title: Antibody h-R3-dendrimer mediated siRNA has excellent endosomal escape and tumor targeted delivery ability, and represents efficient siPLK1 silencing and inhibition of cell proliferation, migration and invasion.
abstract: The major obstacle to developing siRNA delivery is their extracellular and intracellular barriers. Herein, a humanized anti-EGFR monoclonal antibody h-R3 was developed to modify the self-assembled binary complexes (dendriplexes) of PAMAM and siRNA via electrostatic interactions, and two common ligands HSA and EGF were used as a control. Compared to dendriplexes, h-R3/EGF/HSA-dendriplexes showed increased particle size, decreased zeta potentials and lower cytotoxicity. Moreover, h-R3-dendriplexes presented greater cellular uptake and excellent endosomal escape ability in HepG2 cells. Ex vivo fluorescence imaging revealed that h-R3-dendriplexes showed higher targeted delivery and gene expression in the tumors than dendriplexes, HSA-dendriplexes and EGF-dendriplexes, which was in agreement with confocal results of cryosections. Furthermore, h-R3-dendriplexes for siPLK1 delivery indicated efficient gene silencing, potentiated cell growth inhibition and cell apoptosis, and suppressed cellular migration/invasion. These results indicate that h-R3-dendriplexes represent a great potential to be used as efficient targeted siRNA delivery carriers.
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China.|Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D002465:Cell Movement; D049109:Cell Proliferation; D050091:Dendrimers / Q000737:chemistry*; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018797:Cell Cycle Proteins; D050091:Dendrimers; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C104700:PAMAM Starburst; C512478:EGFR protein, human
keywords: EGFR; h-R3; siPLK1; siRNA delivery; targeted delivery