A prostate-specific membrane antigen targeted small molecule-drug conjugate for efficient prostate cancer therapy at a low dosage.

Prostate-specific membrane antigen (PSMA), which is overexpressed in most prostate cancer cells, serves as an ideal target for precision therapy. The clinical utility of the potent chemotherapeutic agent SN38 is hindered by its poor water solubility and systemic toxicity. Herein, we present a novel, fully water-soluble small-molecule drug conjugate (SMDC), SN38-SS-3PEG24-3PSMA (SPP), designed for enhanced prostate cancer targeting and tumor-selective drug release. SPP integrates three PSMA-targeting ligands, a glutathione (GSH)-responsive disulfide linker, and three monodisperse polyethylene glycol (PEG) chains, achieving exceptional water solubility (>1 mM) and tumor-specific payload activation. In vivo fluorescence imaging revealed efficient tumor accumulation with minimal hepatic distribution, as evidenced by predominant renal clearance, thereby reducing hepatotoxicity risks. Remarkably, SPP demonstrated potent tumor growth inhibition at low doses (20 nmol) in PSMA-positive xenograft models, outperforming controls without PEG spacers or disulfide linkers. The GSH-triggered release of SN38 within the tumor cells ensured high cytotoxicity against cancer cells while maintaining stability in circulation, thereby minimizing off-target toxicity. Collectively, this study highlights SPP as a promising therapeutic candidate, combining enhanced water solubility, precise tumor targeting, and low-dose efficacy with an excellent safety profile, offering a transformative strategy for prostate cancer treatment.