Inhibition of ABCB1 (MDR1) Expression by an siRNA Nanoparticulate Delivery System to Overcome Drug Resistance in Osteosarcoma
Copyright policy )Inhibition of ABCB1 (MDR1) Expression by an siRNA Nanoparticulate Delivery System to Overcome Drug Resistance in Osteosarcoma
The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy.In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOS(R2) and U-2OS(R2)) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines.Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.
- Northwestern University United States
- Northeastern University United States
- Massachusetts General Hospital United States
- University of California, San Francisco United States
- Harvard University United States
Medical Biotechnology, Drug Resistance, Intracellular Space, Nanotechnology, RNA, Small Interfering, Cancer, Pediatric, Osteosarcoma, Tumor, Cell Death, Blotting, Q, R, Gene Transfer Techniques, Dextrans, Fluoresceins, Lipids, Subfamily B, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Medicine, Development of treatments and therapeutic interventions, Western, Biotechnology, Research Article, Subcellular Fractions, Member 1, ATP Binding Cassette Transporter, Subfamily B, Pediatric Cancer, General Science & Technology, ATP Binding Cassette Transporter, Science, Blotting, Western, Green Fluorescent Proteins, 610, Bioengineering, Small Interfering, Cell Line, Rare Diseases, Cell Line, Tumor, Genetics, Animals, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Biomedical and Clinical Sciences, Evaluation of treatments and therapeutic interventions, 620, Orphan Drug, Doxorubicin, Drug Resistance, Neoplasm, Neoplasm, RNA, Nanoparticles
Medical Biotechnology, Drug Resistance, Intracellular Space, Nanotechnology, RNA, Small Interfering, Cancer, Pediatric, Osteosarcoma, Tumor, Cell Death, Blotting, Q, R, Gene Transfer Techniques, Dextrans, Fluoresceins, Lipids, Subfamily B, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Medicine, Development of treatments and therapeutic interventions, Western, Biotechnology, Research Article, Subcellular Fractions, Member 1, ATP Binding Cassette Transporter, Subfamily B, Pediatric Cancer, General Science & Technology, ATP Binding Cassette Transporter, Science, Blotting, Western, Green Fluorescent Proteins, 610, Bioengineering, Small Interfering, Cell Line, Rare Diseases, Cell Line, Tumor, Genetics, Animals, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Biomedical and Clinical Sciences, Evaluation of treatments and therapeutic interventions, 620, Orphan Drug, Doxorubicin, Drug Resistance, Neoplasm, Neoplasm, RNA, Nanoparticles
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