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Published on: May 2, 2019
Reversion of multidrug resistance by tumor targeted delivery of antisense oligodeoxynucleotides in
Jiaqi Wang1, Xinyi Tao, Yufei Zhang
1State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
Abstract:
Chitosan and its derivatives have shown great potential as non-viral vectors for gene delivery therapy. Folic acid receptor (FR) is an important anti-cancer therapy target that is applicable to many cancer types. In this study, we developed an efficient and targeted delivery of antisense oligodeoxynucleotides asODNs, using folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS). These nanoparticles were designed to reduce production of P-gp, in order to overcome tumor drug resistance. Nanoparticles prepared were found to be 181 nm in diameter. Spectrofluorimetry was utilized to evaluate the effect of charge ratio of the nanoparticles on loading efficiency. In PBS buffer, 40% of asODNs were released from the nanoparticles at first 24 h. However, just another 15% was released between 24 and 48 h. The antitumor effect of the nanoparticles was evaluated in KB-A-1 cells implanted in Balb/c-nu/nu mice. They inhibited the growth of tumor by 35% compared to the bare asODNs. The FA-HPCS-asODNs nanoparticles demonstrated significantly inhibition of the multi drug resistance (MDR) 1 gene levels and P-gp levels in vitro and in vivo, respectively, related with bare asODNs and HPCS-asODNs ones. During in vivo studies, FA-HPCS-asODNs nanoparticles were also found to bind specifically and efficiently to FR high-expressing cancer cells. These results suggested that the use of targeted, antisense agent nanoparticles would be potential approach to overcome tumor drug resistance.
Insights
Targeted nanoparticles using folic acid-conjugated chitosan effectively delivered antisense oligodeoxynucleotides, overcoming tumor drug resistance by inhibiting P-gp and reducing tumor growth by 35%.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapy
Background:
- Chitosan derivatives show promise as non-viral vectors for gene therapy.
- Folic acid receptor (FR) is a key target for anti-cancer therapies.
- Tumor drug resistance, often mediated by P-glycoprotein (P-gp), remains a significant challenge.
Purpose of the Study:
- To develop targeted nanoparticles for delivering antisense oligodeoxynucleotides (asODNs).
- To utilize folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS) for targeted delivery.
- To overcome tumor drug resistance by reducing P-gp production.
Main Methods:
- Preparation of FA-HPCS-asODNs nanoparticles with a diameter of 181 nm.
- Evaluation of loading efficiency using spectrofluorimetry.
- Assessment of drug release kinetics in PBS buffer.
- In vitro and in vivo evaluation of antitumor effects in KB-A-1 cells and tumor-bearing mice.
- Analysis of multi drug resistance (MDR) 1 gene and P-gp levels.
- In vivo studies to assess specific binding to FR-expressing cancer cells.
Main Results:
- Nanoparticles demonstrated efficient loading of asODNs.
- Controlled release of asODNs from nanoparticles was observed.
- FA-HPCS-asODNs nanoparticles inhibited tumor growth by 35% compared to bare asODNs.
- Significant inhibition of MDR 1 gene and P-gp levels was achieved.
- Demonstrated specific and efficient binding to FR-high expressing cancer cells in vivo.
Conclusions:
- FA-HPCS-asODNs nanoparticles represent an effective targeted delivery system for asODNs.
- This approach shows potential for overcoming tumor drug resistance.
- Targeted antisense agent nanoparticles offer a promising strategy for cancer therapy.
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