Novel AP39-Loaded Liposomes Sustain the Release of Hydrogen Sulphide, Enhance Blood-Brain Barrier Permeation, and Abrogate Oxidative Stress-Induced Mitochondrial Dysfunction in Brain Cells.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-19 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S507697

Mohamad Anas Al Tahan, Mandeep Kaur Marwah, Mandheer Dhaliwal, Lorena Diaz Sanchez, Hala Shokr, Manjit Kaur, Shakil Ahmad, Raj K S Badhan, Irundika H K Dias, Lissette Sanchez-Aranguren

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引用次数: 0

Abstract

Background: Neurodegenerative diseases are often linked to oxidative stress (OS), which worsen neuroinflammation and cause neuronal damage. Managing OS with gasotransmitters such as hydrogen sulphide (H₂S) is a promising therapeutic approach to protecting brain cells from oxidative damage. AP39, a mitochondria-targeted H₂S donor, has shown neuroprotective potential by reducing OS and improving mitochondrial function. However, its clinical application is limited due to poor stability and rapid release, necessitating a drug delivery system to enhance therapeutic efficacy.

Purpose: This study aimed to develop a novel AP39-loaded liposomal formulation to provide controlled H₂S release, facilitate AP39 permeation across the blood-brain barrier (BBB), and assess functional effects in mitigating oxidative stress and preserving mitochondrial function.

Methods: AP39-loaded unilamellar liposomes were prepared via ethanol injection and characterised for size, polydispersity, and zeta potential. Entrapment efficiency was determined using HPLC, while cytotoxicity was assessed in human vein endothelial (HUVEC) and neuroblastoma (SHSY5Y) cells. Liposomal permeability, AP39 release kinetics, and cellular uptake were evaluated using a microvasculature BBB model. Mitochondrial function under oxidative stress was assessed using a Seahorse XFe24 Analyzer.

Results: AP39-loaded liposomes had an average size of 135.92 ± 10.05 nm, a zeta potential of 17.35 ± 3.40 mV, and an entrapment efficiency of 84.48% ± 4.7. Cytotoxicity studies showed no adverse effects after 4 h. Cellular uptake of encapsulated AP39 was significantly higher (7.13 ± 0.28 µg) than the free form (5.8 ± 0.31 µg). The BBB model demonstrated sustained AP39 release (7.28 µg/mL vs 6.44 µg/mL for free AP39). Mitochondrial assays confirmed liposomal AP39 preserved H₂S antioxidant properties and enhanced oxygen consumption.

Conclusion: Our novel liposomal formulation encapsulating AP39 improves stability, promotes sustained release, and enhances BBB permeability while preserving antioxidant effects. These findings indicate that liposomal AP39 is a suitable therapeutic approach to further investigate in the treatment of neurodegenerative diseases.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.