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

13 Citations (Scopus)

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

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Integrins
Ligands
Peptides
Neoplasms
Cyclic Peptides
Glioblastoma
Streptavidin
Optical Imaging
Heterografts
Libraries
Lung Neoplasms
Flow Cytometry
Breast Neoplasms
Neoplasm Metastasis
Cell Line
In Vitro Techniques

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

Cite this

Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of α3 integrin-expressing human tumors. / Xiao, Wenwu; Li, Tianhong; Bononi, Fernanda C.; Lac, Diana; Kekessie, Ivy A.; Liu, Yanlei; Sanchez, Eduardo; Mazloom, Anisha; Ma, Ai hong; Lin, Jia; Tran, Jimmy; Xiang, Yang Kevin; Lam, Kit; Liu, Ruiwu.

In: EJNMMI Research, Vol. 6, No. 1, 18, 01.12.2016, p. 1-12.

Research output: Contribution to journalArticle

Xiao, Wenwu ; Li, Tianhong ; Bononi, Fernanda C. ; Lac, Diana ; Kekessie, Ivy A. ; Liu, Yanlei ; Sanchez, Eduardo ; Mazloom, Anisha ; Ma, Ai hong ; Lin, Jia ; Tran, Jimmy ; Xiang, Yang Kevin ; Lam, Kit ; Liu, Ruiwu. / Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of α3 integrin-expressing human tumors. In: EJNMMI Research. 2016 ; Vol. 6, No. 1. pp. 1-12.
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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.",
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AU - Xiao, Wenwu

AU - Li, Tianhong

AU - Bononi, Fernanda C.

AU - Lac, Diana

AU - Kekessie, Ivy A.

AU - Liu, Yanlei

AU - Sanchez, Eduardo

AU - Mazloom, Anisha

AU - Ma, Ai hong

AU - Lin, Jia

AU - Tran, Jimmy

AU - Xiang, Yang Kevin

AU - Lam, Kit

AU - Liu, Ruiwu

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N2 - 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.

AB - 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.

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