Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 63, Issue 4, Pages 711-722Publisher
SPRINGER
DOI: 10.1007/s00280-008-0790-y
Keywords
Multidrug resistance; MDR-1 gene silencing siRNA; Paclitaxel; SKOV3 human ovarian adenocarcinoma cells; Poly(beta-amino ester); Poly(epsilon-caprolactone)
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Funding
- NCI NIH HHS [R01-CA119617] Funding Source: Medline
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In this study, the effect of MDR-1 gene silencing, using small interfering RNA (siRNA), and paclitaxel (PTX) co-therapy in overcoming tumor multidrug resistance was examined. Poly(ethylene oxide)-modified poly(beta-amino ester) (PEO-PbAE) and PEO-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were formulated to efficiently encapsulate MDR-1 silencing siRNA and PTX, respectively. Upon administration in multidrug resistant SKOV3(TR) human ovarian adenocarcinoma cells, siRNA-mediated MDR-1 gene silencing was evident at 100 nM dose. Combination of MDR-1 gene silencing and nanoparticle-mediated delivery significantly influenced the cytotoxic activity of PTX in SKOV3TR cells similar to what was observed in drug sensitive SKOV3 cells. We speculate that the enhancement in cytotoxicity was due to an increase in intracellular drug accumulation upon MDR-1 gene silencing leading to an apoptotic cell-kill effect. Taken together, these preliminary results are highly encouraging for the development of combination nano-therapeutic strategies that combine gene silencing and drug delivery to provide more potent therapeutic effect, especially in refractory tumors.
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