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Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer

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Abstract

Purpose

Approaches for the synthesis of biomaterials to facilitate the delivery of “biologics” is a major area of research in cancer therapy. Here we designed and characterized a hyaluronic acid (HA) based self-assembling nanoparticles that can target CD44 receptors overexpressed on multidrug resistance (MDR) ovarian cancer. The nanoparticle system is composed of HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) designed to deliver MDR1 siRNA for the treatment of MDR in an ovarian cancer model.

Methods

HA-PEI/HA-PEG nanoparticles were synthesized and characterized, then the cellular uptake and knockdown efficiency of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles was further determined. A human xenograft MDR ovarian cancer model was established to evaluate the effects of the combination of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles and paclitaxel on MDR tumor growth.

Results

Our results demonstrated that HA-PEI/HA-PEG nanoparticles successfully targeted CD44 and delivered MDR1 siRNA into OVCAR8TR (established paclitaxel resistant) tumors. Additionally, HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and P-glycoprotein (Pgp), inhibited the functional activity of Pgp, and subsequently increased cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment inhibited tumor growth in MDR ovarian cancer mouse models.

Conclusions

These findings suggest that this CD44 targeted HA-PEI/HA-PEG nanoparticle platform may be a clinicaly relevant gene delivery system for systemic siRNA-based anticancer therapeutics for the treatment of MDR cancers.

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Abbreviations

ABC:

ATP-binding cassette

CD44:

Cluster of differentiation 44

HA:

Hyaluronic acid

HA-PEI:

A-poly(ethyleneimine)

HA-PEG:

HA-poly(ethylene glycol)

IF:

Immunofluorescence

MDR:

Multidrug resistance

MDR1 :

Multidrug resistance gene 1

MTT:

Methyl thiazolyl tetrazorium

RNAi:

RNA interference

siRNA:

Small interfering RNA

TEM:

Transmission electron micrographs

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Acknowledgments and Disclosures

We thank Dr. Meghna Talekar for measurement of the particle size and surface charge. Dr. Yang is supported by Scholarship from China Scholarship Council. This study is supported by the NIH/NCI, Cancer Nanotechnology Platform Partnership (CNPP) grants U01- CA151452.

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Authors and Affiliations

  1. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Jackson 1115, Boston, Massachusetts, 02114, USA

    Xiaoqian Yang, Edwin Choy, Francis J. Hornicek & Zhenfeng Duan

  2. Department of Gynaecology and Obstetrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China

    Xiaoqian Yang

  3. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, 02114, USA

    Arun K. Iyer, Amit Singh, Lara Milane & Mansoor M. Amiji

  4. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, 48201, USA

    Arun K. Iyer

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  1. Xiaoqian Yang
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Correspondence to Zhenfeng Duan.

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Yang, X., Iyer, A.K., Singh, A. et al. Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer. Pharm Res 32, 2097–2109 (2015). https://doi.org/10.1007/s11095-014-1602-1

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