Killing hypoxic cell populations in a 3D tumor model with EtNBS-PDT.
Killing hypoxic cell populations in a 3D tumor model with EtNBS-PDT.
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DOI：
10.1371/journal.pone.0023434
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hasan T
中科院分区：
文献类型：
--
作者：
Evans CL;Abu-Yousif AO;Park YJ;Klein OJ;Celli JP;Rizvi I;Zheng X;Hasan T
癌症治疗中的一个突出问题是对抗治疗抵抗性疾病。这对于卵巢癌尤其如此，其中大多数患者最终死于治疗抵抗性转移性癌病。有限的灌注和扩散、酸中毒和缺氧在对大多数一线治疗方案的耐药性的发展中起主要作用。为了克服这些局限性并消除其他幸免的癌细胞，我们利用阳离子光敏剂EtNBS治疗转移性卵巢癌体外3D模型深处的缺氧区域。与不能渗透超过150 μm的标准方案不同，发现EtNBS不仅渗透整个大的（>200 μm）无血管结节，而且还浓缩到结节的酸性和缺氧核心。观察到EtNBS的光动力疗法即使在低治疗剂量下也对这些缺氧区域非常有效，并且能够在较高的治疗水平下破坏常氧和缺氧区域。利用多光子和共聚焦显微镜，以及时间推移光学相干断层扫描（TL-OCT）的成像研究，揭示了一个由内而外的模式的细胞死亡，细胞凋亡的主要机制的细胞杀伤。关键的是，发现基于EtNB的光动力疗法即使在严重缺氧下也能有效对抗模型肿瘤结节。EtNBS光动力疗法在宽范围的肿瘤氧合水平上赋予细胞毒性的固有能力表明其消除治疗抗性细胞群体的潜力。
An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations.
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DOI：
10.1038/sj.neo.7900037
发表时间：
1999-08-01
期刊：
Neoplasia (New York)
影响因子：
--
作者：
Gillies, Robert J.;Schornack, Paul A.;Raghunand, Natarajan
通讯作者：
Raghunand, Natarajan
影响因子：
3.5
作者：
Hill, Richard P.;Marie-Egyptienne, Delphine T.;Hedley, David W.
通讯作者：
Hedley, David W.
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
3.8
作者：
Evans, Conor L.;Rizvi, Imran;de Boer, Johannes F.
通讯作者：
de Boer, Johannes F.
影响因子：
10.3
作者：
del Carmen, MG;Rizvi, I;Hasan, T
通讯作者：
Hasan, T