Abstract
Abstract
Background: Osteosarcoma accounts for approximately 60% of primary malignant bone tumors diagnosed in the first two decades of life. 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. One of the innovative approaches to addressing MDR is to inhibit MDR1 mRNA expression by RNA interference (RNAi). 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.
Materials and Methods: 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. The mean particle size of the MDR1 siRNA loaded nanoparticles as determined by dynamic light scattering (DLS) measurement was 104.4+3.7 nm and the zeta potential was almost neutral (−0.19+1.13 mV). Multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluorescence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed.
Results: We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. With the delivery of nanoparticles loaded with MDR1 siRNA, growth inhibition with doxorubicin was substantially more marked than with the administration of 100 fold higher amounts of free drugs. 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. Furthermore, subcellular distribution of doxorubicin in MDR cells mimicked that of the drug sensitive variant when nanoparticles were utilized.
Conclusions: 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.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3526.