Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems

Abstract

Various peptide sequences have been discovered by selecting peptide-phage display libraries in vitro against specific receptors or in vivo in tumor-bearing animals. One class of these peptides is characterized by the presence of Asn-Gly-Asp (NGR), a structural motif that can recognize the endothelium and other cells of neoangiogenic vessels. Because of this property these peptides have been used by several investigators to deliver a variety of drugs, cytokines, nanoparticles, viruses and imaging agents to tumor blood vessels. Here we review the reports on these conjugates and discuss the structural, functional and stability properties of NGR embedded into different molecular scaffolds.

Passive versus Active Tumor Targeting Using RGD- and NGR-Modified Polymeric Nanomedicines

“…RGD-and NGR-containing oligopeptides bind to integrin (α v β 3 ) and aminopeptidase N (CD13) receptors, and are routinely used ligands for active targeting to tumor blood vessels [42,43]. As depicted schematically in Figure 1, we prepared prototypic ~10 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide) (i.e.…”

Development of Cyclic NGR Peptides with Thioether Linkage: Structure and Dynamics Determining Deamidation and Bioactivity

“…7 Cyclic and/or linear peptides containing either the c [CNGRC] or the GNGRG motives were described as appropriate target ligands in delivery of tumor necrosis factor alpha (TNF-α), 5,21,22 interferon gamma (IFNγ), [23][24][25] liposomal doxorubicin 26,27 and Pt-complex 28,29 as well as radio metal isotope labeled derivatives for PET and SPECT. 30,31 By comparing c [CNGRC] and GNGRG, a cyclic and a linear peptide, not only the higher CD13 binding affinity of cyclic variant was detected but also its increased stability in PBS solution (half-lives were [6][7][8] h and 3-4 h, respectively at pH 7.3, 37°C) and in serum (5 h and 3 h, respectively) was measured. 13 However, chemo-stability of NGR-peptides under relevant biological conditions is not studied.…”

Single-component self-assembled RNAi nanoparticles functionalized with tumor-targeting iNGR delivering abundant siRNA for efficient glioma therapy

“…The NGR motif in the sequence of iNGR has been reported to specifically home to CD13 receptors (Scheme 2), which are overexpressed in glioma [23,41]. To investigate the glioma-homing ability of iNGR, expressions of CD13 in both glioma and normal brain tissues were verified by the immunofluorescent brain slices (Fig.…”

“…After binding to CD13, iNGR has been reported to go through a proteolysis process and generate the corresponding enzymolyzed iNGR (iNGRt), which has been proved to specifically bind to the NRP-1 receptors, rendering a following efficient gliomapenetration (Scheme 2) [23,41]. To deeply investigate the gliomatargeting ability of iNGR, and verify the tumor-penetrating ability of iNGRt, expression of NRP-1 in glioma were detected.…”

“…The annular iNGR in blood specifically and rapidly bound to CD13, guaranteeing the potent tumor-vessel-targeting capacity [23]. Afterwards, proteolytic process took place on the surface of tumor vessels, exposing the internal R/KXXR/K motif at the C-terminus of this truncated peptide [24].…”