Combined Experimental and DFT Study of Tamoxifen Adsorption on PEG-Modified Graphene Oxide for Enhanced Drug Delivery.

Abstract

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 hours. 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 GO-O-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.