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Abstract
One of the most studied nanocarriers for drug delivery are polyamidoamine (PAMAM) dendrimers. However, the alterations produced by PAMAM dendrimers in neuronal function have not been thoroughly investigated, and important aspects such as effects on synaptic transmission remain unexplored. We focused on the neuronal activity disruption induced by dendrimers and the possibility to prevent these effects by surface chemical modifications. Therefore, we studied the effects of fourth generation PAMAM with unmodified positively charged surface (G4) in hippocampal neurons, and compared the results with dendrimers functionalized in 25% of their surface groups with folate (PFO25) and polyethylene glycol (PPEG25). G4 dendrimers significantly reduced cell viability at 1 µM, which was attenuated by both chemical modifications, PPEG25 being the less cytotoxic. Patch clamp recordings demonstrated that G4 induced a 7.5-fold increment in capacitive currents as a measure of membrane permeability. Moreover, treatment with this dendrimer increased intracellular Ca2+ by 8-fold with a complete disruption of transients pattern, having as consequence that G4 treatment increased the synaptic vesicle release and frequency of synaptic events by 2.4- and 3-fold, respectively. PFO25 and PPEG25 treatments did not alter membrane permeability, total Ca2+ intake, synaptic vesicle release or synaptic activity frequency. These results demonstrate that cationic G4 dendrimers have neurotoxic effects and induce alterations in normal synaptic activity, which are generated by the augmentation of membrane permeability and a subsequent intracellular Ca2+ increase. Interestingly, these toxic effects and synaptic alterations are prevented by the modification of 25% of PAMAM surface with either folate or polyethylene glycol.
Highlights
The improvement of the effectivity of pharmacological agents, such as small molecules, peptides and genes, is a permanent concern to the scientific community
The use of drug nanocarrier systems to improve current and new therapeutic alternatives has been an important concern to pharmacological research [6,33]
These results demonstrate that only the intracellular Ca2+ increment induced transients frequency induced by PFO25 and PPEG25 are not correlated with2+ changes in normal synaptic by G4 leads to an increase in synaptic vesicle release, and the increments in Ca transients frequency vesicle dynamics
Summary
The improvement of the effectivity of pharmacological agents, such as small molecules, peptides and genes, is a permanent concern to the scientific community. Nanomaterials 2018, 8, 7 as nanocarriers, polyamidoamine (PAMAM) dendrimers appear as one of the most successfully used and studied [3,5,7] These dendrimers are hyperbranched polymers organized from an ethylenediamine central core that gives way to expansive growing layers, known as generations, terminating in a surface of primary amines that are positively charged at physiological pH. This structure generates inner cavities, which are able to encapsulate small molecules and an modifiable surface that can covalently link pharmacological agents or ligands for specific targeting. The terminal positive charges allow the electrostatic interaction with larger macromolecules such as nucleic acids [3,8,9]
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