In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors

Michele De Palma, Mary Anna Venneri, Luigi Naldini

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Tumor angiogenesis is a rate-limiting factor for tumor growth, and the endothelial cells of tumor vessels display specific features that can be exploited for the selective delivery of cancer therapeutics. To specifically target exogenous genes to angiogenic tumor vessels, we generated a panel of vesicular stomatitis virus-pseudotyped lentiviral vectors (LVs) engineered for endothelial cell (EC)-specific expression. We cloned a wide repertoire of transcription regulatory sequences from genes preferentially expressed in ECs (Tie1, Tie2, Flk-1, VE-Cad, and ICAM-2) into self-inactivating LVs to drive expression of the marker gene encoding green fluorescent protein (GFP) or of the conditionally toxic gene encoding nitroreductase, and compared them with the ubiquitously expressing phosphoglycerate kinase (PGK) and cytomegalovirus (CMV) promoters. We evaluated the efficiency and specificity of vector expression in vitro in a panel of human primary cultures, including ECs, fibroblasts, neurons, lymphocytes, and hematopoietic progenitors, and in tumor cell lines. We found that vectors containing promoter and enhancer sequences from the Tie2 gene achieved remarkable specificity of expression in ECs in vitro and in vivo. On intravenous delivery into tumor-bearing mice, the Tie2 vector targeted expression to the ECs of tumor vessels. In contrast, LVs carrying the PGK or CMV promoter gave widespread GFP marking in ECs and non-ECs of tumors and other organs. The previously reported upregulation of the Tie2 gene in ECs activated for angiogenesis may explain the remarkable selectivity of expression of the Tie2 vector in ECs of tumor vessels. The new vector provides the means for selective delivery of gene therapy to tumor sites in vivo.

Original languageEnglish
Pages (from-to)1193-1206
Number of pages14
JournalHuman Gene Therapy
Volume14
Issue number12
DOIs
Publication statusPublished - Aug 10 2003

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Endothelial Cells
Neoplasms
Phosphoglycerate Kinase
Green Fluorescent Proteins
Cytomegalovirus
Genes
Nitroreductases
Vesicular Stomatitis
Poisons
Regulator Genes
Tumor Cell Line
Genetic Therapy
Intercellular Signaling Peptides and Proteins
Up-Regulation
Fibroblasts
Lymphocytes
Viruses
Gene Expression
Neurons

ASJC Scopus subject areas

  • Genetics

Cite this

In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors. / De Palma, Michele; Venneri, Mary Anna; Naldini, Luigi.

In: Human Gene Therapy, Vol. 14, No. 12, 10.08.2003, p. 1193-1206.

Research output: Contribution to journalArticle

De Palma, Michele ; Venneri, Mary Anna ; Naldini, Luigi. / In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors. In: Human Gene Therapy. 2003 ; Vol. 14, No. 12. pp. 1193-1206.
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