List references from the University of Geneva Physical Chemistry reference database

Previously, we have shown that the use of a cyclopeptidic carrier could be of great interest for the design of fully characterized prodrugs for further use in photodynamic therapy. In order to further optimize the design, we decided to modify the highly quenched conjugate uPA-cPPP_4/5 by co-loading a long-distance fluorescence quencher. For this purpose we tethered two black hole quenchers (BHQ3) together with two pheophorbide A moities onto the same PEGylated backbone and assessed the modified photophysical properties. In addition, to prove the reliability of our concept, we designed two analogues, uPA-cPPQ_2+2/5 and CathB-cPPQ_2+2/5, by using two different peptidic linkers as substrates for uPA and cathepsin B, respectively. These two conjugates proved to be much more water-soluble than their analogues bearing only Phas. These conjugates are not only highly quenched in their native state with regard to their fluorescence emission (up to 850 Â± 287 times less fluorescent for CathB-cPPQ_2+2/5 as compared to the unquenched monosubstituted reference uPA-cPPP_1/5), but also prevent singlet oxygen production (with a total quenching of the emission when the quenchers are co-loaded with photosensitizers) when the photosentistizers are excited. After proteolytic activation, these conjugates recover their photophysical properties in the same way as occurred for uPA-cPPP_4/5, with up to a 120-fold increase in fluorescence emission for uPA-cPPQ_2+2/5 after two hours of incubation with uPA.

Herein, we report the synthesis of a new prodrug system consisting of regioselectively addressable functionalized templates bearing multiple pheophorbide A moieties for use in photodynamic therapy. These coupling reactions were achieved using copper-free â€œclickâ€ chemistry, namely a strain-promoted azideâ€“alkyne cycloaddition. This new design was used to obtain well-defined quenched photosensitizer prodrugs with perfect knowledge of the number and position of loaded photosensitizers, providing structures bearing up to six photosentitizers and two PEG chains. These conjugates are ideally quenched in their native state regarding their fluorescence emission (up to 155 Â± 28 times less fluorescent for an hexasubstituted conjugate than a monosubstituted non-quenched reference compound) or singlet oxygen production (decreased 8.7-fold in the best case) when excited. After 2 h of proteolytic activation, the fluorescence emission of a tetrasubstituted conjugate was increased 17-fold compared with the initial fluorescence emission.

Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II co-loading of pheophorbide A and black hole quencher J. Bouilloux, O. Yuschenko, B. Dereka, G. Boso, A. Babic, H. Zbinden, E. Vauthey and N. Lange Photochemical & Photobiological Sciences, 17 (11) (2018), p1739-1748 DOI:10.1039/C8PP00318A \| Abstract \| Article HTML \| Article PDF
Previously, we have shown that the use of a cyclopeptidic carrier could be of great interest for the design of fully characterized prodrugs for further use in photodynamic therapy. In order to further optimize the design, we decided to modify the highly quenched conjugate uPA-cPPP_4/5 by co-loading a long-distance fluorescence quencher. For this purpose we tethered two black hole quenchers (BHQ3) together with two pheophorbide A moities onto the same PEGylated backbone and assessed the modified photophysical properties. In addition, to prove the reliability of our concept, we designed two analogues, uPA-cPPQ_2+2/5 and CathB-cPPQ_2+2/5, by using two different peptidic linkers as substrates for uPA and cathepsin B, respectively. These two conjugates proved to be much more water-soluble than their analogues bearing only Phas. These conjugates are not only highly quenched in their native state with regard to their fluorescence emission (up to 850 Â± 287 times less fluorescent for CathB-cPPQ_2+2/5 as compared to the unquenched monosubstituted reference uPA-cPPP_1/5), but also prevent singlet oxygen production (with a total quenching of the emission when the quenchers are co-loaded with photosensitizers) when the photosentistizers are excited. After proteolytic activation, these conjugates recover their photophysical properties in the same way as occurred for uPA-cPPP_4/5, with up to a 120-fold increase in fluorescence emission for uPA-cPPQ_2+2/5 after two hours of incubation with uPA.

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