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).
Tumor targeting with an isoDGR-Drug conjugate / S. Zanella, S. Angerani, A. Pina, P. Lopez Rivas, C. Giannini, S. Panzeri, D. Arosio, M. Caruso, F. Gasparri, I. Fraietta, C. Albanese, A. Marsiglio, L.L. Pignataro, L. Belvisi, U. Piarulli, C.M.A. Gennari. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 23:33(2017 Jun), pp. 7910-7914.
Tumor targeting with an isoDGR-Drug conjugate
S. Zanella;A. Pina;P. Lopez Rivas;C. Giannini;L.L. Pignataro;L. Belvisi;C.M.A. Gennari
2017
Abstract
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).File | Dimensione | Formato | |
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