Stearic acid-modified PSMA-targeting peptide–drug conjugate for long-acting prostate cancer therapy

-iodophenylbutyric acid (PIBA) conjugation. Among them, the stearic acid-modified PSMA-targeting PDC (PDC-C18) is identified as a long-acting candidate for treating prostate cancer. PDC-C18 rapidly forms stable nanocomplexes with human serum albumin (HSA) through hydrophobic interactions, effectively shielding its hydrophobic moiety while preserving PSMA specificity. Notably, PDC-C18 exhibits a more than 160-fold extension in half-life compared to conventional PDCs, prolongs mean residence time (MRT) from 12.47 h to 23.93 h relative to PIBA-modified PDCs, and achieves a 60-fold reduction in clearance rate. This long-acting property translates into a remarkable tumor suppression rate of 96.91%, simultaneously avoiding the side effects associated with traditional PIBA modification strategies. Overall, this study presents an effective approach to improving the pharmacokinetic behavior of PDCs and provides valuable insights for the development of next-generation tumor-targeted therapies.