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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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Related in: MedlinePlus

Western blot assay was performed to assess the duration of MDR1 siRNA loaded nanoparticle.siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (A). Inhibition of P-gp started slower when MDR1 siRNA was loaded in to nanoparticles, but exhibited longer inhibition compared to MDR1 siRNA transfected with commercially available agent (B). P values are shown as follows: *P<0.05.
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pone-0010764-g004: Western blot assay was performed to assess the duration of MDR1 siRNA loaded nanoparticle.siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (A). Inhibition of P-gp started slower when MDR1 siRNA was loaded in to nanoparticles, but exhibited longer inhibition compared to MDR1 siRNA transfected with commercially available agent (B). P values are shown as follows: *P<0.05.

Mentions: Western blotting was performed to estimate the effect of MDR1 siRNA loaded nanoparticle on P-gp expression. P-gp expression has been previously confirmed in the two drug resistant cell lines KHOSR2 and U-2OSR2 (data not shown). MDR1 siRNA loaded nanoparticle inhibited the expression of P-gp at a concentration of as low as 30 nM (Fig. 3A, B). siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (Fig. 4A). siRNA loaded nanoparticles were slower in achieving the suppression of P-gp, but were able to maintain suppression for 96 hours (Fig. 4B).


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)

Western blot assay was performed to assess the duration of MDR1 siRNA loaded nanoparticle.siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (A). Inhibition of P-gp started slower when MDR1 siRNA was loaded in to nanoparticles, but exhibited longer inhibition compared to MDR1 siRNA transfected with commercially available agent (B). 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-g004: Western blot assay was performed to assess the duration of MDR1 siRNA loaded nanoparticle.siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (A). Inhibition of P-gp started slower when MDR1 siRNA was loaded in to nanoparticles, but exhibited longer inhibition compared to MDR1 siRNA transfected with commercially available agent (B). P values are shown as follows: *P<0.05.
Mentions: Western blotting was performed to estimate the effect of MDR1 siRNA loaded nanoparticle on P-gp expression. P-gp expression has been previously confirmed in the two drug resistant cell lines KHOSR2 and U-2OSR2 (data not shown). MDR1 siRNA loaded nanoparticle inhibited the expression of P-gp at a concentration of as low as 30 nM (Fig. 3A, B). siRNA transfected with siPORT™ NeoFX™ Transfection Agent was able to suppress P-gp expression for 48 hours (Fig. 4A). siRNA loaded nanoparticles were slower in achieving the suppression of P-gp, but were able to maintain suppression for 96 hours (Fig. 4B).

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