Document Type
Article
Publication Date
2-12-2026
Abstract
Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs’ small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss key design elements (targeting peptides, cleavable/non-cleavable linkers, and payloads) and how these drive mechanisms of tumor delivery and intracellular drug release. Mechanistically, PDCs bind receptors or translocate across membranes, undergo endocytosis, and exploit stimuli-responsive linkers or cell-penetrating peptides to release drugs. Many PDCs can self-assemble into nanoscale structures in aqueous environments. We illustrate PDC concepts through specific instances, such as the brain-penetrant paclitaxel trevatide (ANG1005, paclitaxel-Angiopep-2), the radiotherapeutic lutetium (177Lu)-DOTATATE (Lutathera), and the LyP-1-conjugated doxorubicin-loaded liposomes (LyP-1-doxorubicin conjugate) for triple-negative breast cancer. Persistent challenges include in vivo stability (premature drug release and metabolic clearance), tumor heterogeneity (variable receptor expression), and manufacturing scale-up. We also address regulatory hurdles that have limited PDC clinical success; for example, currently, only lutetium (177Lu)-DOTATATE is FDA-approved (others, like melphalan flufenamide (melflufen), have faced setbacks). Finally, we outline future directions, including theranostic PDCs, AI-assisted peptide optimization, dual-stimuli linkers, and integration with nanomaterials, to further enhance targeting and efficacy. This comprehensive review integrates findings from recent literature and provides an in-depth perspective on the design, advantages, limitations, and future prospects of PDCs in cancer therapy.
Recommended Citation
Parang K, Do T, Dinh C, Davani-Davari D, Foroughi M, Khong T, Moazen M, Nasrolahi Shirazi A. Tumor Targeting with Peptide-Drug Conjugates: Showcasing Key Progress and Hurdles. Drug Des Devel Ther. 2026;20:562135 https://doi.org/10.2147/DDDT.S562135
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Included in
Amino Acids, Peptides, and Proteins Commons, Medicinal and Pharmaceutical Chemistry Commons, Oncology Commons, Pharmaceutics and Drug Design Commons, Therapeutics Commons
Comments
This article was originally published in Drug Design, Development and Therapy, volume 20, in 2026. https://doi.org/10.2147/DDDT.S562135