Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of α3 integrin-expressing human tumors

Wenwu Xiao, Tianhong Li, Fernanda C. Bononi, Diana Lac, Ivy A. Kekessie, Yanlei Liu, Eduardo Sanchez, Anisha Mazloom, Ai hong Ma, Jia Lin, Jimmy Tran, Yang Kevin Xiang, Kit Lam, Ruiwu Liu

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background: α3β1 integrin is overexpressed in several types of human cancer and is associated with poor prognosis, metastasis, and resistance to cancer treatment. We previously identified a cyclic peptide ligand LXY1 that specifically binds to the α3β1 integrin on human glioblastoma U-87MG cells. Here, we optimized LXY1 through one-bead one-compound combinatorial library screening and site-specific modifications to improve its in vivo binding property. Methods: Three bead libraries were synthesized and whole-cell binding assays were performed. The binding capacity of individual peptide ligands against different tumor cells was determined by flow cytometry and confirmed by optical imaging. A complex joining biotinylated ligand with streptavidin-Cy5.5 was used for in vivo target imaging in both subcutaneous and orthotopic U-87MG xenograft mouse models. Results: LXY30, a cyclic peptide with the sequence cdG-Phe(3,5-diF)-G-Hyp-NcR, emerged as the most potent and selective ligand for the α3 subunit of α3β1 integrin with improved in vitro and in vivo tumor-targeting effects compared to LXY1 in U-87MG cells. LXY30 is considerably stable in plasma as demonstrated in an in vitro stability study in 90 % human plasma. LXY30 also binds to several other known α3β1 integrin-expressing glioblastoma, lung, and breast cancer cell lines with various affinities. Conclusions: Our data support further investigating the role of LXY30 as a human tumor-targeting peptide ligand for systemic and intracranial delivery of imaging agents and cancer therapeutics.

Original languageEnglish (US)
Article number18
Pages (from-to)1-12
Number of pages12
JournalEJNMMI Research
Volume6
Issue number1
DOIs
StatePublished - Dec 1 2016

Keywords

  • Cancer-targeting peptide
  • Glioblastoma
  • One-bead one-compound combinatorial peptide library
  • Optical imaging
  • α3β1 integrin

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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