Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II – co-loading of pheophorbide A and black hole quencher†,Photochemical & Photobiological Sciences

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Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II – co-loading of pheophorbide A and black hole quencher†
Photochemical & Photobiological Sciences ( IF 2.7 ) Pub Date : 2018-08-30 00:00:00 , DOI: 10.1039/c8pp00318a
Jordan Bouilloux _{1,

2,

3,

4,

5} , Oleksandr Yuschenko _{3,

5,

6,

7,

8} , Bogdan Dereka _{3,

5,

6,

7,

8} , Gianluca Boso _{3,

5,

9,

10} , Andréj Babič _{1,

2,

3,

4,

5} , Hugo Zbinden _{3,

5,

9,

10} , Eric Vauthey _{3,

5,

6,

7,

8} , Norbert Lange _{1,

2,

3,

4,

5}

Affiliation

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 ± 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.

中文翻译：

环肽光敏剂前药作为脱镁脱镁叶绿酸A的蛋白水解触发药物递送系统：第二部分–脱镁脱镁叶绿酸A和黑洞淬灭剂的共同装载†

以前，我们已经表明，对于设计进一步用于光动力疗法的完全表征的前药，使用环肽载体可能会引起极大的兴趣。为了进一步优化设计，我们决定通过共同装载长距离荧光猝灭剂来修饰高度猝灭的偶联物uPA-cPPP _4/5。为此，我们将两个黑洞淬灭剂（BHQ3）和两个脱镁叶绿酸A分子束缚在同一PEG化骨架上，并评估了修饰的光物理性质。此外，为了证明我们概念的可靠性，我们设计了两个类似物uPA-cPPQ _{2 +} 2/5和CathB-cPPQ _{2 +} 2/5，分别使用两个不同的肽类接头作为uPA和组织蛋白酶B的底物。事实证明，这两种结合物比仅带有Phas的类似物具有更高的水溶性。这些缀合物不仅在其天然状态方面就其荧光发射进行了高度淬灭（与未淬灭的单取代参比uPA-cPPP _1/5相比，CathB-cPPQ _{2 +} 2/5的荧光强度最多低850±287倍），而且还可以防止在激发光敏化剂时产生单重态氧（当猝灭剂与光敏剂共同负载时，会完全释放出发射光）。蛋白水解激活后，这些缀合物以与uPA-cPPP _4/5相同的方式恢复其光物理性质与uPA孵育两个小时后，uPA-cPPQ _{2 +} 2/5的荧光发射增加了120倍。

更新日期：2018-08-30

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