Linkers for effective peptide-drug conjugates

Despite their notable anticancer efficacy, many established cancer drugs such as Doxorubicin, camptothecin, paclitaxel, gemcitabine, and methotrexate exhibit limited selectivity to target cancer cells over normal cells. Because these conventional chemotherapeutic agents frequently impact both healthy and cancerous cells, they have high side effects constraining their overall therapeutic index. The challenge arises from their inability to selectively target tumor cells with cytotoxic effects while sparing the surrounding healthy tissues. In response to these limitations, peptide-drug conjugate (PDC) strategies have emerged as an innovative category of targeted therapies designed to improve drug delivery and reduce off-target effects. PDCs utilize the specificity of peptides to deliver cytotoxic agents more accurately to cancer cells, thereby improving therapeutic outcomes and reducing adverse side reactions. PDCs employ peptides that selectively bind to overexpressed receptors on tumor cells, enabling targeted therapy with minimal side effects in cancer patients. To successfully synthesize peptide-drug conjugates, it is essential to have a solid understanding of the active site of the drug, recognition site of the peptide, and where the drug will be release inside the tumor cells. The linker between the drug and the peptide plays a critical role in the stability and release profile of the conjugates, which influence how effectively the drug reaches its target site of action and how it is released within the tumor cells. The choice of linker can determine the pharmacokinetics and bioavailability profiles of PDCs, making it a vital aspect of their design. The review is aimed at providing a comprehensive review of various drug-peptide conjugates with a particular emphasis on the linkers and PDC synthetic methods. Here, we described the advancements PDC chemistries and potential future research areas in drug delivery systems. In addition, we hope to contribute valuable insights into optimizing PDC design for enhanced efficacy in cancer therapy.