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

• Published in: Angewandte Chemie International Edition Vol. 55; no. 34; pp. 9894 - 9897
• Main Authors: Cox, Nick, Kintzing, James R., Smith, Mark, Grant, Gerald A., Cochran, Jennifer R.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 16.08.2016; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: antitumor agents; Chemistry; Chemistry, Multidisciplinary; drug delivery; integrins; knottins; Pancreatic cancer; Peptides; Pharmaceutical industry; Physical Sciences; Science & Technology; Tumors; CANCER-CHEMOTHERAPY; peptides; drug delivery; knottins; ANTITUMOR-ACTIVITY; GEMCITABINE; antitumor agents; CYSTINE-KNOT; NUCLEOSIDE TRANSPORTERS; LIVING SUBJECTS; integrins; ALPHA(V)BETA; THERAPEUTIC TARGETS; ANTICANCER DRUGS; EXPRESSION
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201603488

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. Tied up in knottins: Tumor‐targeted knottin peptide‐drug conjugates (KDC) are significantly smaller than antibody–drug conjugates, allowing for facile synthesis and conjugation. A KDC bearing the nucleoside gemcitabine is internalized by an integrin‐mediated mechanism, releases its payload intracellularly, and is shown to be a highly potent inhibitor of several malignant cell lines.