Enhanced therapeutics of cabazitaxel via polycarboxylate conjugation: improved solubility, safety, and antitumor efficacy.

Introduction: Cabazitaxel (CTX) is a potent anticancer agent whose clinical utility is severely limited by poor aqueous solubility and severe systemic toxicity. To overcome these challenges, we designed and synthesized two water-soluble polycarboxylate conjugates, CTX-DTPA and CTX-TTHA. Methods: The conjugates were characterized via NMR and mass spectrometry. Their hydrophilicity was assessed by lipid-water partition coefficient. Antitumor activity was evaluated in vitro across multiple cancer cell lines and in vivo using xenograft and immunocompetent models. Mechanisms were investigated via molecular docking, immunofluorescence, and tubulin polymerization assays. Safety profiles were assessed through hemocompatibility, myelosuppression, and thymic toxicity evaluations. Pharmacokinetics and biodistribution were analyzed in SD rats. Results: The derivatives exhibited potent antitumor activity comparable to unmodified CTX, effectively inducing apoptosis and G2/M cell cycle arrest. Mechanistic studies revealed moderately reduced binding affinity to β-tubulin but more sustained microtubule stabilization. Remarkably, the conjugates demonstrated a 64-fold improvement in hemocompatibility, significantly minimized myelosuppression, and preserved thymic architecture and immune function. Pharmacokinetic analysis showed prolonged circulation, efficient clearance, and drastically diminished off-target tissue accumulation for CTX-DTPA. Discussion: This study establishes polycarboxylate conjugation as a promising strategy for developing safer and more effective chemotherapeutic agents through rational molecular design, successfully decoupling antitumor efficacy from systemic toxicity.