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<p>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 <i>Drosophila</i> tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, <i>p</i> ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, <i>p</i> ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in <i>Drosophila</i> revealed that N5NM15 (3.5:1 and 44:12.5&#xa0;µg/mL) and PAA (44&#xa0;µg/mL) were toxic to adult flies expressing the eye-specific driver (<i>GMR</i>-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver <i>ELAV</i>-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&#xa0;µg/mL) at the early stage of the disease, but at a higher dose (44:12.5&#xa0;µg/mL) was significantly toxic, in both wild-type (<i>p</i> ≤ 0.0001) and tauopathy models (<i>p</i> &lt; 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 <i>Drosophila</i> tauopathy models for AD treatment.</p>

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Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Nuruddin Mahadik,
  • Sri Nithya Paruchuri,
  • Rohina Arif,
  • Amanda S. Coutts,
  • Gemma A. Barron,
  • Paul Kong Thoo Lin,
  • Shreyasi Chatterjee,
  • Colin J. Thompson

摘要

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.