Journal article
Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy
- Abstract:
- Hyperphosphorylated tau contributes to synaptic damage and neuronal dysfunction in neurodegenerative diseases such as Alzheimer's disease (AD), making it a key therapeutic target. This study evaluated the toxicity and therapeutic potential of a novel polymer-drug nano-polyplex, N5NM15, and polyacrylic acid (PAA) in Drosophila tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, p ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, p ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in Drosophila revealed that N5NM15 (3.5:1 and 44:12.5 µg/mL) and PAA (44 µg/mL) were toxic to adult flies expressing the eye-specific driver (GMR-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver ELAV-GAL4. Furthermore, treatment with N5NM15 and PAA did not improve the ommatidial arrangement, eye bristle count, or eye length in tauopathy models. Climbing and survival assays indicated a potential mild protective effect at a lower concentration (3.5:1 µg/mL) at the early stage of the disease, but at a higher dose (44:12.5 µg/mL) was significantly toxic, in both wild-type (p ≤ 0.0001) and tauopathy models (p < 0.05). These findings highlight the need for N5NM15 and PAA dose optimisation and reformulation with non-toxic buffers to enhance therapeutic potential while minimising adverse effects in normal and Drosophila tauopathy models for AD treatment.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.3MB, Terms of use)
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(Preview, Supplementary materials, pdf, 1.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41598-025-22924-0
Authors
+ Tenovus Scotland
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- Funder identifier:
- https://ror.org/037866t57
- Grant:
- G22.06 BG
+ Royal Society of Chemistry
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- Funder identifier:
- https://ror.org/025sbr097
- Grant:
- C23-1720928079
- Publisher:
- Springer Nature
- Journal:
- Scientific Reports More from this journal
- Volume:
- 15
- Issue:
- 1
- Article number:
- 39454
- Place of publication:
- England
- Publication date:
- 2025-11-11
- Acceptance date:
- 2025-10-03
- DOI:
- EISSN:
-
2045-2322
- Pmid:
-
41219231
- Language:
-
English
- Keywords:
- Pubs id:
-
2409673
- Local pid:
-
pubs:2409673
- Source identifiers:
-
W4416113290
- Deposit date:
-
2026-04-21
- ARK identifier:
Terms of use
- Copyright holder:
- Mahadik et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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