title: Epidermal growth factor-PEG functionalized PAMAM-pentaethylenehexamine dendron for targeted gene delivery produced by click chemistry.
abstract: Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined multifunctional carriers for targeted gene delivery. For this purpose, at first propargyl amine cored PAMAM dendrons with ester ends were synthesized. The chain terminal ester groups were then modified by oligoamines with different secondary amino densities. The oligoamine-modified PAMAM dendrons were well biocompatible, as demonstrated in cytotoxicity assays. Among the different oligoamine-modified dendrons, PAMAM-pentaethylenehexamine (PEHA) dendron polyplexes displayed the best gene transfer ability. Conjugation of PAMAM-PEHA dendron with PEG spacer was conducted via click reaction, which was performed before amidation with PEHA. The resultant PEG-PAMAM-PEHA copolymer was then coupled with EGF ligand. pDNA transfections in HuH-7 hepatocellular carcinoma cells showed a 10-fold higher efficiency with the polyplexes containing conjugated EGF as compared to the ligand-free ones, demonstrating the concept of ligand targeting. Overall gene transfer efficiencies, however, were moderate, suggesting that additional measures for overcoming subsequent intracellular bottlenecks in delivery have to be taken.
authors.affiliation: Department of Pharmacy, and Center for Nanoscience (CeNS), Ludwig-Maximilians Universität , Butenandtstrasse 5-13, D-81377 Munich, Germany.
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.forename: Christian
authors.initials: C
authors.lastname: Dohmen
authors.forename: Yunqiu
authors.initials: Y
authors.lastname: Li
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D004247:DNA / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D050091:Dendrimers / Q000138:chemical synthesis* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010957:Plasmids / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
chemical_list: D000588:Amines; D050091:Dendrimers; C522249:PEG-PAMAM; D011073:Polyamines; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; D004247:DNA; C031122:pentaethylenehexamine