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Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1-conjugated nattokinase enzyme for inhibition of A?40 plaques in Alzheimer's disease.

ABSTRACT: According to the World Health Organization, globally there are around 18 million patients suffering from Alzheimer's disease (AD), and this number is expected to double by 2025. The pathophysiology of AD includes selective deposition of A? peptide in the mitochondria of cells, which inhibits uptake of glucose by neurons and key enzyme functions. Current drug treatments for AD are unable to rectify the underlying pathology of the disease; they only provide short-term symptomatic relief, so there is a need for the development of newer treatment regimes. The antiamyloid activity, antifibrinolytic activity, and antithrombotic activity of nattokinase holds potential for the treatment of AD. As nattokinase is a protein, its stability restricts its usage to a greater extent, but this limitation can be overcome by nanoencapsulation. In this work, we successfully synthesized polymeric nanoparticles of nattokinase and characterized its use by different techniques: transmission electron microscopy, scanning electron microscopy, DTS Nano, differential scanning calorimetry, Fourier-transform infrared spectroscopy, thioflavin T-binding assay, in vitro drug release, antifibrinolytic activity, and in vivo antiamyloid activity. As brain targeting of hydrophilic drugs is complicated due to the stringent nature of blood-brain barrier, in the current experimental study, we conjugated poly(lactic-co-glycolic acid) (PLGA)-encapsulated nattokinase with Tet1 peptide, which exhibits retrograde transportation properties because of its affinity to neurons. Our study suggests that PLGA-encapsulated nattokinase polymeric nanoparticles are able to downregulate amyloid aggregation and exhibit antifibrinolytic activity. The encapsulation of nattokinase in PLGA did not affect its enzyme activity, so the prepared nanoformulation containing nattokinase can be used as an effective drug treatment against AD.

SUBMITTER: Bhatt PC

PROVIDER: S-EPMC5732557 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1-conjugated nattokinase enzyme for inhibition of Aβ<sub>40</sub> plaques in Alzheimer's disease.

Bhatt Prakash Chandra PC Verma Amita A Al-Abbasi Fahad A FA Anwar Firoz F Kumar Vikas V Panda Bibhu Prasad BP

International journal of nanomedicine 20171213

According to the World Health Organization, globally there are around 18 million patients suffering from Alzheimer's disease (AD), and this number is expected to double by 2025. The pathophysiology of AD includes selective deposition of Aβ peptide in the mitochondria of cells, which inhibits uptake of glucose by neurons and key enzyme functions. Current drug treatments for AD are unable to rectify the underlying pathology of the disease; they only provide short-term symptomatic relief, so there ...[more]

PMID: 29263666

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Project description:BackgroundThe reduction-sensitive cationic polymer is a promising nonviral carrier for gene delivery. Until now, disulfide bonds have been the only golden standard for its design. The aim of this research was to develop a novel reduction-responsive cationic polymer as a gene carrier.MethodsPolycationic carriers were synthesized by addition of branched oligoethylenimine 800 Da (OEI(800)) via an active ester containing diselenide bonds. Disulfide bonds cross-linked with OEI(800)-SS(x) and monoselenide bonds linked with OEI(800)-Se(x) were synthesized and compared. Their molecular weights and degradation properties were determined using gel permeation chromatography. Changes in particle size, morphology, and DNA binding were investigated by dynamic light scattering, transmission electron microscopy, and electrophoresis assay in a reduction environment. Cytotoxicity and transfection in vitro were evaluated in a murine melanoma cell line (B16F10) and a human cervical epithelial carcinoma cell line (HeLa), while intracellular degradation and dissociation with DNA were studied by confocal laser scanning microscopy with FITC-labeled OEI(800) derivatives and Cy5-labeled DNA.ResultsDiselenide-conjugated OEI(800) (OEI(800)-SeSe(x)) polymer carriers of high molecular weight were successfully synthesized. After compacting with DNA, the OEI(800)-SeSe(x) polymers formed nanoparticles with an average size of 140 nm at an adequate C/P ratio. OEI(800)-SeSe(x) showed reduction-responsive degradation properties similar to those of the OEI(800)-SS(x) via gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. OEI(800)-SeSe(x) showed much lower cytotoxicity than PEI(25k), and significantly higher transfection efficiency than OEI(800) in both B16F10 and HeLa cells. Transfection of luciferase in the OEI(800)-SeSe(x) group was comparable with that of standard PEI(25k) and traditional reduction-sensitive polymer OEI(800)-SS(x) groups. Furthermore, intracellular degradation of OEI(800)-SeSe(x) and dissociation with DNA were also confirmed by confocal laser scanning microscopy.ConclusionThe OEI(800)-SeSe(x) obtained was able to bind plasmid DNA efficiently to yield nanosized particles and had reduction sensitivity which is as efficient as that for OEI(800)-SS(x). In vitro experiments confirmed its low cytotoxicity and high transfection ability. Diselenide bonds can be used as effective and novel reduction-sensitive linkages for gene delivery.

Dataset Information

Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1-conjugated nattokinase enzyme for inhibition of A?40 plaques in Alzheimer's disease.

Publications

Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1-conjugated nattokinase enzyme for inhibition of Aβ<sub>40</sub> plaques in Alzheimer's disease.

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