Development of surface-engineered PLGA nanoparticulate-delivery system of Tet-1-conjugated nattokinase enzyme for inhibition of Aβ₄₀ 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 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 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.

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“…Polymeric nanoparticles have pliable physical properties, synthesis techniques, and degradation rates in vivo that make them useful drug carriers. They can reduce immunogenicity of the cargo and improve pharmacokinetic properties of encapsulated proteins [96]. The most commonly used polymeric materials include poly(lactic acid) (PLA), poly( D,L -lactic- co -glycolic acid) (PLGA), poly(aspartic acid), poly (glycolic acid) (PGA), and poly(butylcyanoacrylate) (PBCA).These polymers have also been broadly applied to other regenerative fields, and are therefore promising materials for treating neurodegeneration [2,97].…”

“…PLGA is hydrolyzed into glycolic acid and lactic acid in vivo , making it highly biocompatible. It is particularly useful for sustained drug release and brain-specific targeting through conjugation with various surface ligands [96]. One recent study enhanced the delivery of the hydrophilic drug, nattokinase, across the BBB through encapsulation in PLGA followed by coating of the NP with Tet1 peptide, which has a high affinity for neurons and promotes retrograde transport.…”

“…One recent study enhanced the delivery of the hydrophilic drug, nattokinase, across the BBB through encapsulation in PLGA followed by coating of the NP with Tet1 peptide, which has a high affinity for neurons and promotes retrograde transport. These PLGA NPs successfully downregulated amyloid aggregation and improved the stability of the nattokinase protein as a treatment for Alzheimer's [96].…”

Protective Effect of Hyperforin on β Amyloid Protein Induced Apoptosis in PC12 Cells and Colchicine Induced Alzheimer’s Disease: An Anti-oxidant and Anti-inflammatory Therapy

“…Briefly, in the Morris water maze method a circular pool 60 cm in height and 180 cm in diameter with completely filled with water. All rodent put into the any quadrant during retention and acquisition phase 23 .…”

“…Several researchers suggest that the oxidative stress and inflammation play an important role in the pathogenesis of AD 9 11 . Superoxide dismutase SOD and catalase CAT , both are the primary endogenous anti-oxidant defense system, they catalyzes toxic hydroxyl radical and superoxide into the oxygen, hydrogen peroxide and water 11,12 . Nuclear factor-kB NF-kB is a significant protein complex which manages the DNA transcription.…”