Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging.
Small peptide-based agents have attracted wide interest as cancer-targeting agents for diagnostic imaging and targeted therapy. There is a need to develop new high-affinity and high-specificity peptidomimetic or small-molecule ligands against cancer cell surface receptors. Here we report on the identification of a high-affinity peptidomimetic ligand (LLP2A; IC50 = 2 pM) against alpha4beta1 integrin using both diverse and highly focused one-bead-one-compound combinatorial peptidomimetic libraries in conjunction with high-stringency screening. We further demonstrate that LLP2A can be used to image alpha4beta1-expressing lymphomas with high sensitivity and specificity when conjugated to a near infrared fluorescent dye in a mouse xenograft model. Thus, LLP2A provides an important tool for noninvasive monitoring of alpha4beta1 expression and activity during tumor progression, and it shows great potential as an imaging and therapeutic agent for alpha4beta1-positive tumors.
Peng
Li
L
Division of Hematology & Oncology, Department of Internal Medicine, UC Davis Cancer Center, University of California, Davis, 4501 X Street, Sacramento, California 95817, USA.
Liu
Ruiwu
R
Marik
Jan
J
Wang
Xiaobing
X
Takada
Yoshikazu
Y
Lam
Kit S
KS
D000818:Animals; D001710:Biotin; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D004151:Dipeptides / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry
D004151:Dipeptides; D039041:Integrin alpha4beta1; C512274:LLP2A compound; D008024:Ligands; D010455:Peptides; D010671:Phenylurea Compounds; D001710:Biotin