Colon Disease Targeted Therapy: Functional Therapeutic Peptides-Based Agents

Abstract

Therapeutic peptides composed of a small amino acid chain have gained significant attention as therapeutic agents. These therapeutic peptides exhibit high specificity and affinity for targets, providing advantages such as lower immunogenicity and production costs compared to biological agents. Inflammation, a natural defense mechanism, plays a crucial role in the development of chronic diseases such as asthma, cancer, and neurodegenerative disorders, and many side effects have been reported in related diseases, requiring the development of new therapeutic approaches. Thus, therapeutic peptides have emerged as potential candidates for anti-inflammatory therapy, offering the potential to mitigate side effects. Additionally, conventional targeted therapies for cancer have been associated with several side effects, leading to increased spotlight in peptide-based delivery systems that improve efficiency, enhance therapeutic payload, and enhance cancer-specific targeting capabilities. This study focused on discover therapeutic peptides that disrupt the interaction between damage-associated molecular patterns (DAMPs) involved in colonic inflammation, such as S100A8 and S100A9, and pattern recognition receptors (PRRs) such as toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE). The development of a colonic-targeting S100-PRR interaction inhibitor, rCT-S100A8/A9, was undertaken to inhibit this interaction and enhance targeting capability for the colon. rCT-S100A8/A9 effectively protected in acute and chronic colitis mice models as well as in a colitis-associated colon cancer mice model. Moreover, it demonstrated therapeutic efficacy in a xenograft mouse model of oxaliplatin-resistant colon cancer. These findings highlight the potential role of rCT-S100A8/A9 in cancer treatment and colonic inflammation control. Furthermore, this study aimed to investigate a therapeutic candidate with advanced therapeutic effect that overcomes the limitations of peptide-based therapies using nanoparticles such as liposome, and tumor-targeted liposome delivery system PCD2-lipo-ATRAM had been developed. PCD2-lipo-ATRAM demonstrated successful tumor targeting ability with the effect of ATRAM peptide and liposome in a xenograft mouse model of colorectal cancer, and platycodin D2 (PCD2), a natural compound, not only exerts anti-tumor effect It also contributed to increasing the structural stability of liposomes. In addition, PCD2-lipo-ATRAM demonstrated inhibition of BCL-2 family proteins, anti-apoptosis proteins that induce enhanced cytotoxicity against colon cancer cells and induced of intrinsic caspase-9/-3-mediated apoptosis. These findings validated that the tumor-targeted liposome delivery system PCD2-lipo-ATRAM has the potential value as a promising strategy for colorectal cancer treatment. Overall, these studies present new possibilities for the development of therapeutic peptides through the discovery of novel target peptides and the development of therapeutic candidates for inflammatory diseases and cancer via complementing the advantages and overcoming the disadvantages of peptides.