Limits...
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.

Show MeSH

Related in: MedlinePlus

Characterization of stearylamine-dextran modified nanoparticles.500 MHz 1H NMR spectra of dextran and dextran conjugated stearyl amine after purification using D2O as the solvent. The spectra clearly show the additional peaks of the long chain fatty amine at ∼1ppm indicating the successful lipid modification of dextran. The % fat modification was estimated to be 7 mole % of dextran.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2875382&req=5

pone-0010764-g001: Characterization of stearylamine-dextran modified nanoparticles.500 MHz 1H NMR spectra of dextran and dextran conjugated stearyl amine after purification using D2O as the solvent. The spectra clearly show the additional peaks of the long chain fatty amine at ∼1ppm indicating the successful lipid modification of dextran. The % fat modification was estimated to be 7 mole % of dextran.

Mentions: A desired amount (200mg) of dextran acrylate obtained from above step was dissolved in dry DMF and stirred in a 20ml glass vial with varying amounts (5–10 mole %) of stearylamine and a catalyst (0.01 mole % AlCl3). The reaction mixture was heated to 40–50°C in an oil bath for 24 h. The product obtained (stearylamine - modified dextran) was precipitated and washed in cold ethanol several times to purify the product. Finally, the lipid-modified dextran derivative was dissolved in small amount of deionized water and lyophilized to yield the pale yellow colored final product. The fatty amine modification of dextran was confirmed by 1H NMR spectroscopy (Varian 500MHz NMR spectrometer, Varian Inc, CA) and the % lipid modification was estimated to be 7 mole% (Fig. 1).


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)

Characterization of stearylamine-dextran modified nanoparticles.500 MHz 1H NMR spectra of dextran and dextran conjugated stearyl amine after purification using D2O as the solvent. The spectra clearly show the additional peaks of the long chain fatty amine at ∼1ppm indicating the successful lipid modification of dextran. The % fat modification was estimated to be 7 mole % of dextran.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0010764-g001: Characterization of stearylamine-dextran modified nanoparticles.500 MHz 1H NMR spectra of dextran and dextran conjugated stearyl amine after purification using D2O as the solvent. The spectra clearly show the additional peaks of the long chain fatty amine at ∼1ppm indicating the successful lipid modification of dextran. The % fat modification was estimated to be 7 mole % of dextran.
Mentions: A desired amount (200mg) of dextran acrylate obtained from above step was dissolved in dry DMF and stirred in a 20ml glass vial with varying amounts (5–10 mole %) of stearylamine and a catalyst (0.01 mole % AlCl3). The reaction mixture was heated to 40–50°C in an oil bath for 24 h. The product obtained (stearylamine - modified dextran) was precipitated and washed in cold ethanol several times to purify the product. Finally, the lipid-modified dextran derivative was dissolved in small amount of deionized water and lyophilized to yield the pale yellow colored final product. The fatty amine modification of dextran was confirmed by 1H NMR spectroscopy (Varian 500MHz NMR spectrometer, Varian Inc, CA) and the % lipid modification was estimated to be 7 mole% (Fig. 1).

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