Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs

Albumin nanoparticles (ANPs) offer unique advantages for antitumor drug delivery system, including non-immunogenicity and inherent tumor-targeting capacity. At present, only a few products, such as ABRAXANE® and FYARRO™, have been approved for clinical applications. The poor affinity of doxorubicin (DOX) for albumin, coupled with its numerous severe adverse reactions, poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX. In this study, we developed prodrugs by conjugating fatty acids of varying lengths with DOX. Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules. We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs. Compared to free DOX, all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm. Additionally, DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells. Significantly, the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids, impacting their in vivo pharmacokinetics, antitumor effectiveness and tumor accumulation. This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs, and it builds a good platform for creating ANPs which prioritize high drug loading, high efficiency, and minimal side effects.