title: Arginine-engrafted biodegradable polymer for the systemic delivery of therapeutic siRNA.
abstract: Small interfering RNA (siRNA) represent an interesting class of developmental nucleic acid-based therapeutics. Cationic carriers for deoxyribonucleic acids (DNA) are potential vehicles for siRNA delivery. However, in contrast to supercoiled plasmid DNA, the physical properties of siRNA molecules induces the formation of larger, loosely-packed complexes with most polycationic carriers, and consequently, poor target silencing. Here, we investigate a gene delivery agent, arginine-grafted bioreducible poly (disulfide amine) polymer (ABP) for siRNA delivery as it contains arginine residues with siRNA binding properties. ABP combines the attributes of polycations and poly disulfide-amines namely- excellent cell-penetrability and rapid release after disulphide bond reduction in the intracellular compartment. ABP bound siRNA, assembled into stable 150 nm sized nanoparticles and efficiently released complexed siRNA upon cellular entry. We investigated the utility of ABP in a combinatorial RNAi strategy for solid cancer therapy. Systemic administration of ABP-siRNA resulted in a preferential and enhanced accumulation of carrier-siRNA complexes in the tumor tissue. Two administrations of the formulation with a siRNA cocktail targeting Bcl-2, VEGF and Myc at 0.3 mg total siRNA/kg body weight could effectively regress advanced stage tumors. Our results establish the promise of ABP as a common systemic delivery platform for both siRNA and DNA therapeutics.
authors: Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
authors: Jagadish
authors: J
authors: Beloor
authors: Chang Seon
authors: CS
authors: Choi
authors: Hye Yeong
authors: HY
authors: Nam
authors: Minsun
authors: M
authors: Park
authors: Sung Hwa
authors: SH
authors: Kim
authors: Andrew
authors: A
authors: Jackson
authors: Kuen Yong
authors: KY
authors: Lee
authors: Sung Wan
authors: SW
authors: Kim
authors: Priti
authors: P
authors: Kumar
authors: Sang-Kyung
authors: SK
authors: Lee
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001672:Biocompatible Materials / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055598:Chemical Phenomena; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D008545:Melanoma / Q000473:pathology / Q000628:therapy; D051379:Mice; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D011108:Polymers; D034741:RNA, Small Interfering; D001120:Arginine