BACKGROUND: Targeting of a specific subset of cells is mandatory for the successful application of siRNA mediated silencing in anticancer therapy. A recent theory suggests that colon cancer is sustained by a small subpopulation of cells, termed cancer stem cells (CSCs). These cells are characterized by their innate drug resistance properties, which is one of the key factors of chemotherapy failure. The goal of this study was to assess whether a novel siRNA delivery carrier, with an appropriate siRNA, targeted to CD133+ cells has the potential to improve the efficacy of conventional chemotherapy. METHODS: In this study, a novel synthetic siRNA carrier platform was designed and synthesized. This carrier was composed of a cationic oligomer (PEI(1200)), a hydrophilic polymer (polyethylene glycol) and a biodegradable lipid-based crosslinking moiety. Libraries of polymers were synthesized by varying their lipid composition. Their transfection efficacy was evaluated in vitro using CHOK1 cells. The polymer was characterized using molecular weight, particle encapsulation assay, particle size and surface charge analysis. RESULTS: It was demonstrated that the lipid composition in the polymer plays a critical role in transfection. Optimizing the physicochemical properties of the polymers is crucial in achieving favorable knockdown. Lipid nano complex with composition PEI-Lipid(1:16) was the optimum ratio for gene silencing. Additionally, silencing of multidrug resistance gene (MDR1) and treatment with paclitaxel play a synergistic role in increasing the efficacy as compared to the drug alone. CONCLUSIONS: In the present study a novel siRNA delivery carrier system with an MDR1-targeting siRNA (siMDR1) effectively reduced the expression of MDR1 in human colon CSCs (CD133+ enriched cell population), resulting in significantly increasing the chemosensitivity to paclitaxel.
BACKGROUND: Targeting of a specific subset of cells is mandatory for the successful application of siRNA mediated silencing in anticancer therapy. A recent theory suggests that colon cancer is sustained by a small subpopulation of cells, termed cancer stem cells (CSCs). These cells are characterized by their innate drug resistance properties, which is one of the key factors of chemotherapy failure. The goal of this study was to assess whether a novel siRNA delivery carrier, with an appropriate siRNA, targeted to CD133+ cells has the potential to improve the efficacy of conventional chemotherapy. METHODS: In this study, a novel synthetic siRNA carrier platform was designed and synthesized. This carrier was composed of a cationic oligomer (PEI(1200)), a hydrophilic polymer (polyethylene glycol) and a biodegradable lipid-based crosslinking moiety. Libraries of polymers were synthesized by varying their lipid composition. Their transfection efficacy was evaluated in vitro using CHOK1 cells. The polymer was characterized using molecular weight, particle encapsulation assay, particle size and surface charge analysis. RESULTS: It was demonstrated that the lipid composition in the polymer plays a critical role in transfection. Optimizing the physicochemical properties of the polymers is crucial in achieving favorable knockdown. Lipid nano complex with composition PEI-Lipid(1:16) was the optimum ratio for gene silencing. Additionally, silencing of multidrug resistance gene (MDR1) and treatment with paclitaxel play a synergistic role in increasing the efficacy as compared to the drug alone. CONCLUSIONS: In the present study a novel siRNA delivery carrier system with an MDR1-targeting siRNA (siMDR1) effectively reduced the expression of MDR1 in humancolon CSCs (CD133+ enriched cell population), resulting in significantly increasing the chemosensitivity to paclitaxel.
Authors: Gemma Navarro; Rupa R Sawant; Sean Essex; Conchita Tros de Ilarduya; Vladimir P Torchilin Journal: Drug Deliv Transl Res Date: 2011-02-01 Impact factor: 4.617