Tumor Targeting with an isoDGR-Drug Conjugate

Here we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin αVβ3. Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin αVβ3 receptor (IC50 = 11.0 nM). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin αVβ3 expression: human glioblastoma U87 (αVβ3 +) and U87 β3-KO (αVβ3 -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI = 9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI = 2.4).