NGR-tagged nano-gold: A new CD13-selective carrier for cytokine delivery to tumors

Abstract

Colloidal gold (Au), a well-tolerated nanomaterial, is currently exploited for several applications in nanomedicine. We show that gold nanoparticles tagged with a novel tumor-homing peptide containing Asn-Gly-Arg (NGR), a ligand of CD13 expressed by the tumor neovasculature, can be exploited as carriers for cytokine delivery to tumors. Biochemical and functional studies showed that the NGR molecular scaffold/linker used for gold functionalization is critical for CD13 recognition. Using fibrosarcoma-bearing mice, NGR-tagged nanodrugs could deliver extremely low, yet pharmacologically active doses of tumor necrosis factor (TNF), an anticancer cytokine, to tumors with no evidence of toxicity. Mechanistic studies confirmed that CD13 targeting was a primary mechanism of drug delivery and excluded a major role of integrin targeting consequent to NGR deamidation, a degradation reaction that generates the isoAsp-Gly-Arg (isoDGR) integrin ligand. NGR-tagged gold nanoparticles can be used, in principle, as a novel platform for single-or multi-cytokine delivery to tumor endothelial cells for cancer therapy.

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

“…Recently, peptides containing the asparagine-glycine-arginine (Asn-Gly-Arg, NGR) motif [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] and their deamidation products containing the iso DGR motif [38,41,46,48,56,59,74,76,77,78,79,80,81...…”

Combination of nanotechnology with vascular targeting agents for effective cancer therapy

“…For example, NGR recognizes CD13 on tumor and tumor endothelial cells (Corti & Curnis, ). Interestingly, NGR deamidation provides an additional recognition moiety called Iso‐DGR, which targets several integrins including α v β 5 , α v β 6 , α v β 8 , and α 5 β 1 on tumor neovasculature (Curnis et al, ). NGR‐tagged gold NPs are successfully used for delivery of TNF‐α cytokine to tumor endothelial cells for cancer therapy (Curnis et al, ).…”

“…Interestingly, NGR deamidation provides an additional recognition moiety called Iso‐DGR, which targets several integrins including α v β 5 , α v β 6 , α v β 8 , and α 5 β 1 on tumor neovasculature (Curnis et al, ). NGR‐tagged gold NPs are successfully used for delivery of TNF‐α cytokine to tumor endothelial cells for cancer therapy (Curnis et al, ). Similarly, employing NPs decorated with RGD that contain anti‐angiogenic cytotoxic agents offers a safe route for the delivery of these agents to the tumor site and lessens systemic toxicity (Banerjee, Harfouche et al, ).…”

Boosting Interleukin‐12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR‐Tagged Nanogold

“…In particular, we have identified a head‐to‐tail‐cyclized hexapeptide, CGisoDGRG (called Iso1), which recognizes αvβ3 with high selectivity and affinity, binds tumor vessels, and works as an efficient ligand for delivering fluorescent nanoparticles or radioactive compounds to tumors . The Iso1 peptide, after chemical conjugation to human serum albumin, has been exploited for tagging gold nanoparticles loaded with tumor necrosis factor‐alpha (TNF), a cytokine endowed with antitumor activity . Interestingly, nontoxic doses of this nanodrug can induce anticancer effects in tumor‐bearing mice, by virtue of an active targeting mechanism …”

“…The Iso1 peptide, after chemical conjugation to human serum albumin, has been exploited for tagging gold nanoparticles loaded with tumor necrosis factor‐alpha (TNF), a cytokine endowed with antitumor activity . Interestingly, nontoxic doses of this nanodrug can induce anticancer effects in tumor‐bearing mice, by virtue of an active targeting mechanism …”