Tumor targeting integrin ligands: from computational design to biomedical applications

The integrin family of adhesion molecules regulates diverse cell functions crucial to the initiation, progression and metastasis of tumors. aVb3, aVb5 and a5b1 integrins appear to be particularly important in angiogenesis and cancer, where preclinical studies have provided rationale for the development of small-molecule integrin antagonists related to the common recognition motif Arg-Gly-Asp, as both anti-tumor and anti-angiogenic agents [1]. In addition to their appeal as targets for cancer therapy, integrins have recently proved valuable targets for tumor directed delivery of diagnostics and/or therapeutics. Integrin-targeted molecular systems containing imaging biomarkers or anticancer drugs have great potential to improve the efficacy of diagnostic tools and decrease the toxic side effects of conventional chemotherapy [1]. In this context, we have recently developed an interdisciplinary approach, based on the interplay between synthetic organic, computational, structural chemistry and biology, to target integrins involved in tumor angiogenesis and overexpressed in tumor cells. We have investigated the synthesis and the biological properties of a new class of cyclic peptidomimetics containing a bifunctional diketopiperazine (DKP) scaffold and the tripeptide sequence Arg-Gly-Asp (RGD) [2] or isoAsp-Gly-Arg (isoDGR) [3] as potent integrin ligands. The conformation of the cyclic peptidomimetics and their interactions with integrin receptors were studied by computational techniques and NMR experiments with intact cancer cells. The different stereochemistry and the different substitution of the scaffold, as well as the RGD or RGD-like recognition sequence, strongly influence the conformations adopted in the free-state and the binding mode of these ligands in the active site of aVb3 and a5b1 integrins [4]. A small library of integrin ligand – Paclitaxel conjugates was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. These Paclitaxel-RGD constructs showed in vitro cytotoxic activity similar to that of Paclitaxel, and a superior in vivo activity despite the lower (ca. half) molar dosage used [5].