Triple negative breast cancer (TNBC) is an aggressive subtype of
breast cancer for which there is no available targeted
therapy. TNBC cases contribute disproportionately to
breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI)
investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular
micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12
amino acid peptide targeting
epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC
tumors. These unimolecular
micelles possessed excellent stability and preferentially released
drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting
peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loaded, GE11-conjugated (targeted) unimolecular
micelle NPs significantly inhibit orthotopic TNBC
tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular
micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and
tumor level of AF among different treatment groups yet exhibited no increase in plasma
aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular
micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC.