Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.
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.
McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, Madison, WI, USA.|Molecular and Environmental Toxicology Center, University of Wisconsin - Madison, Madison, WI, USA.
Ashley M
AM
Brinkman
Department of Materials Science and Engineering, University of Wisconsin - Madison, Madison, WI, USA.|Wisconsin Institutes for Discovery, University of Wisconsin - Madison, Madison, WI, USA.
Guojun
G
Chen
McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, Madison, WI, USA.
Yidan
Y
Wang
Wisconsin State Laboratory of Hygiene, Madison, WI, USA.
Curtis J
CJ
Hedman
McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, Madison, WI, USA.
Nathan M
NM
Sherer
Department of Biostatistics and Medical Informatics, University of Wisconsin - Madison, Madison, WI, USA.
Thomas C
TC
Havighurst
Department of Materials Science and Engineering, University of Wisconsin - Madison, Madison, WI, USA.|Wisconsin Institutes for Discovery, University of Wisconsin - Madison, Madison, WI, USA.|Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA.
Shaoqin
S
Gong
McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, Madison, WI, USA.|Molecular and Environmental Toxicology Center, University of Wisconsin - Madison, Madison, WI, USA.
Wei
W
Xu
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005419:Flavonoids; C572557:GE11 peptide; D008823:Micelles; D010455:Peptides; C413760:aminoflavone; D066246:ErbB Receptors
Aminoflavone; GE11; Targeted drug delivery; Triple negative breast cancer; Unimolecular micelle nanoparticles