An indocyanine green-potentiated gastrin releasing peptide receptor-targeting multifunctional peptide-drug conjugate for prostate cancer therapy.

Prostate cancer (PCa) remains highly prevalent and deadly, and its progression to castration resistance is still difficult to treat despite recent therapeutic advances. Peptide-drug conjugates (PDCs) have emerged as promising targeted therapeutics for cancer, yet their clinical translation is hindered by unsatisfactory in vivo performance and limited ability for reliable tracking. Here, we present PXC-4, a Gastrin Releasing Peptide Receptor (GRPR)-targeting multifunctional PDC based on GRPR antagonist JMV-594 and the cytotoxic payload monomethyl auristatin E (MMAE), for precise PCa therapy. PXC-4, by leveraging indocyanine green (ICG) and radionuclide (64Cu/177Lu), acquired multifunctionality and optimized antitumor activity. Installing of ICG substantially increased cell penetration (6.25-fold at 4 h) and tumor accumulation (3.82-fold at 4 h) of PXC-4, resulting in 89% inhibition of prostate tumor growth via lysosome-mediated toxin release with markedly improved safety. Upon 808 nm laser irradiation, PXC-4 further achieved 99% tumor suppression through photodynamic therapy coupled with its cytotoxic payload. Incorporation of DOTA enabled precise in vivo tracking via64Cu-based PET imaging and facilitated multimodal synergistic tumor inhibition via177Lu-based radionuclide therapy. Collectively, our findings suggest that rational ICG installation markedly elevates the functional competence of GRPR-targeted PDC, giving rise to an enhanced multifunctional therapeutic entity capable of diagnosis, image-guided surgery, and targeted treatment for PCa.