title: Lipid modified triblock PAMAM-based nanocarriers for siRNA drug co-delivery.
abstract: RNA interference by small interfering RNA (siRNA) holds promise to attenuate production of specific target proteins but is challenging in practice owing to the barriers for its efficient intracellular delivery. We have synthesized a triblock co-polymeric system, poly(amidoamine) dendrimer (generation 4)-poly(ethylene glycol)-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (G(4)-D-PEG-(2K)-DOPE). G(4)-PAMAM dendrimer was utilized as a cationic source for efficient siRNA condensation; DOPE provided optimum hydrophobicity and compatible cellular interaction for enhanced cell penetration; PEG rendered flexibility to the G(4)-D for easy accessibility of siRNA for condensation; PEG-DOPE system provided stable micellization in a mixed micellar system. G(4)-D-PEG-(2K)-DOPE was incorporated into the self-assembled PEG-(5K)-PE micelles at a 1:1 molar ratio. Our results demonstrate that the modified dendrimer, G(4)-D-PEG-(2K)-DOPE and the micellar nanocarrier form stable polyplexes with siRNA, shows excellent serum stability and a significantly higher cellular uptake of siRNA that results in target protein down-regulation when compared to the G(4)-PAMAM dendrimer. Moreover, the mixed micellar system showed efficient micellization and higher drug (doxorubicin) loading efficiency. The G(4)-D-PEG-(2K)-DOPE has the higher efficacy for siRNA delivery, whereas G(4)-D-PEG-(2K)-DOPE/PEG-(5K)-PE micelles appear to be a promising carrier for drug/siRNA co-delivery, especially useful for the treatment of multi-drug resistant cancers.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, 360 Huntington Avenue, 140 The Fenway, Northeastern University, Boston, MA 02115, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Pranali P
authors.initials: PP
authors.lastname: Deshpande
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Namita S
authors.initials: NS
authors.lastname: Dodwadkar
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage*; D004338:Drug Combinations; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000970:Antineoplastic Agents; D050091:Dendrimers; D004338:Drug Combinations; D053769:Nanocapsules; C104700:PAMAM Starburst; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; D004317:Doxorubicin