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

## TL;DR

A new stearic acid-modified drug conjugate improves prostate cancer treatment by extending drug half-life and reducing side effects.

## Contribution

A stearic acid-modified PDC is developed with significantly improved pharmacokinetics and tumor suppression.

## Key findings

- PDC-C18 forms stable nanocomplexes with human serum albumin, extending drug half-life over 160-fold.
- The conjugate achieves a 60-fold reduction in clearance rate and a 96.91% tumor suppression rate.
- PDC-C18 avoids side effects of traditional modification strategies while maintaining PSMA specificity.

## Abstract

Prostate-specific membrane antigen (PSMA)-targeting peptide–drug conjugates (PDCs) offer promise for the treatment of PSMA-positive prostate cancer, but their applications are limited by rapid clearance, poor pharmacokinetics, and low efficacy. Herein, we design a series of PDCs incorporating rational functional moieties, including a Glu–Ureido–Lys PSMA-targeting ligand, the cytotoxic payload monomethyl auristatin E (MMAE), and a cathepsin B-cleavable Val–Cit linker, combined with structural modifications such as free amine exposure, acetylation, stearic acid acylation, or p-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.

Prostate-specific membrane antigen (PSMA)-targeting peptide–drug conjugates (PDCs) offer promise for the treatment of PSMA-positive prostate cancer, but their applications are limited by rapid clearance, poor pharmacokinetics, and low efficacy.