3 years ago

Tumor Targeting with an isoDGR–Drug Conjugate

Tumor Targeting with an isoDGR–Drug Conjugate
Simone Zanella, Michele Caruso, Silvia Panzeri, Simona Angerani, Clara Albanese, Umberto Piarulli, Paula López Rivas, Daniela Arosio, Ivan Fraietta, Clelia Giannini, Arianna Pina, Luca Pignataro, Aurelio Marsiglio, Laura Belvisi, Fabio Gasparri, Cesare Gennari
Herein 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). Hitting bullseye: The skillful marksman (isoDGR–drug conjugate) targets cancer cells expressing integrin αVβ3, and releases the warhead (paclitaxel) selectively into them.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701844

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