一种基于肽的药物递送系统用于靶向转移性前列腺癌

While effective treatments for prostate cancer (PC) such as androgen deprivation therapy (ADT) have been developed, it is still a challenge to treat advanced PC, which has become resistant to ADT or has metastasized. Lately, therapeutic agents that selectively target PCs such as [177Lu]Lu-PSMA-617 have shown promise, suggesting that tumor-specific drug delivery may greatly improve the management of metastatic castration-resistant PC. Here, we report a novel peptide, MHP1 (metastasis homing peptide 1), which effectively homes to metastatic PC in vivo.MHP1 was identified by phage display using experimental metastasis mouse models using the androgen-independent PC-3 human cancer cell line. The mouse models were prepared by either directly injecting the cells into the tibia and/or the brain or through intracardiac or intravenous injections to produce disseminated tumors. Phage display was performed using a cyclic CX7C peptide library expressed on T7 phage. To enrich for peptides that effectively home to metastatic PCs, the phage display was performed in mice by first performing 1 round of ex vivo phage panning using cell suspensions prepared from PC-3 tibia xenografts, followed by 3-4 rounds of in vivo selections in disseminated metastasis mice. DNA sequencing of the enriched phage clones yielded 150 candidate peptides. Phage clones that expressed each peptide on the coat protein were then mixed at an equimolar ratio to produce champion phage pools. “Play-off” in vivo phage display studies were performed by systemically injecting the phage pools into disseminated PC-3 tumor mice. A phage clone that expressed the MHP1 peptide showed the highest tumor-specificity by homing to tumors in various organs without accumulating into corresponding normal tissues. The MHP1 peptide chemically synthesized with a fluorescent tag (FAM-MHP1) effectively homed to tibia and brain xenograft PC-3 tumors. It also homed to disseminated metastatic PC-3 tumors in various organs, such as the jaw, femur, lymph nodes, and eye. Of note, in a spontaneous metastasis model prepared with 22Rv1 human PC cells, FAM-MHP1 homed more effectively to metastatic tumors than to the primary tumor. To identify the receptor of MHP1, affinity chromatography was performed by passing tissue lysates of PC-3 tibia tumors over MHP1-coated beads. A protein was eluted with the MHP1 peptide (but not by a control peptide). Mass spectrometry analysis revealed a list of candidate proteins. Preliminary data suggest that one of the candidates appears promising for being highly expressed in PC tissues. Interestingly, while the protein is intracellular in normal cells, it is misplaced onto the surface of some PC cells making it available for affinity-based targeting. These results suggest that the MHP1 peptide may serve as a promising platform to target metastatic PC. Characterization of the receptor may also lead to additional PC-specific therapies and deeper understanding of PC biology.