The role of the electrokinetic charge of neurotrophis-based nanocarriers: protein distribution, toxicity, and oxidative stress in in vitro setting

Abstract

Background The rational chemical design of nanoparticles can be readily controlled and optimized by quantitatively studying protein adsorption at variously charged polymer carriers, determining their fate in biological fluids. We manufactured brain-derived neurotrophic factor (BDNF) -based electrostatic nanocomplexes with a different type of dendrimer core (anionic or cationic), encapsulated or not in polyethylene glycol (PEG), and studied their physicochemical properties and behavior in a biological setting. We investigated whether the electrokinetic charge of dendrimer core influences BDNF loading and desorption from the nanoparticle and serves as a determinant of nanoparticles’ behavior in in vitro setting, influencing mitochondrial dysfunction, lipid peroxidation, and general nanoparticles’ cellular toxicity. Results We found that the electrokinetic charge of the dendrimer core influences nanoparticles in terms of BDNF release profile from their surfaces and their effect on cell viability, mitochondrial membrane potential, cell phenotype, and induction of oxidative stress. The electrostatic interaction of positively charged core of nanoparticles with cell membranes increases their cytotoxicity, as well as serious phenotype alterations compared to negatively charged nanoparticles core in neuron-like differentiated human neuroblastoma cells. Moreover, PEG adsorption at nanoparticles with negatively charged core presents a distinct decrease in metabolic cell activity. On the contrary, charge neutralization due to PEG adsorption on the surface of nanoparticles with positively charged core does not reduce their cytotoxicity, makes them less biocompatible with differentiated cells, and presumably shows non-specific toxicity. Conclusions The surface charge transformation after adsorption of protein or polyelectrolyte during nanocarriers formulation has an important role not only in designing nanomaterials with potent neuroprotective and neuroregenerative properties but also in applying them in a cellular environment. Graphic abstract

Neurotrophin-loaded PDADMAC/HEPARIN multilayers as an unexpected system to damage neuroblastoma cancer cells

“…According to our previous work 11 , BDNF molecule has a slightly positive electrokinetic charge under physiological conditions, which explains a signi cant increase of BDNF adsorption on the negatively charged HP layer. Decreasing the zeta potential of the PDADMAC-terminated multilayer (see Fig.…”

“…It should be underlined that BDNF's role is rather complex. For instance, the literature data suggests that high BDNF levels might be associated with malignant disease progression and cancer cell survival 9,10 , and our previous studies showed that BDNF improves the recovery of damaged neuroblastoma cells 11 .…”

Safety Challenges and Application Strategies for the Use of Dendrimers in Medicine

“…Interestingly, in vivo studies of the embryonic zebrafish model have shown that the surface charge properties of dendrimers is a more important factor in the cytotoxicity of dendrimers than either generation or size [71]. When dendrimers were applied as nanocarriers, positively charged dendrimer cores exhibited significant cytotoxicity and severe phenotypic changes, compared with negatively charged dendrimer cores [72].…”

Biomimetic Gold Nanostructure with a Virus-like Topological Surface for Enhanced Antigen Cross-Presentation and Antitumor Immune Response

“…25,26 Positively charged particles were also reported to be readily taken up into DCs due to the ionic attraction with the negatively charged cell membrane, which initiates efficient binding and facilitates particle internalization. 27,28 However, the effect of the particle topological structure on antigentargeted delivery has remained unexplored. Thus, understanding how the topological structure influences immune responses can greatly aid in the rational design of better vaccines.…”

“…Because the uptake of antigen by DCs plays a critical role in the induction of innate and adaptive immunity, the delivery systems that not only can protect the antigens from degradation , but also can facilitate the interaction with DCs would be a promising strategy for vaccine development. The physicochemical characteristics of particles, such as the size, surface properties, rigidity, and shape, all significantly influence the in vivo trafficking and cellular internalization. − It has been reported that particles with an intermediate size (10–100 nm in diameter) can both efficiently drain to regional draining lymph nodes and become retained there to increase the chance of antigen uptake and presentation by APCs. , Positively charged particles were also reported to be readily taken up into DCs due to the ionic attraction with the negatively charged cell membrane, which initiates efficient binding and facilitates particle internalization. , However, the effect of the particle topological structure on antigen-targeted delivery has remained unexplored. Thus, understanding how the topological structure influences immune responses can greatly aid in the rational design of better vaccines.…”