growth factor‐inducible 14 (Fn14), a tumor necrosis factor receptor that was shown to be overexpressed in different molecular subtypes of breast cancer, particularly TNBC 49,50 . Furthermore, besides Fn14‐selective targeting, these functionalized NPs possessed minimal nonspecific binding to brain extracellular matrix proteins 51 .…”

“…In a study conducted by Dancy et al, a PLGA-PEG polymer NP was formulated with a targeting moiety against the cell surface receptor, fibroblast growth factor-inducible 14 (Fn14), a tumor necrosis factor receptor that was shown to be overexpressed in different molecular subtypes of breast cancer, particularly TNBC. 49,50 Furthermore, besides Fn14-selective targeting, these functionalized NPs possessed minimal nonspecific binding to brain extracellular matrix proteins. 51 Thus, when loaded with paclitaxel, the so-called "decreased non-specific adhesivity, receptor tar- inhibited the adhesion, migration and invasion of murine 4T1 mammary carcinoma cells more effectively compared to unbound lapatinib.…”