The Janus Face of PAMAM Dendrimers Used to Potentially Cure Nonenzymatic Modifications of Biomacromolecules in Metabolic Disorders—A Critical Review of the Pros and Cons

Abstract

Diabetes mellitus, which is characterised by high blood glucose levels and the burden of various macrovascular and microvascular complications, is a cause of much human suffering across the globe. While the use of exogenous insulin and other medications can control and sometimes prevent various diabetes-associated sequelae, numerous diabetic complications are still commonly encountered in diabetic patients. Therefore, there is a strong need for safe and effective antihyperglycaemic agents that provide an alternative or compounding option for the treatment of diabetes. In recent years, amino-terminated poly(amido)amine (PAMAM) dendrimers (G2, G3 and G4) have attracted attention due to their protective value as anti-glycation and anti-carbonylation agents that can be used to limit the nonenzymatic modifications of biomacromolecules. The focus of this review is to present a detailed survey of our own data, as well as of the available literature regarding the toxicity, pharmacological properties and overall usefulness of PAMAM dendrimers. This presentation pays particular and primary attention to their therapeutic use in poorly controlled diabetes and its complications, but also in other conditions, such as Alzheimer's disease, in which such nonenzymatic modifications may OPEN ACCESSMolecules 2013, 18 13770 underlie the pathophysiological mechanisms. The impact of dendrimer administration on the overall survival of diabetic animals and on glycosylation, glycoxidation, the brain-blood barrier and cellular bioenergetics are demonstrated. Finally, we critically discuss the potential advantages and disadvantages accompanying the use of PAMAM dendrimers in the treatment of metabolic impairments that occur under conditions of chronic hyperglycaemia.

How do the full-generation poly(amido)amine (PAMAM) dendrimers activate blood platelets? Activation of circulating platelets and formation of “fibrinogen aggregates” in the presence of polycations

“…Altogether, the above mentioned bulk of evidence strongly supports the idea on the activating and proaggregatory action of PAMAM dendrimers on blood platelets in vivo. Noteworthy, these observations stay in agreement with our earlier reports showing the increased mortality in healthy and diabetic rats administered with PAMAM G2, G3 and G4 dendrimers (Labieniec et al, 2008;Labieniec-Watala et al, 2013). Thus, we demonstrate here that also PAMAM dendrimers of lower generations employed in our studies, especially when used at higher doses, behaved very much alike the procoagulant PAMAM G7 dendrimers (Jones et al, 2012).…”

“…Accordingly, the control samples for PLL or PX contained PBS, while the control samples for PAMAM dendrimers contained methanol diluted in PBS. Our choice of PAMAM dendrimers concentrations used in the present study has been governed by the recognition of the balance between toxicity and non-toxic biological effects reported earlier (Labieniec-Watala et al, 2013). PLL and PX were used as the reference polyamine compounds.…”

“…This naturally implies interactions of the nanoparticles with plasma proteins, blood cells and vascular endothelial cells, even before PAMAMs achieve their supposed target tissues. Interactions with blood cells are of particular interest also in the context of some earlier reports on the experimental use of PAMAM dendrimers as anti-diabetic nanopharmaceuticals, and more even so, considering the biotoxicity of these nanomolecules despite the potential benefits concerning the hypoglycaemizing effects revealed in animals with streptozotocininduced diabetes (Labieniec et al, 2008;Labieniec-Watala et al, 2013. The polycationicity of PAMAM dendrimers enables them to directly interact with various anionic targets on cell surface, including membrane receptors located on blood platelets, which are the key molecules in the phenomena of platelet activation and haemostatic events.…”

Treating cancer with microRNA replacement therapy: A literature review

“…Administration of PAMAM elevates the hepatic accumulation, which in turn imposes serious damage to hepatocytes and diminishes carbohydrate metabolism. In order to prevent the toxicity of PAMAMs, substances with an opposite charge, such as polyethylene glycol (PEG) have been conjugated (Jiang et al, ; Labieniec‐Watala, Karolczak, Siewiera, & Watala, ). Aptamer sequences, as negatively charged single‐strand oligonuclotides, were conjugated with PAMAMs to increase cellular uptake of miR‐34a‐containing plasmid in lung cancer cells in vitro (Wang et al, ).…”

Different patterns of nuclear and mitochondrial penetration by the G3 PAMAM dendrimer and its biotin–pyridoxal bioconjugate BC-PAMAM in normal and cancer cells in vitro

“…Growing research interest over the last 2 decades has resulted in a number of publications concerning dendrimers. In particular, the amine-terminated cationic polyamidoamine (PAMAM) dendrimers of various generations and their bioconjugates have been intensively studied because of their wide range of possible applications as carriers of antibodies and contrast molecules, 1,2 in protection against nonenzymatic modifications of biomacromolecules that cause various metabolic disorders, 3 in therapies for cancer, [4][5][6][7][8] and genetic and immune diseases. 9,10 The unique molecular architecture of dendrimers allows for the precise control of their size, shape, charge and targeting of ligands, and therapeutic compounds attached to surface groups, which determine their function and application.…”