Novel design of (PEG-ylated)PAMAM-based nanoparticles for sustained delivery of BDNF to neurotoxin-injured differentiated neuroblastoma cells

Dąbkowska, Maria; Łuczkowska, Karolina; Rogińska, Dorota; Sobuś, Anna; Wasilewska, Monika; Ulańczyk, Zofia

doi:10.1186/s12951-020-00673-8

Cited by 22 publications

(19 citation statements)

References 53 publications

(55 reference statements)

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“…PEGylation of BDNF can enhance the diffusion of BDNF in the brain tissue and spinal cord [ 427 , 428 ]. PEG-based BDNF nano-system, mediated by electrostatic coupling and hydrogen bonding, is beneficial for stabilizing BDNF, protecting against the nonspecific binding with serum proteins, and activating TrkB as well as other downstream signaling pathways [ 429 – 431 ]. Compared with native BDNF, intranasal administration of the nano-BDNF complex can enhance BDNF levels in the hippocampus and brainstem regions by regulating the viscosity and permeability of nasal mucosa [ 429 ].…”

Section: Bdnf-targeting Strategies For Ad Modificationmentioning

confidence: 99%

Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential

Gao

Zhang

Sterling

et al. 2022

Transl Neurodegener

191

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Synaptic abnormalities are a cardinal feature of Alzheimer’s disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.

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Section: Bdnf-targeting Strategies For Ad Modificationmentioning

confidence: 99%

Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential

Gao

Zhang

Sterling

et al. 2022

Transl Neurodegener

191

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“…The final shell consisted of DTPA, peptides, and methoxy-PEG arms. These masked the positive surface charge, increased the hydrodynamic radius of PAMAM dendrimers, reduced the nonspecific cell membrane interaction and opsonization with plasma proteins, and enhanced the blood circulation time and in vivo tumor accumulation [ 53 ]. The tumor targeting ligands IELLQARCRR and KQEFLINGCRR were selectively conjugated with PEGs via maleimide residues and SH group of peptides, and provided an active targeting function to the final nanocarrier.…”

Section: Resultsmentioning

confidence: 99%

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe

Yabbarov

Nikolskaya

Sokół

et al. 2022

IJMS

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The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety—alpha-fetoprotein receptor-binding peptide—enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.

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“…In order to determine the possibility of toxicity of PAMAM-based nanoparticles with differently charged PAMAM core in biomedical applications, we examined the viability of differentiated neuroblastoma SH-SY5Y cells previously exposed to 6-OHDA and then administered nanoparticles. First and foremost, we differentiated SH-SY5Y cells by combining RA treatment and lowering FBS concentration in cell culture according to our previous report [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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

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Novel design of (PEG-ylated)PAMAM-based nanoparticles for sustained delivery of BDNF to neurotoxin-injured differentiated neuroblastoma cells

Cited by 22 publications

References 53 publications

Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential

Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe

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

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