Pharmaceutical Research

, Volume 32, Issue 6, pp 2097–2109 | Cite as

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

  • Xiaoqian Yang
  • Arun K. Iyer
  • Amit Singh
  • Lara Milane
  • Edwin Choy
  • Francis J. Hornicek
  • Mansoor M. Amiji
  • Zhenfeng Duan
Research Paper



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.


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.


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.


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.

Key Words

CD44 targeting HA-PEI/HA-PEG nanoparticle multidrug resistance ovarian cancer siRNA delivery 



ATP-binding cassette


Cluster of differentiation 44


Hyaluronic acid




HA-poly(ethylene glycol)




Multidrug resistance


Multidrug resistance gene 1


Methyl thiazolyl tetrazorium


RNA interference


Small interfering RNA


Transmission electron micrographs


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.

Supplementary material

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11095_2014_1602_MOESM3_ESM.pptx (68 kb)
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11095_2014_1602_MOESM4_ESM.pptx (238 kb)
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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Xiaoqian Yang
    • 1
    • 2
  • Arun K. Iyer
    • 3
    • 4
  • Amit Singh
    • 3
  • Lara Milane
    • 3
  • Edwin Choy
    • 1
  • Francis J. Hornicek
    • 1
  • Mansoor M. Amiji
    • 3
  • Zhenfeng Duan
    • 1
  1. 1.Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue OncologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of Gynaecology and ObstetricsThe Third Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  3. 3.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  4. 4.Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health SciencesWayne State UniversityDetroitUSA

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