Transferrin functionalized poloxamer-chitosan nanoparticles of metformin: physicochemical characterization, in-vitro, and Ex-vivo studies.

OBJECT: We report the preparation, characterization, and in-vitro therapeutic evaluation of Metformin-Loaded, Transferrin-Poloxamer-Functionalized Chitosan Nanoparticles (TPMC-NPs) for their repurposing in Alzheimer's disease (AD). SIGNIFICANCE: Usefulness of this work to establish the repurposing of metformin for the treatment of AD. METHODS: The TPMC-NPs were prepared by ionic gelation method using sodium tripolyphosphate. The modification and functionalization were confirmed by FTIR and 1H-NMR spectroscopy. The physicochemical characterization was performed using DLS, FTIR,1H-NMR, CD spectroscopy, SEM, DSC, PXRD, HR-TEM, and hot-stage microscopy. RESULTS: The size, PDI, percent entrapment efficiency, and percent drug loading of TPMC-NPs were found to be 287.4 ± 9.5, 0.273 ± 0.067, 81.15 ± 7.17%, 11.75%±8.21%, respectively. Electron microscope analysis revealed smooth and spherical morphology. The transferrin conjugation efficiency was found to be 46% by the BCA method. CD spectroscopy confirmed no significant loss of the secondary structure of transferrin after conjugation. PXRD data indicated the amorphous nature of the TPMC-NPs. Hot-stage microscopy and DSC confirmed the thermal stability of TPMC-NPs. The in-vitro drug release showed a sustained release at pH 7.4. The DPPH assay displayed 80% antioxidant activity of TPMC-NPs in comparison with metformin and blank NPs. The in-vitro cytotoxicity assay revealed 69.60% viable SH- SY5Y cells at 100 µg/mL of TPMC NPs. The ex-vivo nasal ciliotoxicity and mucoadhesion studies showed no significant toxicity, and 98.16% adhesion, respectively. The nasal permeability study showed the release of metformin within 30 min from TPMC-NPs. CONCLUSION: The obtained results suggested the usefulness of TPMC-NPs in the treatment of AD via the intranasal route.

Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.

The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid ß metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aß deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aß monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.