am9b22214_si_001.pdf (2.33 MB)
Near-Infrared Responsive Dopamine/Melatonin-Derived Nanocomposites Abrogating in Situ Amyloid β Nucleation, Propagation, and Ameliorate Neuronal Functions
journal contribution
posted on 2020-01-27, 16:33 authored by Anup K. Srivastava, Subhasree Roy Choudhury, Surajit KarmakarAlzheimer’s
disease (AD) is one of the common causes of
dementia and mild cognitive impairments, which is progressively expanding
among the elderly population worldwide. A short Amyloid-β (Aβ)
peptide generated after amyloidogenic processing of amyloid precursor
protein exist as intermolecular β-sheet rich oligomeric, protofibriler,
and fibrillar structures and believe to be toxic species which instigate
neuronal pathobiology in the brain and deposits as senile plaque.
Enormous efforts are being made to develop an effective anti-AD therapy
that can target Aβ processing, aggregation, and propagation
and provide a synergistic neuroprotective effect. However, a nanodrug
prepared from natural origin can confer a multimodal synergistic chemo/photothermal
inhibition of Aβ pathobiology is not yet demonstrated. In the
present work, we report a dopamine–melatonin nanocomposite
(DM-NC), which possesses a synergistic near-infrared (NIR) responsive
photothermal and pharmacological modality. The noncovalent interaction-mediated
self-assembly of melatonin and dopamine oxidative intermediates leads
to the evolution of DM-NCs that can withstand variable pH and peroxide
environment. NIR-activated melatonin release and photothermal effect
collectively inhibit Aβ nucleation, self-seeding, and propagation
and can also disrupt the preformed Aβ fibers examined using
in vitro Aβ aggregation and Aβ-misfolding cyclic amplification
assays. The DM-NCs display a higher biocompatibility to neuroblastoma
cells, suppress the AD-associated generation of intracellular reactive
oxygen species, and are devoid of any negative impact on the axonal
growth process. In okadaic acid-induced neuroblastoma and ex vivo
midbrain slice culture-based AD model, DM-NCs exposure suppresses
the intracellular Aβ production, aggregation, and accumulation.
Therefore, this nature-derived nanocomposite demonstrates a multimodal
NIR-responsive synergistic photothermal and pharmacological modality
for effective AD therapy.
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Keywords
dopamine oxidative intermediatesβ-misfolding cyclic amplification assaysamyloid precursor proteinEnormous effortsvivo midbrain slice culture-based AD modelβ- sheetSitu Amyloid β Nucleationβ pathobiologyperoxide environmentDM-NCs displayfibrillar structuresDM-NCs exposureanti-AD therapyβ productionmultimodal NIR-responsivepropagationnature-derived nanocompositeAD therapyaxonal growth processneuroblastoma cellsnoncovalent interaction-mediated self-assemblyneuroprotective effectβ fibersβ aggregationβ processingintracellular reactive oxygen speciesmodalityokadaic acid-induced neuroblastomaamyloidogenic processingAD-associated generationβ nucleationAmyloid -βNIR-activated melatonin releasephotothermal effect
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