title: Oral delivery of shRNA and siRNA via multifunctional polymeric nanoparticles for synergistic cancer therapy.
abstract: Galactose modified trimethyl chitosan-cysteine (GTC) conjugates with various galactose grafting densities were developed for oral delivery of Survivin shRNA-expression pDNA (iSur-pDNA) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) in the synergistic and targeted treatment of hepatoma. iSur-pDNA and siVEGF loaded GTC nanoparticles (NPs) were prepared via electrostatic complexation and showed desirable stability in physiological fluids and improved intestinal permeation compared to naked genes. Galactose grafting density of GTC NPs significantly affected their in vitro and in vivo antitumor activities. GTC NPs with moderate galactose grafting density, termed GTC2 NPs, were superior in facilitating cellular uptake, promoting nuclear distribution, and silencing target genes, leading to notable inhibition of cell growth. In tumor-bearing mice, orally delivered GTC2 NPs could effectively accumulate in the tumor tissues and silence the expression of Survivin and VEGF, evoking increased apoptosis, inhibited angiogenesis, and thus the most efficient tumor regression. Moreover, compared with single gene delivery, co-delivery of iSur-pDNA and siVEGF showed synergistic effects on inhibiting in vitro cell proliferation and in vivo tumor growth. This study could serve as an effective approach for synergistic cancer therapy via oral gene delivery, and highlighted the importance of ligand grafting density in the rational design of targeted nanocarriers.
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; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000031:analogs & derivatives*; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D015316:Genetic Therapy; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D048271:Chitosan; D005690:Galactose
keywords: Cancer therapy; Oral delivery; Polymeric nanoparticles; Survivin shRNA; VEGF siRNA