title: Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery.
abstract: Long circulation, cell internalization, endosomal escape and small interfering RNA (siRNA) release to the cytoplasm are the prerequisite considerations for siRNA delivery vectors. Herein, a kind of sheddable nanoparticles (NPs) with micelle architecture for siRNA delivery were fabricated by using an intracellular-activated polycation-detachable copolymer (PECssD), which was prepared by introducing highly reducing environment-responsive disulfide linkages between PEGylated polycaprolactone (PCL) and the grafted polycation, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). The architecture of PECssD self-assembled NPs includes a biodegradable hydrophobic PCL core, a PEG shield and a detachable comb-like polycation surface. The stable nanosized complexes of PECssD NPs with siRNA, termed PECssD/siRNA micelleplexes, were formed, which could prolong circulation, improve accumulation and retention in tumor tissue, and be favorable for internalization. In particular, the cleavage of the disulfide linkages in the intracellular microenvironment and the subsequent dissociation of the PDMAEMA/siRNA polyplexes from the PEGylated PCL cores of PECssD/siRNA micelleplexes were also confirmed, which facilitated the endosomal escape and the efficient release of siRNA. As a result, the distribution of siRNA in cytoplasm was enhanced and subsequently promoted the efficiency of siRNA in gene silencing. Furthermore, systemic administration of the NPs carrying siPlk1 (polo-like kinase 1 specific siRNA) induced a tumor-suppressing effect in the HeLa-Luc xenograft murine model. Therefore, the devised strategy of the polycation-detachable copolymer PECssD NPs could address the requirements of the multistep systemic delivery process of siRNA. The hydrophobic core of the PECssD/siRNA micelleplexes is expected to entrap antitumor drugs or other therapeutic agents for combined therapies.
authors.affiliation: Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering, Ministry of Education of China, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Daoshu
authors.initials: D
authors.lastname: Lin
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cheng
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Huang
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Huang
authors.forename: Shangcong
authors.initials: S
authors.lastname: Han
authors.forename: Shutao
authors.initials: S
authors.lastname: Guo
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
mesh_terms: D000818:Animals; D002412:Cations; D004220:Disulfides / Q000737:chemistry; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008422:Materials Testing; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D009757:Nylons / Q000737:chemistry*; D009928:Organ Specificity; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: D002412:Cations; D004220:Disulfides; D008689:Methacrylates; D053769:Nanocapsules; D009757:Nylons; D011091:Polyesters; D034741:RNA, Small Interfering; C407037:poly(2-(dimethylamino)ethyl methacrylate); C502908:poly(ethylene glycol)-poly(caprolactone)-poly(ethylene glycol); D011092:Polyethylene Glycols