Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

Abstract

Abstract : The endocytic trafficking pathway is the site of action for receptor-targeted drug-delivery strategies, including Antibody-Drug- Conjugates (ADCs) and nanoparticle drug-delivery systems. Effective drug-release requires trafficking of the endocytosed receptor-bound cargo into the lysosomes for efficient disintegration. However, cancer-cell specific alterations that lead to receptor recycling, instead of lysosomal-degradation, can dampen the efficiency of drug delivery. Such changes include receptor overexpression, increased association with the molecular chaperone, chaperones such as HSP90 or alterations in regulators of recycling versus lysosomal pathways (Rab GTPases, c-Src, deubiquitinases). While substantial effort has gone into designing receptor-targeted drug delivery systems, the consequence of factors leading to altered recycling versus lysosomal trafficking on the efficiency of drug delivery have not been considered. The receptor tyrosine kinases ErbB2 and EGFR, which are often overexpressed in breast cancer, are examples of cell surface receptors used for evaluating nanoparticle-based targeted drug delivery systems. However, several studies have established that the ErbB2 receptor is either endocytosis-impaired or undergoes rapid recycling, suggesting that the strategies to enhance receptor internalization and lysosomal routing could further enhance the efficacy of cytotoxic drug being delivered. While, the molecular chaperone HSP90 is critical for maintaining oncogenic ErbB2-activity, it also is thought to be responsible for the altered trafficking of the receptor. The objective of this synergistic DOD-IDEA grant proposal was to evaluate our innovative hypothesis that HSP90 inhibitors can facilitate ErbB2-targeted delivery of chemotherapeutic payloads.