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NGR-DAU Conjugates, a Favorable Tumor-Homing Motif with Potential Dual-Targeting

At present, cancer is one of the major health-related issues world-wide. Strategies to target and defeat tumor are limited due to the access to tumor, side effects and absence of selectivity to the tumor tissue. Small molecule drug conjugates containing the Asn-Gly-Arg (NGR) motif can act as tumor-homing compounds that are recognized by Aminopeptidase N (APN/CD13). CD13 is receiving an accurate attention due to its role in the progression of tumor vasculo-genesis and identifying it as a critical regulator of angiogenesis, generally expressed on the monolayer cell surface of malignant cells [1,2]. As established in the literature the AsnGly-Arg sequence is inclined to Asn deamidation bearing the formation of a five-membered succinimide ring intermediate, that under fast hydrolytic conditions generates isoDGR derivative which can bind to integrins [3-6]. According to literature data, one of the most stable and tumor selective cyclic NGR-peptides is c[KNGRE]-NH2, in which the α-amino group of the N-terminal Lys is coupled to the γ-carboxyl group of the glutamic acid residue (head-to-side chain cycle) [7]. The preparation of a c[KNGRE] conjugate require a sophisticated synthetic route, for this reason the main goal of the present study was to investigate whether the exchange of the lysine in the cycle has any influence on the chemo-stability, selectivity and antitumor activity of the conjugates.