Computational Study of Drug Delivery Systems with Radionuclide and Fluorescence Imaging Modalities. IV. Doxorubicin Delivery Systems Based on Albumin and Hemoglobin

Abstract

The development of multifunctional drug delivery systems that integrate therapeutic and diagnostic capabilities remains a major challenge in oncology. In the present work we investigated hybrid carriers composed of human serum albumin and hemoglobin (HSA-Hb) for doxorubicin (DOX) delivery combined with radionuclide and fluorescence imaging. Using molecular docking simulations, we systematically evaluated the interactions of HSA-Hb assemblies with twelve technetium-99m (^99mTc)-labeled radiopharmaceuticals, DOX, and four near-infrared (NIR) dyes. The results revealed that hemoglobin markedly expands the binding landscape, providing exclusive and high-affinity sites for several ^99mTc complexes (notably TcMEB and TcDIS), while also serving as the primary scaffold for DOX and NIR dyes. Two distinct DOX-binding pockets were identified within Hb subunits, suggesting enhanced drug stability and potential responsiveness to tumor hypoxia. Fluorescent dyes, including methylene blue, indocyanine green, AK7-5, and SQ1, exhibited preferential binding to Hb with affinities higher than those observed for albumin, indicating superior suitability for optical imaging. Importantly, the partitioning of radiopharmaceuticals to albumin and therapeutic/imaging ligands to hemoglobin reduced binding competition and enabled the simultaneous integration of multimodal functions within a single construct. These findings highlight HSA-Hb nanocarriers as promising candidates for next-generation theranostic platforms, combining efficient DOX delivery with non-invasive radionuclide and fluorescence monitoring.