Peptide Drug Conjugates: Overcoming ADC Limitations in Tumor Targeting

Improving the Stability and Pharmacokinetics of Peptides

While peptides provide excellent flexibility and tumor-targeting capability, their clinical translation faces important pharmacokinetic challenges. Compared with larger biomolecules such as antibodies, peptides generally exhibit: 1) short half-life due to rapid degradation by blood proteases. 2) Fast renal clearance, as peptides under ~25 kDa are readily filtered by the kidney glomeruli. 3) Low oral bioavailability, which makes oral dosing impractical in most cases. These limitations often require frequent dosing and restrict the broader application of PDCs. To overcome these hurdles, several strategies have been developed to enhance peptide stability, bioavailability, and circulation time. 

1. Cyclization and Peptide Stapling

Cyclization locks a peptide into a defined secondary structure (α-helix, β-sheet), improving both binding affinity and protease resistance. Common approaches include head-to-tail, head-to-side-chain, and side-chain-to-tail cyclization, which help restrict unwanted conformational changes during circulation. More advanced stapling techniques, such as one or two component peptide stapling, further stabilize peptides and have already produced clinical candidates like ALRN-6924. Bicyclic peptides, stabilized by multiple cross-links, offer an especially favorable “blood-to-tumor ratio,” enabling higher dosing without increased systemic toxicity.

Figure 3. Cyclization and peptide stapling methods.

2.  Amino Acids Modifications

Substituting natural L-amino acids with D-amino acids can reduce enzymatic degradation and extend half-life, as demonstrated by the improved stability of octreotide. Incorporating unnatural amino acids (UAAs) can fine-tune receptor binding and improve metabolic resistance. However, these modifications must be balanced carefully, as they may alter peptide folding or interactions.

Figure 4. Two general amino acids modification methods.

 3. Conjugation with Macromolecules

Attaching peptides to larger macromolecules can significantly prolong their circulation. Among these, PEGylation improves solubility and reduces renal clearance, as seen with HM-3, whose half-life increased nearly six-fold after PEG modification. Albumin-binding strategies also extend exposure by exploiting serum albumin’s long half-life, enabling convenient dosing schedules in drugs like liraglutide and semaglutide. Beyond these, other carriers such as fatty acid, polysialic acid (PSA), and hydroxyethyl starch (HES) have been explored to further enhance peptide stability and therapeutic potential. 

Figure 5. Conjugation with macromolecules methods.

4.   Formulation and Dosage Form Innovations

Innovative formulations also play a key role in improving peptide stability and bioavailability. pH-sensitive coatings can protect peptides from stomach acid and release them later in the intestine, while penetration enhancers facilitate transport across epithelial barriers to increase absorption. For injectable products, long-acting depots such as Sandostatin LAR, which encapsulates octreotide in PLGA microspheres, provide sustained drug release and reduce the frequency of dosing.

Figure 6. Formulation and dosage innovation methods.

Linkers

Just as in ADCs, the linker in a PDC is much more than a simple connector. It determines when and where the toxic payload is released. An effective linker must balance two requirements: remain stable in systemic circulation to prevent premature release, and trigger efficient cleavage once the conjugate reaches the tumor microenvironment or is internalized into target cells. Linkers used in PDCs can be broadly categorized into several classes.

1. Non-cleavable linkers

   These linkers form a permanent bond between the peptide and the payload. Drug release occurs only after the entire conjugate is degraded inside the cell. Non-cleavable linkers, such as thioethers, oximes, and triazoles, provide strong stability in circulation and reduce the risk of premature release, but they may limit flexibility in controlling when the payload becomes active.

     2. Enzyme-sensitive linkers

   These linkers are designed to be cleaved by enzymes overexpressed in tumors, such as cathepsins or matrix metalloproteinases (MMPs). This technology uses specific peptide sequences like Val-Cit and Val-Ala.

    3.  pH-sensitive linkers

   Exploiting the slightly acidic environment of tumors and endosomes, pH-sensitive linkers release the payload under low-pH conditions while remaining intact in the bloodstream. This approach minimizes systemic toxicity and enhances tumor selectivity.

    4. Reduction-sensitive linkers

   Tumor cells often have higher intracellular glutathione (GSH) levels than normal tissues. Linkers containing disulfide bonds can be cleaved in this reducing environment, releasing the payload once inside the cancer cell.

   Table 3. Types of linkers in PDC and representative examples

   Linker types	Representative examples
   Non-cleavable linkers
   Enzyme-sensitive linkers
   pH-sensitive linkers
   Reduction-sensitive linkers

    

   Compared with ADCs, PDC linkers are typically shorter and simpler, reflecting the smaller size of peptides. In many cases, linkers are also tailored to improve the overall stability of the conjugate, such as incorporating PEG chains to reduce proteolysis and extend circulation time. Importantly, the linker must be engineered so that conjugation does not disrupt the peptide’s binding affinity or the cytotoxicity of the payload.

    

   Payloads

   The payload is the effector component of a PDC, responsible for delivering the therapeutic impact once the conjugate reaches its target. While the peptide guides the conjugate to diseased tissue and the linker controls release, it is ultimately the payload that determines the cytotoxic potency, therapeutic scope, and safety profile of the drug. Payloads in PDCs can be categorized into several main classes depending on their therapeutic function.

   1.     Small targeted drugs

   Molecularly targeted inhibitors (e.g., kinase inhibitors, HDAC inhibitors) have better tumor selectivity than conventional chemotherapeutics but still suffer from resistance and systemic side effects. By conjugating them to peptides, their delivery can be refined, increasing efficacy while lowering nonspecific toxicity.

   2.     Chemotherapeutic drugs

   Traditional cytotoxins such as doxorubicin (DOX), paclitaxel (PTX), camptothecin (CPT), and platinum-based agents remain the most widely used payloads. Conjugation with peptides helps to overcome their inherent drawbacks such as poor solubility, short half-life, drug resistance, and system toxicity, by enhancing tumor targeting and improving their safety profile.

   3.     Radionuclides

   Radioactive isotopes serve both diagnostic and therapeutic purposes. Clinically approved examples include ¹¹¹In-DTPA-octreotide (Octreoscan) for neuroendocrine tumor imaging, and ¹⁷⁷Lu-DOTATATE, which prolongs progression-free survival in patients with neuroendocrine cancers. Other radionuclides such as 68Ga, 64Cu, 18F, 123I, and ^99mTc are also used in preclinical and clinical studies.

   4.     Anti-cancer peptides

   Certain peptides have intrinsic cytotoxic or pro-apoptotic activity, such as lytic peptides and the KLA pro-apoptotic peptide. When combined with tumor-targeting or cell-penetrating peptides, these payloads can achieve potent anti-tumor effects with improved safety, as shown in VEGFR-targeting peptide conjugates like QR-KLU.

   5.     Biomacromolecules

   Protein-based drugs and nucleic acids are promising payloads for difficult-to-treat diseases but face challenges in stability and delivery. Examples include NGR-TNF, which improves tumor selectivity while reducing systemic toxicity. Despite their potential, poor pharmacological properties limit their direct clinical translation, and many are now being studies in nanoparticle formulations.

   6.     Gas molecules

   Therapeutic gases such as NO, H2S, O2, CO, and SO2 are being explored for cancer therapy because they cause few side effects and rarely induce resistance. Linking them to peptides allows controlled release and offers new ways to tackle multidrug resistance and tumor relapse, though this approach is still in its early stages.

    

   Selecting a payload for PDCs requires balancing multiple factors. First, the payload must be highly potent, as only a limited number of molecules are delivered to each tumor cell. Second, it must be chemically compatible with peptide conjugation, retaining its anti-tumor activity without disrupting the peptide’s binding affinity. Third, the payload should offer an acceptable safety margin, with the targeting peptide improving selectivity while minimizing systemic toxicity. Finally, favorable drug-like properties such as small molecular weight, adequate stability, and resistance to premature degradation are critical for ensuring clinical success.

    

   Conclusion

   Peptide-drug conjugates are emerging as a complementary modality to antibody-drug conjugates, offering advantages such as better tumor penetration, lower immunogenicity, and easier synthesis. However, challenges remain, including rapid clearance, limited stability, and the need for finely tuned linkers and payloads. Future progress will depend on innovations in peptide design, linker chemistry, and payload diversity. Among these, smart linkers that combine stability in circulation with precise drug release are especially critical.

   At PrecisePEG, we specialize in advanced linker technologies, from PEG-based linkers that enhance stability to both non-cleavable and cleavable linkers optimized for both ADCs and PDCs.

   Explore our offerings at www.precisepeg.com or contact with us at sales@precisepeg.com for custom solutions.

    

   Reference

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   2.     Alas, M.; Saghaeidehkordi, A.; Kaur, K. Peptide–Drug Conjugates with Different Linkers for Cancer Therapy. J. Med. Chem. 2021, 64, 216–232. https://doi.org/10.1021/acs.jmedchem.0c01530.

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   4.     Rizvi, S. F. A.; Zhang, L.; Zhang, H.; Fang, Q. Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic. ACS Pharmacol. Transl. Sci. 2024, 7, 309–334. https://doi.org/10.1021/acsptsci.3c00269.

   5.     Wang, D.; Yin, F.; Li, Z.; Zhang, Y.; Shi, C. Current progress and remaining challenges of peptide–drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)? J. Nanobiotechnol. 2025, 23, 305. https://doi.org/10.1186/s12951-025-03277-2.