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Title: Toxicology of PAMAM Dendrimer Nanoparticles: Impact on EGFR Signaling in Normal and Diabetic Rat Kidney
Authors: Bashaier Jassim Al-Zaid 
Supervisor: Prof. Saghir Akhtar
Keywords: Polyamidoamine;Diabetic Kidneys;EGFR;Toxicology
Issue Date: 2012
Publisher:  Kuwait university - college of graduate studies
Abstract: Polyamidoamine (PAMAM) dendrimers are highly branched, cationic macromolecules that are employed as drug delivery systems in vitro and in vivo. Ideally, delivery vectors should only possess drug delivery enhancing properties and exhibit no other adverse effects in vivo. It is known that PAMAM dendrimers can modulate global gene expression in cell culture but little is known about their in vivo toxicological profiles in term of their proteomic interactions at the level of signal transduction pathways. In this study we investigated, for the first time, the in vivo impact of Superfect (SF) and Polyfect (PF), two PAMAM dendrimers with identical monomer chemistry but different structural architecture, on signaling pathways involving EGFR, and its two potential downstream effector molecules, Extracellular-regulated kinase 1/2 (ERK1/2) and p38 Mitogenactivated protein kinase (MAPK), in the normal and diabetic kidneys of male Wistar rats. Diabetic kidney of streptozotocin-treated rats exhibited significantly enhanced total and phosphorylated levels of EGFR by about 3-fold compared to normal (nondiabetic) kidney thereby providing two animal models of either low (normal) and high (diabetic) basal EGFR expression in which to investigate the effects of dendrimers. To study their impact on the EGFR signaling pathway, SF and PF dendrimers at doses of either 1, 5, or 10 mg/kg as well as the selective EGFR tyrosine kinase inhibitor, AG1478 (1mg/kg), were systemically administered via intraperitoneal (i.p) injection 24 hours prior to sacrifice. Western blot analyses of kidneys isolated from either normal or diabetic animals post-sacrifice showed that AG1478, as expected, inhibited EGFR phosphorylation and that this was accompanied by an inhibition of ERK1/2 and p38 MAPK phosphorylation confirming their role as downstream effectors of the EGFR signalling pathway in the kidney. In contrast to the effects observed with AG1478, both PF and SF PAMAM dendrimers had an inhibitory effect on EGFR phosphorylation at a dose of 1mg/kg and both dendrimers exhibited progressively less inhibition as a function of increasing the dose to 5 and 10 mg/kg to a point where at the highest dose studied, SF actually exhibited stimulatory, whereas PF had inhibitory, effects on EGFR phosphorylation in both normal and diabetic kidneys. These data showed that at the v highest dose studied PF and SF had opposing effects on EGFR signaling in the kidney of both normal and diabetic animals- an effect that might be related to their differing structural architectures. Since dendrimer-mediated changes in EGFR signaling were similar in both normal and diabetic kidney, our data suggested the impact of PAMAM dendrimers, at least on EGFR, was independent of the differing basal EGFR levels in the two animal models investigated. Surprisingly, dendrimer-mediated dose dependent changes in ERK1/2 and p38 MAPK expression or phosphorylation did not match dendrimer-induced changes in EGFR signaling in the diabetic kidney and furthermore, dendrimer-mediated effects on ERK1/2 and p38 MAPK varied between normal and diabetic kidneys. These data imply that PAMAM dendrimers can modulate ERK1/2 and p38 MAPK signaling independent of the EGFR pathway, possibly via modulation of other upstream effectors whose signaling also involves these molecules, and that their effects on ERK1/2 and p38 MAPK appeared to be dependent on the different basal levels of these signaling pathways. Finally, SF and PF dendrimer effects on ERK1/2 and p38 MAPK in the diabetic kidney cortex and medulla were similar to each other and also were consistent with those obtained in the whole kidney thereby implying that both dendrimers were able to distribute evenly within the two main regions of the kidney following systemic i.p. administration. Taken together, these data imply that SF and PF PAMAM dendrimer delivery systems, aside from their drug delivery enhancing properties, can exert complex and often differential effects on important in vivo signaling cascades involving EGFR, ERK1/2 and p38 MAPK in the normal and diabetic rat kidney. The direct biological and pathological consequences of these dendrimer-mediated effects require further study and therefore, further more detailed understanding of their toxicology at the proteomic level will be important in assessing their safety prior to their potential use in the clinic.
Appears in Programs:0550 Pharmacology (M.Sc.)

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