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Published online: 7 June 2013
© The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.
1 Introduction
The efficacy of cytokines in cancer therapy is often limited by systemic toxicity and counter-regulatory mechanisms. Recent studies suggest that these limitations can be overcome by targeting strategies based on the conjugation of these proteins with ligands capable of delivering them to the tumor site, thereby allowing administration of lower doses and reducing systemic effects [1, 2]. Among the various approaches that have been developed, cytokine conjugation or fusion with antibodies or peptide ligands capable of recognizing specific receptors in tumor tissues are the most advanced. These ligands typically recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature [1]. A comprehensive database of most tumor-homing peptides so far developed and their receptors has been recently reported [3]. Remarkably, a large proportion of these peptides have some common motifs, such as NGR and RGD...