Development, characterisation and neuroprotective effects of polymer-drug conjugate nano-polyplex: working towards a multi-target treatment for neurodegenerative diseases.

Mahadik, Nuruddin; Barron, Gemma A.; Kong Thoo Lin, Paul; Thompson, Colin J.

Abstract

Neurodegenerative diseases (NDs) are complex, multifaceted conditions that require novel, multi-targeted therapeutic approaches. This study aimed to develop a multifunctional polymer-drug conjugate (PDC) by employing a novel strategy of utilizing PDC-based nano-polyplexes as a multi-target treatment for NDs. The nano-polyplex (N5NM15) was formulated by combining polyallylamine hydrochloride-vanillin (NM15) and polyacrylic acid-naphthalimidohexylamine (N5) conjugates. Antioxidant capacity was measured via ORAC assay, and cholinesterase inhibition was evaluated using Ellman’s assay. Cytotoxicity, neuroprotective effects, and anti-inflammatory activity were tested in undifferentiated SH-SY5Y and BV-2 cells via MTT assay. Amyloid-beta aggregation was assessed using Thioflavin T assay and TEM imaging in a cell-free system. The results demonstrated that N5NM15 resulted in uniform nanoparticles with an average size of 30.5±7.9 nm, confirmed via Cryo-TEM. Cytotoxicity studies indicated high biocompatibility with SH-SY5Y cells (viability >90%) and moderate toxicity in BV-2 cells (viability 75%, p ≤ 0.001). Furthermore, N5NM15 demonstrated significantly enhanced in vitro antioxidant activity (p ≤ 0.001, after adjustment) and cholinesterase inhibition (p ≤ 0.0001 for AChE and p ≤ 0.01 for BuChE, after adjustment) compared to starting materials. N5NM15 also protected SH-SY5Y cells from hydrogen peroxide-induced oxidative stress (p ≤ 0.0001), reduced lipopolysaccharide-induced inflammation in BV-2 cells (p ≤ 0.05), inhibited BuChE activity in SH-SY5Y cells (p ≤ 0.01), and reduced amyloid-beta aggregation (p ≤ 0.01). Notably, polyacrylic acid demonstrated protective and anti-inflammatory effects in both cell lines (p ≤ 0.0001) and inhibited amyloid-beta aggregation (P ≤ 0.001). These findings suggest the potential use of N5NM15 and polyacrylic acid as treatment options for NDs.

Citation

MAHADIK, N., BARRON, G.A., KONG THOO LIN, P. and THOMPSON, C.J. 2025. Development, characterisation and neuroprotective effects of polymer-drug conjugate nano-polyplex: working towards a multi-target treatment for neurodegenerative diseases. Materials advances [online], 6(13), pages 4438-4455. Available from: https://doi.org/10.1039/D5MA00174A

• Journal Article Type: Article
• Acceptance Date: May 29, 2025
• Online Publication Date: May 30, 2025
• Publication Date: Jul 7, 2025
• Deposit Date: Jun 2, 2025
• Publicly Available Date: Jun 2, 2025
• Journal: Materials advances
• Print ISSN: 2633-5409
• Electronic ISSN: 2633-5409
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 13
• Pages: 4438-4455
• DOI: https://doi.org/10.1039/D5MA00174A
• Keywords: Neurodegenerative diseases (ND); Polymer-drug conjugates (PDC); Nano-polyplexes; Polyacrylic acid
• Public URL: https://rgu-repository.worktribe.com/output/2702547
• Additional Information: This article has been published with separate supporting information. This supporting information has been incorporated into a single file on this repository and can be found at the end of the file associated with this output.