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  • Review Article
  • Published:

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Key Points

  • Ligand targeting allows selective delivery of therapeutic and imaging agents to cancer cells while avoiding collateral damage to healthy tissues.

  • Small-molecule–ligand conjugates more readily penetrate dense solid tumours than do high-molecular-weight conjugates.

  • Following the delivery of cytotoxic drug conjugates to their target cells, cleavage of the ligand from its therapeutic cargo and release from endosomes into the cytoplasm are necessary for optimal killing of the targeted cell.

  • Typically, cytotoxic agents with nanomolar potencies are required in an effective ligand-targeted strategy, as receptor-mediated delivery may limit the maximum intracellular concentration of drug to 100 nM or less.

Abstract

Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand–drug conjugates and ligand–imaging-agent conjugates that are currently in development.

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Figure 1: Schematic of a typical ligand–drug conjugate.
Figure 2: Ligand–drug conjugate entry into the cell.
Figure 3: The effect of epithelial-cell transformation on the accessibility of apical receptors.
Figure 4: Common strategies for intracellular drug release using self-cleaving linkers.
Figure 5: Structures of ligand-targeted therapeutic agents that are currently undergoing clinical trials.
Figure 6: Structures of ligand-targeted imaging agents that are currently undergoing clinical trials.
Figure 7: Additional structures of ligand-targeted imaging agents that are currently undergoing clinical trials.

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Correspondence to Philip S. Low.

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P.S.L. owns shares in Endocyte, which develops small-molecule drug conjugates using the folate-targeting technology discussed in the article. M.S. and C.V.G. declare no competing interests.

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Glossary

Ligand–drug conjugates

Receptor-targeted drugs that are conjugated, typically via chemical linkers, to non-peptide, low-molecular-weight targeting ligands.

Internalization

Receptor-mediated endocytosis of the conjugate inside the cell.

Receptor overexpression

The high expression level of a receptor in one tissue relative to other tissues (for example, in tumours versus healthy cells).

Receptor recycling rate

The rate at which a surface receptor internalizes and then returns to the cell surface.

Self-cleaving linkers

Tethers between targeting ligands and the imaging or therapeutic cargo that cleave upon (but not before) internalization of the conjugate inside tumour cells.

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Srinivasarao, M., Galliford, C. & Low, P. Principles in the design of ligand-targeted cancer therapeutics and imaging agents. Nat Rev Drug Discov 14, 203–219 (2015). https://doi.org/10.1038/nrd4519

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