title: Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo.
abstract: Cationic polyamidoamine (PAMAM) dendrimers are branch-like spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery. Emerging evidence suggests they exhibit intrinsic biological and toxicological effects but little is known of their interactions with signal transduction pathways. We previously showed that the activated (fragmented) generation (G) 6 PAMAM dendrimer, Superfect (SF), stimulated epidermal growth factor receptor (EGFR) tyrosine kinase signaling-an important signaling cascade that regulates cell growth, survival and apoptosis- in cultured human embryonic kidney (HEK 293) cells. Here, we firstly studied the in vitro effects of Polyfect (PF), a non-activated (intact) G6 PAMAM dendrimer, on EGFR tyrosine kinase signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in cultured HEK 293 cells and then compared the in vivo effects of a single administration (10mg/kg i.p) of PF or SF on EGFR signaling in the kidneys of normal and diabetic male Wistar rats. Polyfect exhibited a dose- and time-dependent inhibition of EGFR, ERK1/2 and p38 MAPK phosphorylation in HEK-293 cells similar to AG1478, a selective EGFR inhibitor. Administration of dendrimers to non-diabetic or diabetic animals for 24h showed that PF inhibited whereas SF stimulated EGFR phosphorylation in the kidneys of both sets of animals. PF-mediated inhibition of EGFR phosphorylation as well as SF or PF-mediated apoptosis in HEK 293 cells could be significantly reversed by co-treatment with antioxidants such as tempol implying that both these effects involved an oxidative stress-dependent mechanism. These results show for the first time that SF and PF PAMAM dendrimers can differentially modulate the important EGFR signal transduction pathway in vivo and may represent a novel class of EGFR modulators. These findings could have important clinical implications for the use of PAMAM dendrimers in nanomedicine.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Bashayer
authors.initials: B
authors.lastname: Al-Zaid
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: El-Hashim
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Bindu
authors.initials: B
authors.lastname: Chandrasekhar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Attur
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait.
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University, Safat 13110, Jabriya, Kuwait; Faculty of Medicine, Eastern Mediterranean University, Famagusta, North Cyprus.
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines; D066246:ErbB Receptors