Context <p>The rational design of metal nanoparticle-based drug delivery systems requires understanding not only drug loading but also intracellular drug release mechanisms. By computing the thermodynamic feasibility of glutathione (GSH)-mediated competitive displacement of four anticancer drugs—5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), hydroxyurea (HU), and cytarabine (Ara-C)—from icosahedral <InlineEquation ID="IEq6"> <EquationSource Format="TEX">${\text{Au}}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mtext>Au</mtext> <mn>13</mn> </msub> </math></EquationSource> </InlineEquation>, <InlineEquation ID="IEq7"> <EquationSource Format="TEX">${\text{Ag}}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mtext>Ag</mtext> <mn>13</mn> </msub> </math></EquationSource> </InlineEquation>, and <InlineEquation ID="IEq8"> <EquationSource Format="TEX">${\text{Pt}}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mtext>Pt</mtext> <mn>13</mn> </msub> </math></EquationSource> </InlineEquation> nanoclusters, we predict whether elevated intracellular GSH concentrations in tumor cells can trigger drug release. Our results reveal a striking metal dependence: Au13 emerges as the optimal GSH-responsive drug carrier, with moderate drug binding (−11.6 to −28.0 kcal/mol) and strong GSH binding (−44.0 kcal/mol), yielding large positive displacement energies (+16.0 to +32.4 kcal/mol) for three of four drugs. Ag13 shows viable but tighter release margins (+5.1 to +14.4 kcal/mol). In contrast, <InlineEquation ID="IEq9"> <EquationSource Format="TEX">$P{t}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi>P</mi> <msub> <mi>t</mi> <mn>13</mn> </msub> </mrow> </math></EquationSource> </InlineEquation> is fundamentally unsuitable for GSH-triggered delivery, as all drugs bind too strongly (−56.0 to −75.9 kcal/mol) while GSH binding is anomalously weak (−18.0 kcal/mol). The thiol-containing drug 6-mercaptopurine resists GSH displacement on all three metals due to exceptionally strong metal-sulfur bonds. These predictions are validated by basis set superposition error corrections (<5% effect), PBE0-D4 functional cross-validation (<InlineEquation ID="IEq10"> <EquationSource Format="TEX">${R}^{2}$</EquationSource> <EquationSource Format="MATHML"><math> <msup> <mrow> <mi>R</mi> </mrow> <mn>2</mn> </msup> </math></EquationSource> </InlineEquation>= 0.90), and approximate Gibbs free energy corrections. Our findings provide a computational framework for metal-selective drug carrier design and identify <InlineEquation ID="IEq11"> <EquationSource Format="TEX">$A{u}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi>A</mi> <msub> <mi>u</mi> <mn>13</mn> </msub> </mrow> </math></EquationSource> </InlineEquation> as the most promising platform for GSH-responsive anticancer drug delivery.</p> Methods <p>Geometry optimizations were performed using the GFN2-xTB and GFN1-xTB Hamiltonians with ALPB implicit solvation for water, implemented in the xTB 6.7.1 program. An adaptive convergence strategy with elevated electronic temperatures (up to 5000 K Fermi smearing) was employed for metal-containing systems. Single-point energies were computed at the B3LYP-D4/def2-TZVP level with CPCM (water) solvation and RIJCOSX acceleration using ORCA 5.x. Basis set superposition error was evaluated via the counterpoise method. Functional validation was performed at the PBE0-D4/def2-TZVP level. Approximate Gibbs free energy corrections were obtained from xTB frequency calculations. Icosahedral <InlineEquation ID="IEq12"> <EquationSource Format="TEX">${M}_{13}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>M</mi> <mn>13</mn> </msub> </math></EquationSource> </InlineEquation> cluster structures were generated using the Atomic Simulation Environment (ASE) Python library, and drug structures were obtained from the PubChem database.</p>

Comparative DFT investigation of glutathione-mediated drug release from ${Au}_{13}$, $Ag_{13}$, and $Pt_{13}$nanoclusters: implications for metal-selective anticancer drug delivery

期刊论文
发表日期：

2026年5月21日

查看全文

Saurav Mishra,
Brijesh Kumar Pandey,
Abhay Prakash Srivastava

摘要

Context

The rational design of metal nanoparticle-based drug delivery systems requires understanding not only drug loading but also intracellular drug release mechanisms. By computing the thermodynamic feasibility of glutathione (GSH)-mediated competitive displacement of four anticancer drugs—5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), hydroxyurea (HU), and cytarabine (Ara-C)—from icosahedral ${\text{Au}}_{13}$ ${Au}_{13}$ , ${\text{Ag}}_{13}$ ${Ag}_{13}$ , and ${\text{Pt}}_{13}$ ${Pt}_{13}$ nanoclusters, we predict whether elevated intracellular GSH concentrations in tumor cells can trigger drug release. Our results reveal a striking metal dependence: Au13 emerges as the optimal GSH-responsive drug carrier, with moderate drug binding (−11.6 to −28.0 kcal/mol) and strong GSH binding (−44.0 kcal/mol), yielding large positive displacement energies (+16.0 to +32.4 kcal/mol) for three of four drugs. Ag13 shows viable but tighter release margins (+5.1 to +14.4 kcal/mol). In contrast, $P{t}_{13}$ $P t_{13}$ is fundamentally unsuitable for GSH-triggered delivery, as all drugs bind too strongly (−56.0 to −75.9 kcal/mol) while GSH binding is anomalously weak (−18.0 kcal/mol). The thiol-containing drug 6-mercaptopurine resists GSH displacement on all three metals due to exceptionally strong metal-sulfur bonds. These predictions are validated by basis set superposition error corrections (<5% effect), PBE0-D4 functional cross-validation ( ${R}^{2}$ $R^{2}$ = 0.90), and approximate Gibbs free energy corrections. Our findings provide a computational framework for metal-selective drug carrier design and identify $A{u}_{13}$ $A u_{13}$ as the most promising platform for GSH-responsive anticancer drug delivery.

Methods

Geometry optimizations were performed using the GFN2-xTB and GFN1-xTB Hamiltonians with ALPB implicit solvation for water, implemented in the xTB 6.7.1 program. An adaptive convergence strategy with elevated electronic temperatures (up to 5000 K Fermi smearing) was employed for metal-containing systems. Single-point energies were computed at the B3LYP-D4/def2-TZVP level with CPCM (water) solvation and RIJCOSX acceleration using ORCA 5.x. Basis set superposition error was evaluated via the counterpoise method. Functional validation was performed at the PBE0-D4/def2-TZVP level. Approximate Gibbs free energy corrections were obtained from xTB frequency calculations. Icosahedral ${M}_{13}$ $M_{13}$ cluster structures were generated using the Atomic Simulation Environment (ASE) Python library, and drug structures were obtained from the PubChem database.

Comparative DFT investigation of glutathione-mediated drug release from \({Au}_{13}\), \(Ag_{13}\), and \(Pt_{13}\)nanoclusters: implications for metal-selective anticancer drug delivery

摘要