Breast cancer continues to be a devastating disease in spite of targeted therapies against the estrogen receptor alpha (ER?), the progesterone receptor, and the human epidermal growth factor receptor-2 (Her2). Breast cancers lacking expression of all three receptors are named triple-negative breast cancer (TNBCs). TNBCs are hard to treat due to lack of targeted therapy. Over half of TNBCs overexpress EGFR. Recently our lab showed a NCI investigational drug aminoflavone (AF) exhibits strong cytotoxicity in TNBC cells with GC50 at nM range. AF induces DNA damage, cell cycle arrest and apoptosis in TNBC cell lines. Despite promising growth inhibitory effects, several human clinical trials on AF had been terminated due to systematic toxicity. Thus, there is a pressing need to develop multifunctional nanocarriers to encapsulate AF for targeted cancer therapy. In collaboration with Dr. Gong's group, we have recently designed a unique unimolecular micelle nanoparticle platform as AF nanocarrier for targeted TNBC therapy. We have promising preliminary data indicating that conjugation of an EGFR targeting peptide, GE11, to unimolecular micelles enhances the cellular uptake of the AF-loaded nanoparticles in EGFR-overexpressing TNBC cells. This application will further examine the specificity and efficacy of AF-loaded, GE11-conjugated unimolecular micelles in in vitro and in vivo models. The grant proposal includes two specific aims:
Aim 1 will test the specificity of AF-loaded, GE11-conjugated unimolecular micelles towards EGFR overexpressing vs. non-expressing triple negative breast cancer cells.
Aim 2 will determine the therapeutic efficacy and systemic toxicity of AF-loaded unimolecular micelles in various in vivo models. Collectively, our study will determine whether unimolecular micelles conjugated with an EGFR-recognizing peptide, i.e. GE11, allows for targeted delivery of AF to EGFR- overexpressing TNBC, minimizing systemic toxicity while improving therapeutic efficacy.
Triple Negative Breast cancer lacks expression of ER?, PR, and Her2, constitutes 15-20% of all breast cancer diagnosis. TNBC has the worst prognosis compared to other subtypes of breast cancer and non- targeted therapy is currently available. This study aims to develop a nanoparticle-based, aminoflavone (AF) drug delivery system that would increase tumor-targeting efficacy while circumventing the systemic toxicity associated with AF treatment.
|Brinkman, Ashley M; Chen, Guojun; Wang, Yidan et al. (2016) Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer. Biomaterials 101:20-31|
|Chen, Guojun; Jaskula-Sztul, Renata; Harrison, April et al. (2016) KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy. Biomaterials 97:22-33|