Virus-mimetic polymeric micelles for targeted siRNA delivery.
In this study, an engineered non-viral polymer based delivery systems with structural features mimicking that of viral vectors was developed and the potential of this carrier for siRNA delivery was assessed. The developed siRNA carrier was based on poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles decorated with integrin alphavbeta3 targeting peptide (RGD4C) and/or cell penetrating peptide (TAT) on the PEO shell, and modified with a polycation (spermine) in the PCL core for siRNA binding and protection. We observed increased cellular uptake and effective endosomal escape of siRNA delivered with the peptide-functionalized micelles especially those with dual functionality (RGD/TAT-micelles) compared to unmodified micelles (NON-micelles) in MDA435/LCC6 resistant cells. Transfection of mdr1 siRNA formulated in peptide-modified micelles led to P-gp down regulation both at the mRNA and protein level. Subsequent to P-gp down regulation, increased cellular accumulation of P-gp substrate, doxorubicin (DOX), in the cytoplasm and nucleus of resistant MDA435/LCC6 cells after treatment with peptide decorated polymeric micelle/mdr1 siRNA complexes was observed. As a result, resistance to DOX was successfully reversed. Interestingly, RGD/TAT-micellar siRNA complexes produced improved cellular uptake, P-gp silencing, DOX cellular accumulation, DOX nuclear localization and DOX induced cytotoxicity in MDA435/LCC6 cells when compared to micelles decorated with individual peptides. Results of this study indicated a potential for RGD/TAT-functionalized virus-like micelles as promising carriers for efficient delivery of mdr1 siRNA to MDA435/LCC6 resistant cells as means to reverse the P-gp mediated multidrug resistance to DOX.
Xiong
Xiao-Bing
XB
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2N8, Canada.
Uludağ
Hasan
H
Lavasanifar
Afsaneh
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D040761:Biomimetic Materials / Q000737:chemistry*; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D008823:Micelles; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection; D014780:Viruses / Q000737:chemistry*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D011108:Polymers; D034741:RNA, Small Interfering