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.
Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics.
A major obstacle in the success of chemotherapy in ovarian cancer is the emergence of multidrug resistance (MDR). Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) efflux pumps is one of the best characterized MDR mechanisms. Although MDR1 siRNA based strategies are emerging as highly promising approaches to reverse MDR, the systemic delivery still remains a great challenge. In the present study, CD44 targeting hyaluronic acid (HA) based self-assembling nanoparticle systems were designed with MDR1 siRNA to evaluate its delivery efficiency and combination anticancer therapeutic efficacy with paclitaxel in vitro and in vivo. The results showed that HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) nanoparticle successfully delivered MDR1 siRNA into MDR ovarian cancer cell lines, SKOV-3TR and OVCAR8TR. Western blot analysis, calcein AM retention assay, and MTT assay further demonstrated that HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and inhibited the functional activity of Pgp, and subsequently increase cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment produced a significant inhibitory effect on the drug-resistant tumor growth as compared with control groups in MDR ovarian cancer xenograft mouse models. These results indicated CD44-targeted HA-PEI/HA-PEG nanoparticle platform is an effective siRNA delivery system for potential siRNA-based anticancer therapeutics in ovarian cancer. Citation Format: Xiaoqian Yang, Arun lyer, Francis hornicek, Mansoor Amiji, Zhenfeng Duan. Hyaluronic acid-based CD44 targeted nanoparticle delivery of combination MDR1 siRNA/paclitaxel to overcome drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-13. doi:10.1158/1538-7445.AM2014-LB-13
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