Specific Targets in Tumor Tissue for the Delivery of Therapeutic Genes

Michael      Gunther; Ernst      Wagner; Manfred      Ogris

Abstract

Gene therapy is part of a growing field in molecular medicine, which will gain importance in the treatment of human diseases. Until now, almost two thirds of all clinical trials performed in gene therapy are directed against Cancer As solid tumors exceeding a certain size rely on blood supply, the administration of particulate gene delivery vectors via the bloodstream is a promising concept. Tumor cells and the tumor vasculature both offer specific molecular targets, which can be utilized for the site directed delivery of therapeutic genes. Passive targeting of macromolecular drugs including gene delivery vectors to tumors can be achieved by the so called enhanced permeability and retention (EPR) effect. The specificity can be markedly enhanced when tumor targeting ligands are used. Viral vectors, which usually do not have a natural tropism for tumor tissue, were generated to carry tumor targeting molecules on their surface. Synthetic gene delivery vectors, based on cationic lipids or cationic polymers were biochemically modified to incorporate ligands specific for tumor cells or tumor vasculature. For systemic application, these delivery systems have to fulfill certain conditions. The delivery vector should not induce any immunogenic and inflammatory responses. Several studies were conducted to reduce the immunogenicity of viral vectors; surface modification of non-viral gene delivery systems reduced their non-specific interaction with blood components. On the genetic level, tumor specific promoters add additional layers of specificity restricting the transgene expression to the tumor tissue. This review will cover the systemic application of particulate gene transfer vectors targeted to tumors and will give an overview of therapeutic concepts for cancer gene therapy.

Keywords: cancer, gene therapy, angiogenesis, receptor targeting, vascular targeting, transcriptional targeting

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