Despite dramatic improvements in the treatment of primary breast cancers, there currently are no effective targeted therapeutics for women diagnosed with metastatic triple negative breast cancer (mTNBC), resulting in an overall survival of just ~13 months in these patients. Drug-loaded nanoparticles (NPs) offer the potential to improve the therapeutic efficacy and pharmacokinetic profile of drugs through use of passive and active targeting to metastatic tumors. However, effective and active targeting of nanodrug formulations to tumor cells is complicated by the adsorption of proteins to NP surfaces upon exposure to the systemic circulation. Termed ‘protein coronas’, this protein coat can drastically reduce the blood circulation time and targeting capability of NPs in vivo. We have developed paclitaxel (PTX)-loaded NPs that are engineered for decreased non-specific adhesivity and receptor-targeting (‘DART’) characteristics, which balance minimal recognition by circulating immune cells and low non-specific binding to tumor extracellular matrix proteins with maximal targeting to tumor tissues. These DARTs selectively bind the fibroblast growth factor-inducible 14 (Fn14) cell surface receptor, which is overexpressed in over a dozen solid cancers and their metastases, including mTNBC tumors. We recently demonstrated the enhanced therapeutic efficacy of Fn14-targeted DARTs in comparison to a non-targeted nanoformulation and Abraxane, an FDA-approved nanoformulation for mTNBC, in xenograft models of primary and intracranial TNBC. In addition, we found that these DARTs retain targeting capability and traffic to Fn14+ tumors in the presence of an endogenous protein corona in vitro and in vivo. This encouraged further investigation into the specific mechanisms of DART NP uptake in tumor cells in both the presence and absence of protein coronas using surface plasmon resonance, flow cytometry, total internal reflection fluorescence and confocal microscopy, and cytotoxicity assays. Understanding the role of protein coronas on this drug delivery platform is crucial for its clinical development and these results provide valuable new information pertaining to the optimization of NP surface properties for minimizing the impact of protein coronas and improving mTNBC tumor targeting in vivo.

Citation Format: Christine P Carney, Anshika Kapur, Nikhil Pandey, Jimena G Dancy, Aniket S Wadajkar, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim. Impact of protein corona formation on Fn14-targeted DART nanoparticle selectivity, uptake, and cytotoxicity on TNBC cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-24.