title: Enhanced transfection efficiency and targeted delivery of self-assembling h-R3-dendriplexes in EGFR-overexpressing tumor cells.
abstract: The efficient gene transfection, cellular uptake and targeted delivery in vivo are key issues for non-viral gene delivery vectors in cancer therapy. To solve these issues, we designed a new targeted gene delivery system based on epidermal growth factor receptor (EGFR) targeting strategy. An anti-EGFR monoclonal antibody h-R3 was introduced to dendriplexes of PAMAM and DNA via electrostatic interactions to form self-assembled h-R3-PAMAM-DNA complexes (h-R3-dendriplexes). Dendriplexes h-R3-dendriplexes represented excellent DNA encapsulation ability and formed unique nanostructures. Compared to dendriplexes, h-R3-dendriplexes presented lower cytotoxicity, higher gene transfection efficiency, excellent endosome escape ability and high nuclear accumulation in the EGFR-overexpressing HepG2 cells. Both ex vivo fluorescence imaging and confocal results of frozen section revealed that h-R3-dendriplexes showed higher targeted delivery and much better gene expression in the tumors than dendriplexes at the same N/P ratio, and h-R3-dendriplexes had accumulation primarily in the tumor and kidney. Moreover, h-R3-dendriplexes for p53 delivery indicated efficient cell growth inhibition and potentiated paclitaxel-induced cell death. These results indicate that the h-R3-dendriplexes represent a great potential to be used as efficient targeted gene delivery carriers in EGFR-overexpressing tumor cells.
authors: School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Jun
authors: J
authors: Li
authors: The Third Clinical College, Southern Medical University, Guangzhou 510515, China.|Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors: Shengnan
authors: S
authors: Li
authors: Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors: Songyun
authors: S
authors: Xia
authors: School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Jinfeng
authors: J
authors: Feng
authors: School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Xuedi
authors: X
authors: Zhang
authors: School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Yanli
authors: Y
authors: Hao
authors: The Third Clinical College, Southern Medical University, Guangzhou 510515, China.|Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors: Lei
authors: L
authors: Chen
authors: School of Medicine, Tsinghua University, Beijing 100084, China.|Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China.
authors: Xiaoning
authors: X
authors: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D050091:Dendrimers / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D050091:Dendrimers; C104700:PAMAM Starburst; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel
keywords: EGFR; PAMAM; gene therapy; h-R3; targeted delivery