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.

Composites of Polymer Hydrogels and Nanoparticulate Systems for Biomedical and Pharmaceutical Applications

“…Among the various types of polymeric NPs, dendrimer, a synthetic polymeric macromolecule of nanometer dimensions, are particularly fascinating, due to its unparalleled molecular uniformity, narrow molecular weight distribution, defined size and shape characteristics, highly branched structure, available internal cavity as well as a multifunctional terminal surface. These physicochemical characteristics of dendrimers, especially the multitude of functional groups on their periphery and abundant cavities within their interior, lead to higher reactivity and loading efficiency compared to the linear polymers, which make these macromolecules appropriate candidates for drug delivery [ 417 , 454 , 455 ]. Dendritic nanoparticles can also be incorporated into the hydrogel network via covalent or non-covalent interactions between dendrimers and the polymeric chains to obtain reinforced nanocomposite hydrogels with specific performance.…”

Targeted nanosystems: Advances in targeted dendrimers for cancer therapy

“…48 Activated (i.e., SuperFect) and non-activated (i.e., Polyfect) PAMAM dendrimers can differentially modulate EGFR signaling pathway. 49 Such intrinsic therapeutic functions endowed by dendrimers themselves may be integrated into drug delivery system design and offer additional therapeutic benefits for cancer therapy.…”

Pathway-Based Drug-Repurposing Schemes in Cancer: The Role of Translational Bioinformatics

“…Anlotinib main use in cancer was already established to treat aggressively, drug-resistant tumors such as glioblastoma ( 85 ); Poziotinib ( 86 – 88 ). Other available EGFR-targeting molecules include Dacomitinib ( 89 ) and cationic polyamidoamine dendrimers ( 90 ).…”