Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen.
Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen.
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近红外激活原药释放的抗癌药物克服了单线态氧的时空限制。
DOI：
10.1016/j.bmc.2016.02.025
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
You Y
中科院分区：
文献类型：
--
作者：
Rajaputra P;Bio M;Nkepang G;Thapa P;Woo S;You Y
光动力疗法（PDT）是一种癌症治疗方式，其中光敏剂（PS）被可见光和近红外光激活以产生单线态氧（1 O2）。然而，1 O2具有短寿命（< 40 ns）并且不能扩散（< 20 nm）超过电池直径（例如，~ 1，800 nm）。因此，1 O2损伤在空间和时间上都是有限的，不会产生旁观者效应。在异质性肿瘤中，逃避1 O2损伤的细胞可以在PDT治疗后再生。为了克服这些局限性，我们开发了由光敏剂（PS）、抗癌药物（D）和1 O2-可裂解连接体（L）组成的前药概念（PS-L-D）。在照射前体药物时，产生1 O2，其破坏肿瘤并释放抗癌药物。局部释放的药物可以引起空间上更广泛和时间上持续的损伤，杀死PDT损伤后存活的癌细胞。在我们以前的报告中，我们提出了我们的CA 4前药（考布他汀A-4），Pc-（L-CA 4）2，与其不可裂解的类似物，Pc-（NCL-CA 4）2相比，其上级活性，仅产生PDT效应。在这里，我们提供了明确的证据表明，释放的抗癌药物，CA 4，确实损害了生存的癌细胞超过和超过1 O 2的空间和时间限制。在有限光照实验中，由于释放的抗癌药物的作用，整个孔中的细胞被杀死，而在假前药处理的威尔斯孔中仅观察到部分损伤。时间依赖性细胞存活研究显示，由于释放的CA 4的持续损伤，在前药处理的细胞中有更多的细胞死亡。细胞周期分析和显微成像数据显示了前药处理的细胞中CA 4的典型损伤模式。一项时间依赖性组织学研究表明，前药治疗的肿瘤缺乏有丝分裂体，并且与用假前药治疗的肿瘤中观察到的肿瘤尺寸相比，前药引起了更广泛和持续的肿瘤尺寸缩小。该数据一致支持释放的CA 4克服了1 O 2的时空限制，提供了远为优越的上级抗肿瘤作用。
Photodynamic therapy (PDT) is a cancer treatment modality where photosensitizer (PS) is activated by visible and near IR light to produce singlet oxygen (1O2). However, 1O2 has a short lifetime (< 40 ns) and cannot diffuse (< 20 nm) beyond the cell diameter (e.g., ~ 1,800 nm). Thus, 1O2 damage is both spatially and temporally limited and does not produce bystander effect. In a heterogeneous tumor, cells escaping 1O2 damage can regrow after PDT treatment. To overcome these limitations, we developed a prodrug concept (PS-L-D) composed of a photosensitizer (PS), an anti-cancer drug (D), and an 1O2-cleavable linker (L). Upon illumination of the prodrug, 1O2 is generated, which damages the tumor and also releases anticancer drug. The locally released drug could cause spatially broader and temporally sustained damage, killing the surviving cancer cells after the PDT damage. In our previous report, we presented the superior activity of our prodrug of CA4 (combretastatin A-4), Pc-(L-CA4)2, compared to its non-cleavable analog, Pc-(NCL-CA4)2, that produced only PDT effects. Here, we provide clear evidence demonstrating that the released anticancer drug, CA4, indeed damages the surviving cancer cells over and beyond the spatial and temporal limits of 1O2. In the limited light illumination experiment, cells in the entire well were killed due to the effect of released anticancer drug, whereas only a partial damage was observed in the pseudo-prodrug treated wells. A time-dependent cell survival study showed more cell death in the prodrug-treated cells due to the sustained damage by the released CA4. Cell cycle analysis and microscopic imaging data demonstrated the typical damage patterns by CA4 in the prodrug treated cells. A time-dependent histological study showed that prodrug-treated tumors lacked mitotic bodies, and the prodrug caused broader and sustained tumor size reduction compared to those seen in the tumors treated with the pseudo-prodrug. This data consistently support that the released CA4 overcomes the spatiotemporal limitations of 1O2, providing far superior antitumor effect.
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影响因子：
3.4
作者：
Chakraborty A;Held KD;Prise KM;Liber HL;Redmond RW
通讯作者：
Redmond RW
DOI：
10.3322/caac.20114
发表时间：
2011-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Agostinis P;Berg K;Cengel KA;Foster TH;Girotti AW;Gollnick SO;Hahn SM;Hamblin MR;Juzeniene A;Kessel D;Korbelik M;Moan J;Mroz P;Nowis D;Piette J;Wilson BC;Golab J
通讯作者：
Golab J
影响因子：
11.2
作者：
Kluza, J;Gallego, MA;Bailly, C
通讯作者：
Bailly, C
通过原药的双重活化实现抗癌药物的可见光控制释放
影响因子：
4.2
作者：
Hossion, Abugafar M. L.;Bio, Moses;You, Youngjae
通讯作者：
You, Youngjae
影响因子：
2.3
作者：
Nabha, SM;Wall, NR;Al-Katib, AM
通讯作者：
Al-Katib, AM