Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers.
Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers.
复制标题
DOI：
10.1021/jacs.8b08853
复制
发表时间：
2018-10-31
影响因子：
15
通讯作者：
Kodanko JJ
中科院分区：
文献类型：
--
作者：
Arora K;Herroon M;Al-Afyouni MH;Toupin NP;Rohrabaugh TN Jr;Loftus LM;Podgorski I;Turro C;Kodanko JJ
设计、合成了含有半胱氨酸蛋白酶抑制剂和钌基光敏剂的用于光动力疗法（PDT）的双重作用剂，并在三阴性人乳腺癌（TNBC）的2D培养和3D功能成像测定中进行了验证。这些组合药剂将Ru基PDT药剂递送并释放至肿瘤细胞，并且在用可见光照射时引起癌细胞死亡，同时使组织蛋白酶抑制剂B（CTSB）失活，所述组织蛋白酶抑制剂B是一种与侵袭性和转移性行为强烈相关的半胱氨酸蛋白酶。共合成了5个钌配合物，分子式为：[Ru（bpy）2（1）]（O2 CCF 3）2（3），其中bpy为2，2 ′-联吡啶，1为联吡啶基环氧琥珀酰基缓蚀剂; [Ru（tpy）（NN）（2）]（PF 6）2，其中tpy为三联吡啶，2为吡啶基环氧琥珀酰基缓蚀剂，NN为2，2 ′-联吡啶（4）; 6，6 ′-二甲基-2，2 ′-联吡啶（5）;苯并[i]联吡啶并[3，2-a：2′，3 ′-c]吩嗪（6）; 3，6-二甲基苯并[i]联吡啶并[3，2-a：2′，3 ′ -c]吩嗪（7）。化合物3含有[Ru（bpy）3]2+荧光团，并被设计为跟踪缀合物的亚细胞定位，而化合物4-7被设计为经历光活化配体解离和/或单线态氧产生。光化学研究证实，配合物5和7进行光活化配体解离，而6和7产生单线态氧。抑制剂1-7都有效且不可逆地抑制CTSB。在2D和3D培养物中针对MDA-MB-231 TNBC和MCF-10A乳腺上皮细胞评价化合物4-7在黑暗和光照条件下对蛋白水解和细胞活力的影响。总的来说，这些数据揭示了4-7有效地抑制染料淬灭（DQ）胶原降解，而只有化合物7在光条件下引起有效的细胞死亡，这与其释放Ru（II）基光敏剂并且还产生1 O2的能力一致。
Dual action agents containing a cysteine protease inhibitor and Rubased photosensitizer for photodynamic therapy (PDT) were designed, synthesized, and validated in 2D culture and 3D functional imaging assays of triple-negative human breast cancer (TNBC). These combination agents deliver and release Rubased PDT agents to tumor cells and cause cancer cell death upon irradiation with visible light, while at the same time inactivating cathespin B (CTSB), a cysteine protease strongly associated with invasive and metastatic behavior. In total five Rubased complexes were synthesized with the formula [Ru(bpy)2(l)](O2CCF3)2 (3), where bpy = 2,2′-bipyridine and 1 = a bipyridine-based epoxysuccinyl inhibitor; [Ru(tpy)(NN)(2)](PF6)2, where tpy = terpiridine, 2 = a pyridine-based epoxysuccinyl inhibitor and NN = 2,2′-bipyridine (4); 6,6′-dimethyl-2,2′-bipyridine (5); benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (6); and 3,6-dimethylbenzo[i]-dipyrido[3,2-a:2′,3′ -c]phenazine (7). Compound 3 contains a [Ru(bpy)3]2+ fluorophore and was designed to track the subcellular localization of the conjugates, whereas compounds 4–7 were designed to undergo either photoactivated ligand dissociation and/or singlet oxygen generation. Photochemical studies confirmed that complexes 5 and 7 undergo photoactivated ligand dissociation, whereas 6 and 7 generate singlet oxygen. Inhibitors 1–7 all potently and irreversibly inhibit CTSB. Compounds 4–7 were evaluated against MDA-MB-231 TNBC and MCF-10A breast epithelial cells in 2D and 3D culture for effects on proteolysis and cell viability under dark and light conditions. Collectively, these data reveal that 4–7 potently inhibit dye-quenched (DQ) collagen degradation, whereas only compound 7 causes efficient cell death under light conditions, consistent with its ability to release a Ru(II)-based photosensitizer and to also generate 1O2.
登录
查看更多内容
影响因子：
12.4
作者：
Choi KY;Swierczewska M;Lee S;Chen X
通讯作者：
Chen X
影响因子：
4.6
作者：
Bahreman, Azadeh;Limburg, Bart;Bonnet, Sylvestre
通讯作者：
Bonnet, Sylvestre
影响因子：
14.8
作者：
Blum, Galia;von Degenfeld, Georges;Bogyo, Matthew
通讯作者：
Bogyo, Matthew
DOI：
10.1002/prca.201300105
发表时间：
2014-06
期刊：
Proteomics. Clinical applications
影响因子：
--
作者：
Aggarwal N;Sloane BF
通讯作者：
Sloane BF
影响因子：
3.7
作者：
Cutter, Jennifer L.;Cohen, Nathan T.;Basilion, James P.
通讯作者：
Basilion, James P.