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. Epub 2016 Jun 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cystine-Knot Miniproteins / chemistry
  • Cystine-Knot Miniproteins / metabolism*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Gemcitabine
  • Humans
  • Integrins / antagonists & inhibitors*
  • Molecular Conformation
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Cystine-Knot Miniproteins
  • Integrins
  • Deoxycytidine
  • Gemcitabine