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.
Highlights
Cationic polyamidoamine (PAMAM) dendrimers are hyperbranched spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery
We investigated whether PF inhibited the acute stimulation of epidermal growth factor receptor (EGFR) phosphorylation by its ligand
PF dendrimer-mediated inhibition of EGFR phosphorylation is accompanied by inhibition of downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK)
Summary
Cationic polyamidoamine (PAMAM) dendrimers are hyperbranched spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery. These biomacromolecules have an ethylenediamine core and radiating branches with terminal amino (-NH2) groups whose synthesis can be precisely controlled to produce progressive generations with defined molecular architecture, terminal functional chemistry and low polydispersity [1,2,3,4]. PAMAM dendrimers can be further modified to reduce internal structural branching and increase internal volume by controlled heat-treatment in solvolytic solvents to produce so-called “fractured” or “activated” dendrimers for improved drug entrapment [6,7]. As a result of their ability to bind to negatively charged nucleic acids and efficiently enter cells by endocytosis and/or via membrane pore formation [8,9,10], cationic PAMAM polymers have been extensively investigated for gene, oligonucleotide and siRNA delivery [3,8,10,11,12,13,14,15,16,17,18]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.