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<p>In this work, we investigated the synthesis of ZnO nanoparticles using <i>Thymus vulgaris</i> in a framework combining experimental and computational approaches. UV-Vis spectroscopic analysis of the nanomaterials confirmed that they were coated with a thymol-rich phytocorona. Sub-micromolar IC<sub>50</sub> values were recorded for A549 (5.9 ± 2.0&#xa0;µg mL⁻¹), MCF-7 (12.5 ± 1.6&#xa0;µg mL⁻¹), and DLD-1 (14.0 ± 2.1&#xa0;µg mL⁻¹) cancer cell lines. Normal HEK-293 and HDF cells were unaffected at concentrations below 60&#xa0;µg mL⁻¹, yielding tumor-selectivity indices between 4 and 11, substantially higher than those of cisplatin (≤ 2). Phase-contrast microscopy revealed hallmark apoptotic features, including cell rounding and chromatin condensation, within 24&#xa0;h of treatment. Biochemically, measurements of reactive oxygen species (ROS) correlated ZnO nanoparticle degradation with oxidative stress. In addition, molecular docking of thymol on human lymphoma cells 2 (Bcl-2) (PDB 6O0K) indicated a selective binding within the BH3 groove (ΔG ≈ -6&#xa0;kcal mol⁻¹), implicating disruption of Bcl-2/Bax complex formation and the potential release of pro-apoptotic factors. Drug and toxicity predictions indicated that thymol exhibits high gastrointestinal absorption, blood-brain barrier permeability, and a favorable LD50 (640&#xa0;mg kg⁻¹, GHS category 4), contrary to the BH3 mimetic venetoclax, which possesses poor bioavailability despite being clinically approved. Collectively, these results underscore a dual anti-cancer strategy, wherein the ZnO core amplifies ROS generation while the plant-derived thymol halo interferes with anti-apoptotic signaling. Synergistically, the mechanism culminates in selective cancer cell death. Consequently, thymus-mimetic ZnO nanoparticles represent a promising low-cost platform for developing highly effective nanotherapeutics against cancer, confirming the validity of BH3 targeting as a complementary approach to ROS toxicity.</p>

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Re-Synthesis of Anticancer Zinc Oxide Nanoparticles: Comparative ADMET, Acute Toxicity, and Mechanistic In-Silico Assessment of Thymol and Venetoclax Using Docking, POM Analysis, and Molecular Dynamics Simulations

  • 期刊论文

  • 发表日期：

    2026年5月12日

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  • Solhe F. Alshahateet,
  • Aziz Arzine,
  • Salah A. Al-Trawneh,
  • Yousef M. Al-Saraireh,
  • Samir A. Al-Taweel,
  • Mohammad Salem Hareedy,
  • Ahmed A. Al-abadleh,
  • Tala S. Alshahateet,
  • Oussama Khibech,
  • Mohammed Merzouki,
  • Khalil Azzaoui,
  • Shehdeh Jodeh,
  • Taibi Ben Hadda,
  • Belkheir Hammouti,
  • Adam Duong

摘要

In this work, we investigated the synthesis of ZnO nanoparticles using Thymus vulgaris in a framework combining experimental and computational approaches. UV-Vis spectroscopic analysis of the nanomaterials confirmed that they were coated with a thymol-rich phytocorona. Sub-micromolar IC50 values were recorded for A549 (5.9 ± 2.0 µg mL⁻¹), MCF-7 (12.5 ± 1.6 µg mL⁻¹), and DLD-1 (14.0 ± 2.1 µg mL⁻¹) cancer cell lines. Normal HEK-293 and HDF cells were unaffected at concentrations below 60 µg mL⁻¹, yielding tumor-selectivity indices between 4 and 11, substantially higher than those of cisplatin (≤ 2). Phase-contrast microscopy revealed hallmark apoptotic features, including cell rounding and chromatin condensation, within 24 h of treatment. Biochemically, measurements of reactive oxygen species (ROS) correlated ZnO nanoparticle degradation with oxidative stress. In addition, molecular docking of thymol on human lymphoma cells 2 (Bcl-2) (PDB 6O0K) indicated a selective binding within the BH3 groove (ΔG ≈ -6 kcal mol⁻¹), implicating disruption of Bcl-2/Bax complex formation and the potential release of pro-apoptotic factors. Drug and toxicity predictions indicated that thymol exhibits high gastrointestinal absorption, blood-brain barrier permeability, and a favorable LD50 (640 mg kg⁻¹, GHS category 4), contrary to the BH3 mimetic venetoclax, which possesses poor bioavailability despite being clinically approved. Collectively, these results underscore a dual anti-cancer strategy, wherein the ZnO core amplifies ROS generation while the plant-derived thymol halo interferes with anti-apoptotic signaling. Synergistically, the mechanism culminates in selective cancer cell death. Consequently, thymus-mimetic ZnO nanoparticles represent a promising low-cost platform for developing highly effective nanotherapeutics against cancer, confirming the validity of BH3 targeting as a complementary approach to ROS toxicity.