Breast cancer will affect 1 in 8 women in the United States during their lifetime. While earlier detection and improved treatments have increased the overall survival of this disease, undetected and treatment-resistant disease enable breast cancer to remain the second deadliest cancer in women. The most difficult to treat subset of breast cancer, comprising 10-20% of all cases, is triple negative breast cancer (TNBC). TNBC is unresponsive to the receptor targeted treatments which are effective in receptor-positive disease. Instead, current treatment of TNBC is surgery and anthracycline- and taxane-based chemotherapies and overall, TNBC has a worse five-year survival compared to other breast cancers. However, a compelling target in TNBC is the enzyme indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. This depletion of tryptophan and accumulation of kynurenine metabolites inhibits CD8+ T cell proliferation and upregulates regulatory T cells via downstream pathways, such as the mTOR pathway, thereby creating tumor-induced immunosuppression. These effects can be inhibited by 1-methyl-d-tryptophan (1MDT) which is able to function as a tryptophan sufficiency signal in the mTOR pathway and restore P-S6 kinase phosphorylation. Previous studies have demonstrated a synergistic effect between 1MDT and paclitaxel in decreasing tumor size, however, both 1MDT and paclitaxel have poor water solubility. Here, we describe nanoparticles containing 1MDT and paclitaxel (1MDT-PAX-NPs) for enhanced delivery of this combination therapy. The 1MDT-PAX-NPs are characterized via scanning electron microscopy, dynamic light scattering, and release profiles of both 1MDT and paclitaxel. Furthermore, the 1MDT-PAX-NPs are evaluated in the triple negative human breast cancer cell line MDA-MB-231 through <i>in vitro</i> assays assessing restoration of phosphorylated P-S6 kinase and cytotoxicity of the encapsulated paclitaxel.

Development of immunochemotherapeutic nanoparticles for the treatment of triple negative breast cancer

256th National Meeting (2018)

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