Receptor-Targeted Folic Acid Ligand–Drug Conjugate of Exatecan Leads to Complete Tumor Regression in the Preclinical Tumor Model

The folate receptors (FR) are highly overexpressed in various solid tumors and metastatic cancers, whereas they are low or negligible in healthy cells. This provides a window of opportunity to deliver any payload by specifically targeting these receptors. This study develops a delivery strategy for exatecan (payload), a Top1 inhibitor, via the Fol-SS-Exa (8) conjugate, demonstrating its potency against FR-positive cancer cells in vitro and in preclinical studies. The design of the Fol-SS-Exa (8) conjugate features folate as a ligand targeting FRα and a cleavable disulfide linker that remains stable under physiological conditions. Exatecan (6), a highly potent cytotoxic payload, arrests cell division in cancer cells. Fol-SS-Exa (8) exhibited an IC50 value of 4.88 nM in the FR-positive MDA-MB-231 cell line. The Fol-SS-Exa conjugate (8), administered to tumor-induced C57BL/6 mice, exhibited complete regression after three injections (7.5 mg/kg body weight), highlighting its potent antitumor activity. In addition, the conjugate (8) demonstrated the ability to eradicate the toxicity of exatecan (6) when administered alone.