title: Tailoring nanostructured solid-lipid carriers for time-controlled intracellular siRNA kinetics to sustain RNAi-mediated chemosensitization.
abstract: Use of siRNA for silencing major oncogenic/chemoresistance targets such as survivin has strong potential for cancer therapy. However, a key clinical limitation is their short action, preventing them from sustaining their therapeutic RNA-interference activity for optimal chemosensitization. This issue is tackled from the perspective of intracellular siRNA kinetics using a novel lipid-based "nanostructured siRNA carrier" (NSC), which incorporates variable amount of oil phase into the solid-lipid matrix to modify its siRNA release behaviors. We demonstrate that by manipulating the degradation responses of NSC device to lysosomal enzyme, tailoring of intracellular siRNA kinetics is achievable. A tailored NSC design delivering survivin-siRNA can extend the survivin knockdown period to 9 days, translating into steady, effective in vitro and in vivo chemosensitization of prostate cancer to docetaxel for over a week. All in all, this new NSC design provides a convenient mean to set up a clinically more appealing weekly or longer dosing cycle for siRNA therapy, which addresses a significant unmet need for prostate cancer treatment and is potentially useful for other chronic disease conditions as well.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Hui Yi
authors.initials: HY
authors.lastname: Xue
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
mesh_terms: D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D010316:Particle Size; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism*; D055672:Static Electricity; D002787:Sterol Esterase / Q000378:metabolism; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors
chemical_list: C107489:BIRC5 protein, human; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D008055:Lipids; D034741:RNA, Small Interfering; D000077022:Survivin; D043823:Taxoids; D000077143:Docetaxel; D002787:Sterol Esterase