On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR–ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells

Akhtar, Saghir; Chandrasekhar, Bindu; Attur, Sreeja; Yousif, Mariam H. M.; Benter, İbrahim F.

doi:10.1016/j.ijpharm.2013.03.039

Cited by 31 publications

(37 citation statements)

References 40 publications

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“…Human embryonic kidney (HEK 293) cells obtained from ECACC were a gift from Dr S Al-Sabah (Kuwait University) and cultured as described by us previously [ 36 ]. Briefly, cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 4.5 mg/ml glucose, 10% heat-inactivated fetal bovine serum (FBS; Hyclone, USA), 100 mg/ml Antibiotic-Antimycotic (Invitrogen, USA), and in humidified conditions under 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that the activated G6 PAMAM dendrimer, Superfect (SF), stimulated EGFR tyrosine kinase signaling in cultured human embryonic kidney (HEK-293) cells [ 36 ]. Here, we firstly studied the in vitro effects of naked, as supplied, non-activated (intact) G6 PAMAM dendrimer, Polyfect (PF), 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 i.p.…”

Section: Introductionmentioning

confidence: 99%

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Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

et al. 2015

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

et al. 2015

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“…As a result, intracellular uptake promotes the degradation of the dendrimers and release of Mn, thereby causing strong MR signal enhancement. Whereas the presence of the dendrimers did not induce macrophage apoptosis, studies have shown that in vivo distribution and toxicity is directly related to the surface chemistry and charge, with cationic materials inducing most cellular toxicity . However, further studies need to be performed in order to evaluate the safety of the current formulation.…”

Section: Discussionmentioning

confidence: 98%

Manganese G8 dendrimers targeted to oxidation‐specific epitopes: In vivo MR imaging of atherosclerosis

Nguyen

Bryant

Shapsa

et al. 2014

Magnetic Resonance Imaging

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Objective To determine if manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions. Background OSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. It was hypothesized that G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage rich plaques. Methods G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE-/- mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3 Tesla). Results Significant enhancement (normalized enhancement >60%, p=0.0013) of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods (>8 μg Mn/g). Limited signal attenuation (<18%) and Mn deposition (< 1 μg Mn/g) was observed in the arterial wall following injection of the untargeted material. Conclusions This study demonstrates that manganese labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions.

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“…Since dendrimers are synthesized through recurrent chemical reactions, their size is predictable, typically 1 to 10 nm [57]. These strengths make dendrimers advantageous for use as designing gene delivery agents, and many amine group-containing dendrimers such as poly(amidoamine) (PAMAM), melamine-based dendrimers, and polypropylenimine (PPI) dendrimers have been studied [9,58]. Notably, PAMAM dendrimers have been shown to efficiently deliver interfering RNA to ESCs compared to PEI-based lipopolymer controls.…”

Section: Cationic Polymers and Dendrimersmentioning

confidence: 99%

Gene Transfection for Stem Cell Therapy

Baek

Zoldan

et al. 2016

Curr Stem Cell Rep

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Genetic engineering of stem cells is a strategy that holds promise for realizing the potential therapeutic benefits of stem cell therapy. Through precise control of the stem cell genome, stem cells can replace or repair damaged tissues as well as serve as a depot for the sustained delivery of therapeutic molecules. Various individual genes, genome editing techniques, and transfection agents have been studied and developed for use in stem cell gene transfection. The goal for this review is to introduce specific genes and editing techniques used in stem cell therapy. Diverse gene transfection agents such as liposomes, polymers, dendrimers, peptides, inorganic nanoparticles, and physical transfection agents are also discussed with particular focus on stem cell considerations.

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On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR–ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells

Cited by 31 publications

References 40 publications

Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

Manganese G8 dendrimers targeted to oxidation‐specific epitopes: In vivo MR imaging of atherosclerosis

Gene Transfection for Stem Cell Therapy

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