ESTROGEN ANCHORED NANOMICELLES FOR COMBINATIONAL DRUG DELIVERY WITH ENHANCED THERAPEUTIC EFFICACY: A PROTEOMICS GUIDED INVESTIGATION FOR MULTIFUNCTIONAL NANOTHERAPEUTICS

  • Juan-Juan Yin 1Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA
  • Christopher Burgess Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA
  • Liping Shu Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou 550004, China
  • Stepan P. Shumyak Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA
  • Nicholas Raymond Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA
  • Li Xu Ji-Nan Central Hospital, Ji-Nan, ShangDong 250013, China
  • Lu-Lin Li Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China
  • Shu-Ming He Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

Abstract

The employment of the stable isotope labeling with amino acids in cell culture (SILAC) based proteomic analysis as a guidance tool for investigation of cellular response of a multifunctional nanodelivery system has been described for cancer therapy. The multifunctional nanodelivery system in this study was based on an estrogen anchored multimodal nanomicelle (NPG). The key components of the multifunctional nanomicelle consist: β-cyclodextrin conjugated estrone (CDE1), an escort molecule; polymeric BH3 mimetic, a proapoptotic BcL-2 inhibitor; and the mitotic catastrophe agent paclitaxel. They were assembled into the nanomicelle by multiple weak interactions including hydrophobic/hydrophilic interaction and host-guest recognition. The resulting nanomicelle exhibited unimodal morphology with average size of 170 nm with sustained release. It was found that the nanoparticle exhibits excellent anti-tumor activities for the treatment of breast adenocarcinoma with exceptional targeting efficacy both in MCF-7 tumor bearing mice. NPG as a new drug delivery system demonstrated several merits such as the increased drug uptake in breast tumor tissue, low toxicity, potent tumor growth retardation and metastasis inhibition, as well as potential clinical practicality without compromising liver, kidney and immune function and ameliorating the conventional chemotherapeutics induced phlebitis in breast tumor bearing nude mice model. The systematic SILAC based proteomics study and the subsequent validation revealed that the synergistic induction of mitotic catastrophe through enhanced G2/M phase arrest and PI3K/Akt/mTOR mediated autophagy, account for the exceedingly potent anti-tumor activity of this convergent nanomicelle. Additionally, the verification of the top upregulated gene from the proteomics profiling revealed that the overexpression of zinc finger protein 350 (ZNF350/ZBRK1) is associated with the enhanced antitumor effect induced by NPG.

KEYWORDS:  Drug targeting, Estrogen Receptor, Proteomics, Paclitaxel, Gossypol, Synergism

 

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Author Biographies

Juan-Juan Yin, 1Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

1Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

 

Christopher Burgess, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Liping Shu, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou 550004, China

Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou 550004, China

Stepan P. Shumyak, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Nicholas Raymond, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, USA

Li Xu, Ji-Nan Central Hospital, Ji-Nan, ShangDong 250013, China
Ji-Nan Central Hospital, Ji-Nan, ShangDong 250013, China
Lu-Lin Li, Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

Shu-Ming He, Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

Xiaolan Hospital, Southern Medical University, ZhongShan, Guangdong 528415, China

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How to Cite
Yin, J.-J., Burgess, C., Shu, L., Shumyak, S., Raymond, N., Xu, L., Li, L.-L., & He, S.-M. (2018). ESTROGEN ANCHORED NANOMICELLES FOR COMBINATIONAL DRUG DELIVERY WITH ENHANCED THERAPEUTIC EFFICACY: A PROTEOMICS GUIDED INVESTIGATION FOR MULTIFUNCTIONAL NANOTHERAPEUTICS. Journal of Drug Delivery and Therapeutics, 8(2), 41-53. https://doi.org/10.22270/jddt.v8i2.1662