Format

Send to

Choose Destination
Angew Chem Int Ed Engl. 2016 Aug 16;55(34):9894-7. doi: 10.1002/anie.201603488. Epub 2016 Jun 15.

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

Author information

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. jennifer.cochran@stanford.edu.

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

PMID:
27304709
PMCID:
PMC6231717
DOI:
10.1002/anie.201603488
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center