Tumor Targeting with Peptide-Drug Conjugates - Showcasing Key Progress and Hurdles

Sep 22, 2026

Peptide-drug conjugates (PDCs) are modular targeted therapeutics that link a tumor-homing peptide to a cytotoxic or modulating drug payload through cleavable or non-cleavable linkers. This review explains how targeting peptides, linker chemistry, and payload selection control delivery, receptor binding, internalization, and intracellular drug release. Compared with antibody-drug conjugates (ADCs), PDCs’ smaller size supports deeper tumor penetration and faster clearance, but challenges remain in vivo stability, tumor heterogeneity, and manufacturing scale-up, alongside regulatory barriers limiting clinical success.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Introduction

Design principles of peptide-drug conjugates

Mechanisms of tumor delivery and intracellular release

Advantages and comparison with antibody-drug conjugates

Clinical progress and key hurdles

Future directions

Drug Design, Development and Therapy Open Access Full Text Article REVIEW Tumor Targeting with Peptide-Drug Conjugates: Showcasing Key Progress and Hurdles Keykavous Parang 1 , Thuy Do 1 , Clare Dinh 1 , Dorna Davani-Davari 1 , Max Foroughi 1 , Troy Khong 1 , Mahsa Moazen 1 , Amir Nasrolahi Shirazi2 1Department of Biomedical and Pharmaceutical Sciences, Center for Targeted Drug Delivery, Chapman University School of Pharmacy, Irvine, CA, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, USA Correspondence: Keykavous Parang, [Email parang@chapman.edu](Email parang@chapman.edu) | 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, AIassisted 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.
Keywords: antibody-drug conjugate, cancer, drug delivery, linker chemistry, nanotechnology, peptide-drug conjugate, targeting peptide, theranostics, tumor penetration | | --- | | Introduction
Peptide-drug conjugates (PDCs) have emerged as a powerful class of targeted therapeutics that combine the high potency of small-molecule cytotoxic agents with the specificity of peptide homing ligands. In a typical PDC, a tumor-targeting peptide is covalently linked to a cytotoxic or modulating drug (payload) via a linker that can be cleavable or stable. The peptide directs the drug to cancer cells or the tumor microenvironment, enhancing local uptake and sparing normal tissues. Once the PDC reaches its target, the conjugate is internalized by the tumor cell, where intracellular environmental triggers such as pH or elevated enzyme concentration specifically cleave the linker, ensuring precise drug release.
PDCs are structurally simpler and much smaller than antibody-drug conjugates (ADCs); this allows deeper tumor penetration and rapid tissue diffusion.1

FAQs

What is a peptide-drug conjugate (PDC) and how is it constructed?

A PDC links a tumor-targeting peptide to a cytotoxic or modulating drug payload via a cleavable or stable linker. The peptide guides the conjugate to cancer cells or the tumor microenvironment and the linker controls drug release after internalization.

How do PDCs differ from antibody-drug conjugates (ADCs) in targeting and delivery?

PDCs are structurally simpler and much smaller than ADCs, enabling deeper tumor penetration and faster tissue diffusion. ADCs can benefit from prolonged circulation but face limited tissue diffusion due to their larger size.

What are the major challenges preventing broader PDC clinical success?

Key hurdles include in vivo stability problems such as premature drug release and metabolic clearance, tumor heterogeneity from variable receptor expression, and difficulties in manufacturing scale-up. Regulatory barriers have also limited clinical approvals beyond specific examples.

Sep 22, 2026

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