Exatecan-Loaded HSA Nanoparticles for Sustained Release and Enhanced Cancer Treatment

Abstract Exatecan, a potent topoisomerase 1 inhibitor and a potent anticancer agent, is derived from naturally occurring camptothecin. Its clinical development has been halted due to dose-limiting toxicities and a shorter plasma half-life in humans. To overcome these challenges, we synthesized a novel human serum albumin nanoparticle (Exa-HSA-NPs) for selective cancer therapy. The Exa-HSA-NPs exhibited a uniform spherical morphology with an average hydrodynamic diameter of 147 nm, zeta potential of −24 mV, and a very low polydispersity index (PDI < 0.1). STEM-EDS mapping confirmed homogeneous distribution of exatecan within the albumin medium. In vitro release kinetics demonstrated pH-responsive, sustained drug release for up to 9 days, with faster release in acidic (tumor-like) conditions. Molecular docking of exatecan with HSA revealed the formation of a stable complex stabilized by hydrophobic interactions and hydrogen bonding. Exa-HSA-NPs displayed potent cytotoxicity in oral cancer (AW13516) and lung cancer (A549) cells, with significantly reduced toxicity in non-cancerous HEK293T cells. Cellular uptake analysis revealed preferential NPs internalization in cancer cells (70% in AW13516, 63% in A549) compared with normal cells (27%), consistent with gp60 and SPARC-mediated albumin uptake mechanisms. Apoptosis assays confirmed selective induction of cancer cell death with minimal impact on normal cells. The Exa-HSA-NPs exhibited excellent biodegradability and hemocompatibility, indicating favorable safety and potential for clinical translation. Overall, Exa-HSA-NPs offer a promising strategy for the sustained, selective tumor delivery of exatecan, with an improved therapeutic index and reduced systemic toxicity.