Computational Study of Drug Delivery Systems with Radionuclide and Fluorescence Imaging Modalities. I. Albumin-Based Systems for Doxorubicin Delivery

Abstract

Molecular docking and molecular dynamics methodologies were employed to design and evaluate delivery systems for the antineoplastic agent doxorubicin (DOX) utilizing human serum albumin (HSA) as the carrier. To engineer a drug delivery system (DDS) with dual imaging modalities, complexes of the radionuclide technetium-99m (TCC) and near-infrared (NIR) fluorescent dyes, including indocyanine green (IG), methylene blue (MB), heptamethine cyanine dye AK7-5, and squaraine dye SQ1, were integrated into the protein nanocarriers. The highest binding affinities to the proteins were identified for TCC [99mTc]Tc-diisopropyl iminodiacetic acid (TcDIS), [99mTc]Tc-hydrazinonicotinic acid-H6F (TcHYN), [99mTc]Tc-Mebrofenin (TcMEB), as well as the fluorescent dyes IG and SQ1. Molecular docking analyses revealed that most technetium complexes (TCCs) bind to HSA domain I, with some exceptions showing affinity for domains I and III or domain III alone. Ternary and quaternary protein-ligand systems were explored using multiple ligand docking approaches. In ternary systems, DOX binding sites were identified either in domain I or in a region spanning multiple domains, depending on potential overlap with TCC binding sites. For quaternary systems incorporating NIR fluorophores, binding affinities decreased in the order: IG > SQ1 > AK7-5 > MB. Molecular dynamics simulations of HSA-DOX-MB and HSA-DOX-IG complexes demonstrated stable associations between the components, with consistent center-of-mass distances and minimal perturbation of HSA structure. These findings support the potential of HSA as a suitable carrier for developing dual-modality imaging nanocarriers incorporating both radionuclide and fluorescence imaging capabilities.

Keywords

• Drug delivery systems
• Human serum albumin
• Doxorubicin
• Technetium complexes
• Fluorescent dyes
• Molecular docking