title: Enhanced antitumor efficacies of multifunctional nanocomplexes through knocking down the barriers for siRNA delivery.
abstract: Multifunctional nanocomplexes (NCs) consisting of urocanic acid-modified galactosylated trimethyl chitosan (UA-GT) conjugates as polymeric vectors, poly(allylamine hydrochloride)-citraconic anhydride (PAH-Cit) as charge-reversible crosslinkers, and vascular endothelial growth factor (VEGF) siRNA as therapeutic genes, were rationally designed to simultaneously overcome the extracellular, cellular, and intracellular barriers for siRNA delivery. The strong physical stability of UA-GT/PAH-Cit/siRNA NCs (UA-GT NCs) at pH 7.4 and 6.5 endowed protection from massive dilution, competitive ions, and ubiquitous nucleases in the blood and tumorous microenvironment. Their internalization into hepato-carcinoma cells was facilitated through the recognition of galactose receptors, followed by effective escape from endosomes/lysosomes owing to the strong buffering capacity of imidazole residues. At the meantime, the endosomal/lysosomal acidity triggered the charge reversal of PAH-Cit in UA-GT NCs, thus evoking their structural disassembly and subsequently accelerated release of siRNA in the cytosol. As a result, robust in vivo performance in terms of both gene silencing and tumor inhibition was achieved by UA-GT NCs at a low siRNA dose. Moreover, neither histological nor hematological toxicity was detected following repeated intravenous administration. Therefore, UA-GT NCs potentially served as an efficient and safe candidate in the treatment of hepatocellular carcinoma through knocking down the overall barriers for siRNA delivery.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: chyin@fudan.edu.cn.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002021:Buffers; D045744:Cell Line, Tumor; D048271:Chitosan / Q000138:chemical synthesis / Q000737:chemistry; D002949:Citraconic Anhydrides / Q000138:chemical synthesis / Q000737:chemistry; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005690:Galactose / Q000737:chemistry; D020868:Gene Silencing / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D055672:Static Electricity; D014560:Urocanic Acid / Q000138:chemical synthesis / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002021:Buffers; D002949:Citraconic Anhydrides; C118071:N-trimethyl chitosan chloride; D011073:Polyamines; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C063994:polyallylamine; D048271:Chitosan; D014560:Urocanic Acid; D005690:Galactose
keywords: Active targeting; Cancer therapy; Endosomal escape; Extracellular stability; Intracellular release; siRNA delivery