2. Academic Validation
  3. Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation

Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation

  • Angew Chem Int Ed Engl. 2016 Aug 16;55(34):9894-7. doi: 10.1002/anie.201603488.
Nick Cox 1,  James R Kintzing 2,  Mark Smith 1,  Gerald A Grant 3,  Jennifer R Cochran 4
Affiliations

Affiliations

  • 1 Stanford ChEM-H Medicinal Chemistry Knowledge Center, Stanford University, Stanford, CA, 94305, USA.
  • 2 Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
  • 3 Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.
  • 4 Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. [email protected].
PMID: 27304709 DOI: 10.1002/anie.201603488
Abstract

Antibody-drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide-drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide-drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic Cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine-resistance mechanism found in pancreatic Cancer cells. This work expands the therapeutic relevance of knottin Peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.

Keywords

antitumor agents; drug delivery; integrins; knottins; peptides.

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