Tumor targeting with an isoDGR-Drug conjugate

Herein we report the first example of an isoDGR–drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin alphaVbeta3. 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 alphaVbeta3 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 alphaVbeta3 expression: human glioblastoma U87 (alphaVbeta 3+) and U87 beta3-KO (alphaVbeta3-). 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).