Thermodynamic Investigation of Drug–Nanoparticle Interactions in Triple-Negative Breast Cancer
Author(s):
Amal Saheb Mahdi
Date: 09/10/2026
doi: https://doi.org/10.5281/zenodo.8425890
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated
with poor prognosis, limited targeted therapeutic options, and high rates of recurrence. Nanoparticle-based
drug delivery systems have emerged as promising strategies to enhance drug stability, improve tumor
selectivity, and reduce systemic toxicity. However, the thermodynamic mechanisms governing drug
nanoparticle interactions and their influence on therapeutic performance remain insufficiently
characterized. Aims of the study: This study aimed to investigate the thermodynamic behavior of drug
nanoparticle interactions and evaluate their relationships with physicochemical properties, pH-responsive
drug release, cellular uptake, and anticancer activity against TNBC cells. Methodology: Drug-loaded
biodegradable polymeric nanoparticles were prepared using nanoprecipitation and characterized by
dynamic light scattering, transmission electron microscopy, and high-performance liquid
chromatography. Thermodynamic parameters, including binding constant (K), Gibbs free energy (ΔG),
enthalpy (ΔH), and entropy (ΔS), were determined at 298–310 K. In vitro drug release was evaluated at
pH 7.4, 6.5, and 5.5. Cellular uptake, cytotoxicity, apoptosis, correlation analysis, and multiple linear
regression were performed using MDA-MB-231 cells. Results: The nanoparticles exhibited favorable
physicochemical characteristics, including a particle size of 137.5 ± 7.2 nm, encapsulation efficiency of
87.4 ± 3.8%, and excellent stability. Thermodynamic analysis demonstrated spontaneous and energetically
favorable drug binding with consistently negative ΔG values. Drug release increased significantly under
acidic conditions, reaching 93.6 ± 3.5% at pH 5.5 after 48 h (P < 0.001). Compared with the free drug,
nanoparticle delivery significantly enhanced cellular uptake (71.9 ± 5.6% vs. 38.5 ± 4.2%), reduced the
IC₅₀ value (2.11 ± 0.18 vs. 3.92 ± 0.29 µg/mL), and increased apoptosis (P < 0.001). Correlation and
regression analyses identified cellular uptake and binding affinity as the strongest predictors of cytotoxic
efficacy. Conclusions: Thermodynamic optimization significantly improved nanoparticle stability,
controlled drug release, intracellular delivery, and anticancer activity, highlighting the potential of rational
thermodynamic engineering for developing effective targeted nanomedicine strategies against triple
negative breast cancer.
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