MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer.

Xiaoqian Yang,Arun K Lyer,Francis J Hornicek,Amit Singh,Mansoor M Amiji,Edwin Choy,Zhenfeng Duan

doi:10.1038/srep08509

Abstract

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer.

Highlights

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic
Our findings suggest that Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA)-PEI/HA-PEG/MDR gene 1 (MDR1) small interfere RNA (siRNA) nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer
The results showed 80% of the cells remained viable after treatment with HA-PEI/HA-PEG/MDR1 siRNA for 6 h at the concentration of 600 mg/mL, while in current study, the highest concentration of HAPEI/HA-PEG used for transfection was 170 mg/mL

Summary

Introduction

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/ HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. The response rate to paclitaxel and platinum is up to 80% and a great improvement of median overall survival has been made in patients treated with chemotherapy, 50–75% of patients with advanced ovarian cancer will relapse due to the development of multidrug resistance (MDR)[4,5,6]. Cooverexpression of CD44 and Pgp has been associated with drug resistance and progression in different tumor cells including ovarian cancer[28,29,30]

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