Almansour Khaled, Alsaab Hashem O, Pishnamazi Mahboubeh
Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, Saudi Arabia.
Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia.
Eur J Pharm Sci. 2025 Nov 1;214:107293. doi: 10.1016/j.ejps.2025.107293. Epub 2025 Sep 26.
Breast cancer remains a leading cause of cancer-related mortality, with hormone receptor-positive (ER⁺) tumors representing ∼70 % of cases. Tamoxifen (TAM), the gold-standard endocrine therapy, suffers from poor solubility (log P ≈ 6.3), low bioavailability (<30 %), and acquired resistance. To overcome these limitations, we developed a pH-responsive TAM-loaded graphene oxide-polyethylene glycol (TAM@GO-PEG) nanocomposite through integrated experimental and computational approaches. GO-PEG synthesis yielded a stable nanocarrier with high drug-loading efficiency (DLE ≈ 80 %) and pH-dependent charge reversal (+12.6 mV at pH 5.3 vs. +2.1 mV at pH 7.4). In vitro release studies demonstrated tumor-selective kinetics, with 89.3 % cumulative release at pH 5.5 versus 61.1 % at pH 7.4 over 72 h. Density functional theory (DFT) simulations revealed that TAM binds primarily via π-π stacking and hydrogen bonding (1.8-2.2 Å), with oxygen-linked GOO-PEG configurations exhibiting stronger adsorption energy (ΔG = -1.50 eV) than carbon-linked systems (ΔG = -1.30 eV). Electronic structure analysis confirmed enhanced stability (HOMO-LUMO gap = 2.5-3.3 eV) and pH-modulated drug release. Spectroscopic (FTIR, UV-Vis) and microscopic (TEM, XRD) characterization validated nanocomposite formation, while RDG analysis highlighted dominant non-covalent interactions. This study establishes TAM@GO-PEG as a promising nanoplatform for targeted breast cancer therapy, combining high drug loading, pH-triggered release, and tunable electronic properties. The synergy between experimental optimization and DFT modeling provides a robust framework for designing next-generation nanotherapeutics.
乳腺癌仍然是癌症相关死亡的主要原因，其中激素受体阳性（ER⁺）肿瘤约占病例的70%。他莫昔芬（TAM）作为内分泌治疗的金标准，存在溶解度差（log P≈6.3）、生物利用度低（<30%）以及获得性耐药等问题。为克服这些局限性，我们通过综合实验和计算方法开发了一种pH响应型负载他莫昔芬的氧化石墨烯-聚乙二醇（TAM@GO-PEG）纳米复合材料。GO-PEG的合成产生了一种稳定的纳米载体，具有高载药效率（DLE≈80%）和pH依赖性电荷反转（pH 5.3时为+12.6 mV，pH 7.4时为+2.1 mV）。体外释放研究表明其具有肿瘤选择性动力学，在72小时内，pH 5.5时的累积释放率为89.3%，而pH 7.4时为61.1%。密度泛函理论（DFT）模拟显示，TAM主要通过π-π堆积和氢键（1.8 - 2.2 Å）结合，与氧连接的GOO-PEG构型相比，碳连接系统的吸附能更强（ΔG = -1.30 eV），氧连接的GOO-PEG构型表现出更强的吸附能（ΔG = -1.50 eV）。电子结构分析证实了稳定性增强（HOMO-LUMO能隙 = 2.5 - 3.3 eV）和pH调节的药物释放。光谱（FTIR、UV-Vis）和显微镜（TEM、XRD）表征验证了纳米复合材料的形成，而RDG分析突出了主要的非共价相互作用。本研究将TAM@GO-PEG确立为一种有前景的靶向乳腺癌治疗纳米平台，它结合了高载药量、pH触发释放和可调电子性质。实验优化与DFT建模之间的协同作用为设计下一代纳米治疗药物提供了一个强大的框架。
