High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer

Wenwu Xiao, Weijie Ma, Sixi Wei, Qianping Li, Ruiwu Liu, Randy Carney, Yang Kevin Xiang, Joyce S Lee, Alan Nyugen, Ken Y Yoneda, Kit Lam, Tianhong Li

Research output: Contribution to journalArticle

Abstract

Background: α3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models. Methods: The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology. Results: We showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues. Conclusion: LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.

Original languageEnglish (US)
Article number56
JournalJournal of Hematology and Oncology
Volume12
Issue number1
DOIs
StatePublished - Jun 10 2019

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Integrins
Non-Small Cell Lung Carcinoma
Ligands
Peptides
Epidermal Growth Factor Receptor
Exosomes
Neoplasms
Heterografts
Squamous Cell Carcinoma
Western Blotting
Malignant Pleural Effusion
Cyclic Peptides
Lung
Atlases
Optical Imaging
Tumor Biomarkers
Transmission Electron Microscopy
Pharmaceutical Preparations
Monocytes
Blood Cells

Keywords

  • Cancer-targeting peptide
  • Exosomes
  • In vivo imaging
  • Non-small cell lung cancer
  • Patient-derived xenograft
  • α3β1 integrin

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer. / Xiao, Wenwu; Ma, Weijie; Wei, Sixi; Li, Qianping; Liu, Ruiwu; Carney, Randy; Xiang, Yang Kevin; Lee, Joyce S; Nyugen, Alan; Yoneda, Ken Y; Lam, Kit; Li, Tianhong.

In: Journal of Hematology and Oncology, Vol. 12, No. 1, 56, 10.06.2019.

Research output: Contribution to journalArticle

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AU - Xiao, Wenwu

AU - Ma, Weijie

AU - Wei, Sixi

AU - Li, Qianping

AU - Liu, Ruiwu

AU - Carney, Randy

AU - Xiang, Yang Kevin

AU - Lee, Joyce S

AU - Nyugen, Alan

AU - Yoneda, Ken Y

AU - Lam, Kit

AU - Li, Tianhong

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AB - Background: α3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models. Methods: The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology. Results: We showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues. Conclusion: LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.

KW - Cancer-targeting peptide

KW - Exosomes

KW - In vivo imaging

KW - Non-small cell lung cancer

KW - Patient-derived xenograft

KW - α3β1 integrin

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