Abstract 5617: A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin.

Abstract

Abstract Albumin is emerging as a versatile drug carrier in a number of applications in cancer therapy and diagnosis. Basically, albumin can be exploited to enhance the tumor uptake of peptides and low molecular-weight compounds, owing its tendency to accumulate in tumors, and for the preparation of nanoparticles that encapsulate anti-cancer drugs or diagnostic agents. We have addressed the hypothesis that coupling albumin with a peptide containing the isoAsp-Gly-Arg (isoDGR) sequence, a tumor-vasculature targeting motif discovered by our group, might enhance its tumor-homing properties. IsoDGR is a mimetic of Arg-Gly-Asp (RGD), an integrin-recognition motif. Accordingly, isoDGR can recognize RGD-dependent integrins with different affinity and selectivity depending on isoDGR conformation and molecular scaffold. To have at hand isoDGR peptides that can be easily coupled to albumin we designed various head-to-tail-cyclized exapeptides containing free thiol groups, to enable chemical coupling to proteins, and analyzed their integrin binding properties before and after coupling to albumin. We have identified a peptide (c(CGisoDGRG)) that, after coupling to human serum albumin, has a very good selectivity for alphaV/beta3 and alphaV/beta5, two integrins overexpressed in the tumor vasculature. In vitro and in vivo studies showed that isoDGR-tagged albumin binds to endothelial cells, inhibits their adhesion properties, homes in on tumor vessels and inhibits tumor growth, with no evidence of toxicity. IsoDGR-tagged albumin was exploited as a carrier for the preparation of a new nano-gold systems capable of delivering tumor necrosis factor α (TNF), a well known vascular damaging agent, to tumor vessels. In vivo studies, performed with mice bearing WEHI-fibrosarcomas, showed that intravenous administration of gold nanoparticles loaded with isoDGR-tagged albumin and TNF (equivalent 5 pg of bioactive TNF/mouse) could induce stronger anti-tumor effects than nanoparticles loaded with albumin and TNF. These findings support the concept that isoDGR-tagged albumin is superior to albumin as a vector system for targeted delivery of nanomedicines to tumor vessels. Because of its good selectivity for tumor vessels and its inherent anticancer activity isoDGR-tagged albumin might be exploited as a novel and versatile material for the preparation of a wide range of tumor vasculature-selective drugs and nanoparticles for cancer therapy and diagnosis. Citation Format: Flavio Curnis, Angelina Sacchi, Renato Longhi, Barbara Colombo, Anna Gasparri, Angelo Corti. A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5617. doi:10.1158/1538-7445.AM2013-5617