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Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy

Guojun Chen1, 2*, Ashley M. Brinkman3, 4*, Yidan Wang3*, Curtic J. Hedman4*, Thomas C. Havighurst5*, Nathan Sherer3*, Wei Xu3, 4 and Shaoqin Gong1, 2, 6*
  • 1 University of Wisconsin-Madison, Materials Science and Engineering, United States
  • 2 University of Wisconsin-Madison, Wisconsin Institutes for Discovery, United States
  • 3 University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, United States
  • 4 University of Wisconsin-Madison, Molecular and Environmental Toxicology Center, United States
  • 5 University of Wisconsin-Madison, Department of Biostatistics and Medical Informatics, United States
  • 6 University of Wisconsin-Madison, Department of Biomedical Engneering, United States

Introduction: Breast cancer is the second leading cause of cancer-related deaths in American women. Triple-negative breast cancers (TNBCs)—which lack expression of estrogen receptor α, progesterone receptor, and human epidermal growth factor receptor 2—are particularly aggressive and correlated with decreased survival. While TNBCs make up 15 to 20% of all breast cancer cases, they account for a dis­pro­portionately large number of breast cancer deaths. Aminoflavone (AF, NSC 686288) has been exam­ined in multiple clinical trials for TNBCs, but the majority of these trials have been terminated due to toxicity. To address this problem, we have developed a unique unimolecular micelle as an AF delivery system for targeted TNBC therapy. The unimolecular micelles were conjugated with GE11 peptide as an active-tumor targeting ligand that can specifically target the epithermal growth factor receptors (EGFR) overexpressed by the TNBC cells. In the current study, we assessed the antitumor effects of AF-loaded and GE11-conjugated unimolecular micelles both in vitro and in vivo.

Methods: Stable multifunctional unimolecular micelles were prepared in an aqueous solution using multi-arm star amphiphilic block copolymer poly(amidoamine)–polylactide–poly(ethylene glycol)–OCH3/Cy5.5/GE11. The hydrophobic polylactide core was used to encapsulate AF through hydrophobic interaction, and the PEG shell was used to provide water solubility and reduce opsonization in vivo. GE11 peptide and Cy5.5 dye were selectively conjugated onto the distal ends of the PEG for active tumor-targeting and detection of the micelles at the cellular level, respectively. EGFR-overexpressing and AF-sensitive human MDA-MB-468 TNBC cells were treated with the micelles. The effect of the GE11 pep­tide on the cellular uptake of the micelles was studied by flow cytometry and confocal laser scanning microscopy. The effect of GE11 on the cytotoxicity of the micelles was determined using the MTT assay. The antitumor efficacy of AF-loaded and GE11-conjugated micelles was determined in MDA-MB-468 xenografts at an AF dosage of 7 mg/kg BW.

Results: The unimolecular micelles were developed for targeted delivery of AF to TNBCs. The GE11-conjugated micelles exhibited a much higher cellular uptake than non-targeted micelles based on flow cytometry and CLSM analyses. The AF loaded in the targeted micelles had the strongest inhibitory effect on MDA-MB-468 TNBC cell proliferation. Moreover, the AF-loaded and GE11-conjugated unimolecular micelles demonstrated the best antitumor efficacy by remarkable regression of the TNBC tumors without significant weight loss.

Conclusions: The GE11-targeting ligands conjugated onto the surface of the micelles substantially in­creased the cellular uptake of the micelles in MDA-MB-468 TNBC cells and improved the cytotoxic effect of AF. This in vivo anticancer study demonstrates that AF-loaded and GE11-conjugated uni­mole­cular micelles have the best therapeutic effect.

National Institutes of Health (1K25CA166178) to S.G.; D.O.D. Era of Hope Scholar Award W81XWYH-11-1-0237 to W.X.; T32 CA009135 to A.M.B.

Keywords: in vivo, Drug delivery, Micelle, targeting delivery

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: Poster

Topic: Biomaterials for therapeutic delivery

Citation: Chen G, Brinkman AM, Wang Y, Hedman CJ, Havighurst TC, Sherer N, Xu W and Gong S (2016). Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02060

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.

* Correspondence:
Dr. Guojun Chen, University of Wisconsin-Madison, Materials Science and Engineering, Madison, WI, United States, Email1
Dr. Ashley M Brinkman, University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, Madison, WI, United States, abrinkman@wisc.edu
Dr. Yidan Wang, University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, Madison, WI, United States, wang35@oncology.wisc.edu
Dr. Curtic J Hedman, University of Wisconsin-Madison, Molecular and Environmental Toxicology Center, Madison, WI, United States, curtis.hedman@slh.wisc.edu
Dr. Thomas C Havighurst, University of Wisconsin-Madison, Department of Biostatistics and Medical Informatics, Madison, WI, United States, havig@biostat.wisc.edu
Dr. Nathan Sherer, University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, Madison, WI, United States, nsherer@wisc.edu
Dr. Shaoqin Gong, University of Wisconsin-Madison, Materials Science and Engineering, Madison, WI, United States, sgong@engr.wisc.edu