Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery.
Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood, limits the effectiveness of the systemic delivery of siRNA. In order to overcome such difficulties, we constructed a nanocarrier-based delivery system by taking advantage of the lessons learned from the problems in the delivery of DNA. In the present study, siRNA nanoparticles were first formulated with Poly(Propyleneimine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive environment in the blood stream, the formed siRNA nanoparticles were caged with a dithiol containing cross-linker molecules followed by coating them with Poly(Ethylene Glycol) (PEG) polymer. A synthetic analog of Luteinizing Hormone-Releasing Hormone (LHRH) peptide was conjugated to the distal end of PEG polymer to direct the siRNA nanoparticles specifically to the cancer cells. Our results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles stability in plasma and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of siRNA in the cytoplasm of cancer cells, and efficient gene silencing. In addition, in vivo body distribution data confirmed high specificity of the proposed targeting delivery approach which created the basis for the prevention of adverse side effects of the treatment on healthy organs.
Taratula
Oleh
O
Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
Garbuzenko
Olga B
OB
Kirkpatrick
Paul
P
Pandya
Ipsit
I
Savla
Ronak
R
Pozharov
Vitaly P
VP
He
Huixin
H
Minko
Tamara
T
D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry; D016503:Drug Delivery Systems; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D011126:Polypropylenes / Q000737:chemistry*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000097:blood; D013499:Surface Properties; D014018:Tissue Distribution; D014050:Toluene / Q000031:analogs & derivatives
D050091:Dendrimers; D007202:Indicators and Reagents; D011126:Polypropylenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C443641:poly(propyleneimine); D007987:Gonadotropin-Releasing Hormone; D014050:Toluene; C004848:dithiol