Targeted Therapeutics for Tumor Vascular Modulation

Tumor vascular modulation encompasses strategies to reshape or disrupt the abnormal blood vessels that supply solid tumours. Unlike normal vasculature, tumour vessels are tortuous, leaky and poorly organised, leading to hypoxia, high interstitial pressure and impaired drug delivery. Targeted therapeutics aim either to normalise the vasculature—improving perfusion and enhancing the efficacy of chemotherapeutics and immunotherapies—or to induce selective occlusion of tumour vessels, triggering thrombosis and infarction. Key approaches include peptide-based homing ligands that recognise markers such as aminopeptidase N (APN/CD13) or integrins, conjugated to cytotoxic drugs, radiotherapeutic isotopes or coagulation-inducing proteins. Advances in multivalent and heterodimeric ligands have enhanced specificity and retention at the tumour endothelium, while pH-sensitive and nanoparticle formulations offer controlled release. Together, these innovations hold promise for more effective, less toxic cancer treatments by exploiting the unique biochemical and biophysical features of tumour blood vessels.

Research from Nature Portfolio

A fusion protein comprising truncated staphylocoagulase linked to an Arg-Gly-Asp (RGD) motif has been engineered to target αvβ3 integrins on tumour endothelium and activate local coagulation. In preclinical models of colon, breast and ovarian cancer, systemic administration of this bi-functional protein induced extensive and selective thrombosis within tumour vessels, leading to infarction, massive necrosis and significant tumour growth inhibition. The strategy demonstrated a wide therapeutic window and minimal off-target toxicity, highlighting targeted vascular occlusion as a viable anticancer modality.

Targeted Therapeutics for Tumor Vascular Modulation publication trend

The graph below shows the total number of articles in targeted therapeutics for tumor vascular modulation across all publications each year (not limited to Nature Index journals).

Technical terms

Angiogenesis: The physiological process of new blood vessel formation from pre-existing vessels, often co-opted by tumours to sustain growth.

Aminopeptidase N (APN/CD13): A membrane-bound enzyme overexpressed on angiogenic endothelial cells and some tumour cells, serving as a homing target for NGR-containing ligands.

NGR motif: A tripeptide sequence (asparagine-glycine-arginine) that selectively binds APN/CD13, used to deliver therapeutic and imaging agents to tumour vasculature.

Thrombosis: The formation of a blood clot within a blood vessel, here induced selectively in tumour vessels to occlude perfusion and trigger infarction.

Heterodimeric ligand: A synthetic molecule combining two different receptor-targeting sequences to engage multiple endothelial markers simultaneously, improving specificity and retention.

Vascular modulation: Therapeutic alteration of the structure or function of tumour blood vessels, encompassing both normalisation and targeted disruption strategies.

References

1. Therapeutic Performance Evaluation of 213Bi-Labelled Aminopeptidase N (APN/CD13)-Affine NGR-Motif ([213Bi]Bi-DOTAGA-cKNGRE) in Experimental Tumour Model: A Treasured Tailor for Oncology. Pharmaceutics (2023).
2. RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice. Scientific Reports (2017).
3. Radiolabeled NGR-Based Heterodimers for Angiogenesis Imaging: A Review of Preclinical Studies. Cancers (2023).
4. Effect of an NGR Peptide on the Efficacy of the Doxorubicin Phospholipid Delivery System. Nanomaterials (2023).