Abstract
Brain-derived neurotrophic factor (BDNF) is essential for the development and function of human neurons, therefore it is a promising target for neurodegenerative disorders treatment. Here, we studied BDNF-based electrostatic complex with dendrimer nanoparticles encapsulated in polyethylene glycol (PEG) in neurotoxin-treated, differentiated neuroblastoma SH-SY5Y cells, a model of neurodegenerative mechanisms. PEG layer was adsorbed at dendrimer-protein core nanoparticles to decrease their cellular uptake and to reduce BDNF-other proteins interactions for a prolonged time. Cytotoxicity and confocal microscopy analysis revealed PEG-ylated BDNF-dendrimer nanoparticles can be used for continuous neurotrophic factor delivery to the neurotoxin-treated cells over 24 h without toxic effect. We offer a reliable electrostatic route for efficient encapsulation and controlled transport of fragile therapeutic proteins without any covalent cross-linker; this could be considered as a safe drug delivery system. Understanding the polyvalent BDNF interactions with dendrimer core nanoparticles offers new possibilities for design of well-ordered protein drug delivery systems.
Highlights
Nanostructures are a promising tool for efficient therapeutics delivery even to the difficult tissues, like brain, in which blood–brain barrier (BBB) remains a fundamental challenge for drug delivery systems
The prepared Brain-derived neurotrophic factor (BDNF)-Poly(amidoamine) dendrimers (PAMAM) as well as polyethylene glycol (PEG)-ylated BDNF-PAMAM nanoparticles were physicochemically characterized in terms of size, polydispersity index and electrophoretic mobility/zeta potential in phosphate buffered saline (PBS) buffer without calcium and magnesium ions, pH 7.4
Dynamic light scattering analysis for BDNF-PAMAM nanoparticles revealed a mean diameter of 7.1 ± 1.1 nm, suggested by a relatively low polydispersity index (PDI) of less than 0.3
Summary
Nanostructures are a promising tool for efficient therapeutics delivery even to the difficult tissues, like brain, in which blood–brain barrier (BBB) remains a fundamental challenge for drug delivery systems. Since brain-derived neurotrophic factor (BDNF) induces neuronal survival and tissue repair, it is a promising. BDNF is the most abundant member of neurotrophic factors family in the mammalian central nervous system (CNS). BDNF homodimer has about 27 kDa, exerts biological activity in a dimeric state and has a common structural motif consisting of 120 amino acids and Dąbkowska et al J Nanobiotechnol (2020) 18:120 forms three disulfide bridges. The electric charge over BDNF molecules is heterogeneously distributed. The amino acids structural elements of BDNF molecule like Lysine 96, Arginine 97, Glutamine 84 are presented in the active site, which gives the largest positively charged region over protein molecules. The amino acids structural elements of BDNF molecule like Lysine 96, Arginine 97, Glutamine 84 are presented in the active site, which gives the largest positively charged region over protein molecules. [4, 5] BDNF binds with high affinity to tyrosine kinase B (TrkB) receptor to promote trophic signaling and apoptotic events. [6,7,8] low BDNF levels are observed in brains of patients suffering from multiple pathologies of CNS and changes in BDNF concentration or its distribution have been linked with several neurodegenerative and psychiatric disorders, like depression and schizophrenia. [9, 10]
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