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Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma.

Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, Duan Z - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: 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.

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Effect of MDR1 siRNA loaded nanoparticle on P-gp – mediated uptake and efflux was analyzed using calcein AM.Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and this was confirmed by microplate spectrofluorometer analysis. P values are shown as follows: *P<0.05.
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pone-0010764-g005: Effect of MDR1 siRNA loaded nanoparticle on P-gp – mediated uptake and efflux was analyzed using calcein AM.Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and this was confirmed by microplate spectrofluorometer analysis. P values are shown as follows: *P<0.05.

Mentions: Reversal of MDR is usually manifested as an increased intracellular accumulation of chemotherapeutics, which can be achieved by disturbing P-gp-mediated drug uptake and efflux. Therefore, the effect of MDR1 siRNA loaded nanoparticles was examined for the uptake and efflux of a P-gp substrate, calcein AM, in KHOSR2. Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and confirmed by microplate spectrofluorometer analysis (Fig. 5).


Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma.

Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, Duan Z - PLoS ONE (2010)

Effect of MDR1 siRNA loaded nanoparticle on P-gp – mediated uptake and efflux was analyzed using calcein AM.Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and this was confirmed by microplate spectrofluorometer analysis. P values are shown as follows: *P<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2875382&req=5

pone-0010764-g005: Effect of MDR1 siRNA loaded nanoparticle on P-gp – mediated uptake and efflux was analyzed using calcein AM.Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and this was confirmed by microplate spectrofluorometer analysis. P values are shown as follows: *P<0.05.
Mentions: Reversal of MDR is usually manifested as an increased intracellular accumulation of chemotherapeutics, which can be achieved by disturbing P-gp-mediated drug uptake and efflux. Therefore, the effect of MDR1 siRNA loaded nanoparticles was examined for the uptake and efflux of a P-gp substrate, calcein AM, in KHOSR2. Cells treated with MDR1 siRNA were shown to decrease calcein AM efflux in a dose-dependent manner as determined by image analysis, and confirmed by microplate spectrofluorometer analysis (Fig. 5).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: 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.

Show MeSH
Related in: MedlinePlus