Acetyl-lysine human serum albumin nanoparticles activate CD44 receptors, with preferential uptake by cancer stem cells, leading to tumor eradication

CD44 receptors in cancer stem cells (CSCs) are a key biomarker associated with cancer recurrence, progression, and metastasis. Acetylation is a post-translational modification used to regulate protein function at the end of protein synthesis. In this study, we found that acetylated human serum albumin (Ac-HSA) acts an uptake ligand on CD44 receptors. This promising finding motivated us to develop an Ac-HSA-based nanocarrier for cancer chemotherapy. By conjugating maleimide-polylactic acid (MAL-PLA) with Ac-HSA, the resulting amphiphile formed nanoparticles (Ac-HSA-PLA NPs) which were shown to rapidly enter CD44+ cancer cells and cancer stem cells via CD44-mediated endocytosis. This contrasts with the comparatively slow uptake of CD44 antibodies. Abraxane®, an approved human serum albumin (HSA) nanoparticle formulation of paclitaxel (PTX) demonstrates that PTX may be delivered by HSA nanoparticles. However, Abraxane® is not clinically superior to solvent-based PTX formulations. In a CD44+ tumor model, PTX-loaded Ac-HSA-PLA NPs outperformed Abraxane®, achieving complete tumor elimination without recurrence, two months post-treatment, while Abraxane treated tumors continued to grow (tumor volume increased five fold). The Ac-HSA-PLA (PTX) NPs also demonstrated minimal systemic toxicity, suggesting that Ac-HSA could be a promising alternative for targeted cancer therapy in CD44-expressing cancers.