Acetyl-lysine human serum albumin nanoparticles activate CD44 receptors, with preferential uptake by cancer stem cells, leading to tumor eradication
Guojun Xiong, Andreas G. Schätzlein, Ijeoma F. Uchegbu
Abstract
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.