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<p>Autophagy, a critical homeostatic process, is increasingly implicated in cancer progression and therapy resistance. SAR405 is a potent inhibitor of the autophagy related PIK3C3/VPS34 complex, offering potential as an anticancer agent. This study reports the synthesis, characterization, and biological evaluation of SAR405-loaded chitosan nanoparticles (CNP-SAR405) designed to improve therapeutic delivery and efficacy in A549 human lung carcinoma cells. CNPs were prepared via ionic gelation using chitosan and sodium tripolyphosphate (TPP), yielding stable monodisperse nanoparticles ~ 77.4&#xa0;nm, PDI ~ 0.2). Upon SAR405 encapsulation, nanoparticle size increased to ~ 110&#xa0;nm while maintaining uniform distribution. Encapsulation efficiency reached 80% at 200&#xa0;nM SAR405, confirmed by UV–Vis spectroscopy. Morphological analyses using FESEM and TEM verified spherical nanoparticle structures, while FTIR confirmed successful SAR405 incorporation. FITC-labelling enabled real-time tracking of intracellular uptake, revealing detectable internalization as early as 12&#xa0;h post-treatment, with fluorescence intensity peaking at 72&#xa0;h. In vitro cytotoxicity assays demonstrated enhanced anticancer efficacy of CNP-SAR405 compared to free SAR405, CNP-SAR405 achieved similar cytotoxic effects at 69&#xa0;nM compared to 100&#xa0;nM for free SAR405 in A549 cells. Furthermore, co-treatment with the autophagy inducer Torin-2 validated that CNP-SAR405 more effectively inhibited autophagosome formation than SAR405 alone, particularly at the 24-h mark. These findings underscore the potential of chitosan nanoparticle-mediated delivery to increase SAR405 bioavailability and anticancer potency while achieving comparable cytotoxic at a lower dose than free SAR405. The CNP-SAR405 formulation represents a promising nanotechnology-driven approach to targeted lung cancer therapy. All experiments were performed in triplicate biological replicates with technical triplicates, and data were analysed using one-way ANOVA followed by Tukey’s multiple comparison post-hoc test (<i>p</i> &lt; 0.05 considered significant).</p>

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Synthesis of CNP-SAR405 delivery system for improved therapeutics anticancer activity using A549 human lung cancer cell lines

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Ruqayyah A. Bashirah,
  • Nur Balqis Zamri,
  • Noorjahan Banu Alitheen,
  • Saila Ismail,
  • Mas Jaffri Masarudin

摘要

Autophagy, a critical homeostatic process, is increasingly implicated in cancer progression and therapy resistance. SAR405 is a potent inhibitor of the autophagy related PIK3C3/VPS34 complex, offering potential as an anticancer agent. This study reports the synthesis, characterization, and biological evaluation of SAR405-loaded chitosan nanoparticles (CNP-SAR405) designed to improve therapeutic delivery and efficacy in A549 human lung carcinoma cells. CNPs were prepared via ionic gelation using chitosan and sodium tripolyphosphate (TPP), yielding stable monodisperse nanoparticles ~ 77.4 nm, PDI ~ 0.2). Upon SAR405 encapsulation, nanoparticle size increased to ~ 110 nm while maintaining uniform distribution. Encapsulation efficiency reached 80% at 200 nM SAR405, confirmed by UV–Vis spectroscopy. Morphological analyses using FESEM and TEM verified spherical nanoparticle structures, while FTIR confirmed successful SAR405 incorporation. FITC-labelling enabled real-time tracking of intracellular uptake, revealing detectable internalization as early as 12 h post-treatment, with fluorescence intensity peaking at 72 h. In vitro cytotoxicity assays demonstrated enhanced anticancer efficacy of CNP-SAR405 compared to free SAR405, CNP-SAR405 achieved similar cytotoxic effects at 69 nM compared to 100 nM for free SAR405 in A549 cells. Furthermore, co-treatment with the autophagy inducer Torin-2 validated that CNP-SAR405 more effectively inhibited autophagosome formation than SAR405 alone, particularly at the 24-h mark. These findings underscore the potential of chitosan nanoparticle-mediated delivery to increase SAR405 bioavailability and anticancer potency while achieving comparable cytotoxic at a lower dose than free SAR405. The CNP-SAR405 formulation represents a promising nanotechnology-driven approach to targeted lung cancer therapy. All experiments were performed in triplicate biological replicates with technical triplicates, and data were analysed using one-way ANOVA followed by Tukey’s multiple comparison post-hoc test (p < 0.05 considered significant).