Glycine N‐Methylation in NGR‐Tagged Nanocarriers Prevents Isoaspartate Formation and Integrin Binding without Impairing CD13 Recognition and Tumor Homing

NGR (asparagine–glycine–arginine) is a tumor vasculature‐homing peptide motif widely used for the functionalization of drugs, nanomaterials, and imaging compounds for cancer treatment and diagnosis. Unfortunately, this motif has a strong propensity to undergo rapid deamidation. This reaction, which converts NGR into isoDGR, is associated with receptor switching from CD13 to integrins, with potentially important manufacturing and pharmacological and toxicological implications. It is found that glycine N‐methylation of NGR‐tagged nanocarriers completely prevents asparagine deamidation without impairing CD13 recognition. Studies in animal models have shown that the methylated NGR motif can be exploited for delivering radiolabeled compounds and nanocarriers, such as tumor necrosis factor‐α‐bearing nanogold and liposomal doxorubicin, to tumors with improved selectivity. These findings suggest that this NGR derivative is a stable and efficient tumor‐homing ligand that can be used for delivering functional nanomaterials to tumor vasculature. The asparagine of NGR (asparagine–glycine–arginine), a peptide motif used for delivering nanodrugs to CD13+ tumor vessels, can rapidly deamidate. This reaction converts NGR into isoDGR, an integrin‐binding motif, with important pharmacological and toxicological implications. It is shown that glycine N‐methylation in an NGR‐exapeptide prevents deamidation without impairing CD13 recognition and that this peptide can be used for delivering functional nanomaterials to tumors.