Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation.
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.
Stanford ChEM-H Medicinal Chemistry Knowledge Center, Stanford University, Stanford, CA, 94305, USA.
Nick
0000-0002-0374-2902
N
Cox
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
James R
JR
Kintzing
Stanford ChEM-H Medicinal Chemistry Knowledge Center, Stanford University, Stanford, CA, 94305, USA.
Mark
M
Smith
Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.
Gerald A
GA
Grant
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. jennifer.cochran@stanford.edu.
Jennifer R
0000-0002-6532-9873
JR
Cochran
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057771:Cystine-Knot Miniproteins / Q000737:chemistry / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D057771:Cystine-Knot Miniproteins; D016023:Integrins; D003841:Deoxycytidine; D000093542:Gemcitabine
antitumor agents; drug delivery; integrins; knottins; peptides