Utilizing native fluorescence imaging, modeling and simulation to examine pharmacokinetics and therapeutic regimen of a novel anticancer prodrug.
Utilizing native fluorescence imaging, modeling and simulation to examine pharmacokinetics and therapeutic regimen of a novel anticancer prodrug.
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DOI：
10.1186/s12885-016-2508-6
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发表时间：
2016-07-25
期刊：
影响因子：
3.8
通讯作者：
Matin AC
中科院分区：
文献类型：
--
作者：
Wang JH;Endsley AN;Green CE;Matin AC
依赖于外源基因的癌症前药的成功需要将基因特异性递送至癌症，以及诸如更高水平的基因转移和表达的改进。使用我们新发现的hocB-GDEPT的临床前研究将有助于实现这些目标，该研究由前药：6-氯-9-硝基-5-氧代-5H-苯并[a]吩恶嗪（hocB）及其活化酶ChrR 6组成，该酶可产生细胞毒性产物9-氨基-6-氯-5H-苯并[a]吩恶嗪-5-酮（MCHB）。MCHB是荧光的，可以在小鼠中进行非侵入性成像，在这里，我们研究了MCHB荧光是否定量反映了其浓度，因为这将提高其在进一步开发hocB-GDEPT治疗方案中的报告价值。估计PK参数并用于预测更有效的hocB给药方案。将hocB（3.3mg/kg）静脉内注射到植入有表达人源化ChrR 6（HChrR 6）的4 T1肿瘤的小鼠中。使用IVIS Spectrum在活小鼠中对荧光进行成像，并通过Living Image 3.2软件进行定量。还通过LC/MS/MS分析定量MCHB和hocB。我们使用非房室模型估计PK参数。Phoenix WinNonlin软件用于模拟以预测更有效的hocB给药方案。hocB给药显著延长小鼠存活。MCHB荧光定量地反映了其对肿瘤和血浆的暴露水平，如通过LC/MS/MS分析在各个时间点所验证的，包括在2ng/g肿瘤的低浓度下。LC/MS/MS数据用于估计血浆和肿瘤中的血浆峰浓度、暴露量（AUC 0 -24）、分布容积、清除率和半衰期。模拟表明，hocB-GDEPT可以是一种成功的疗法，而不会大幅增加前药剂量。MCHB荧光定量这种药物，hocB可以在相对低的剂量下有效。MCHB荧光特性将通过例如促进特异性基因递送至肿瘤、其延长的表达以及成功的基因递送酶前药疗法所必需的其他属性来加速hocB-GDEPT的进一步开发。本文的在线版本（doi：10.1186/s12885-016-2508-6）包含补充材料，可供授权用户使用。
Success of cancer prodrugs relying on a foreign gene requires specific delivery of the gene to the cancer, and improvements such as higher level gene transfer and expression. Attaining these objectives will be facilitated in preclinical studies using our newly discovered CNOB-GDEPT, consisting of the produrg: 6-chloro-9-nitro-5-oxo-5H-benzo-(a)-phenoxazine (CNOB) and its activating enzyme ChrR6, which generates the cytotoxic product 9-amino-6-chloro-5H-benzo[a]phenoxazine-5-one (MCHB). MCHB is fluorescent and can be noninvasively imaged in mice, and here we investigated whether MCHB fluorescence quantitatively reflects its concentration, as this would enhance its reporter value in further development of the CNOB-GDEPT therapeutic regimen. PK parameters were estimated and used to predict more effective CNOB administration schedules. CNOB (3.3 mg/kg) was injected iv in mice implanted with humanized ChrR6 (HChrR6)-expressing 4T1 tumors. Fluorescence was imaged in live mice using IVIS Spectrum, and quantified by Living Image 3.2 software. MCHB and CNOB were quantified also by LC/MS/MS analysis. We used non-compartmental model to estimate PK parameters. Phoenix WinNonlin software was used for simulations to predict a more effective CNOB dosage regimen. CNOB administration significantly prolonged mice survival. MCHB fluorescence quantitatively reflected its exposure levels to the tumor and the plasma, as verified by LC/MS/MS analysis at various time points, including at a low concentration of 2 ng/g tumor. The LC/MS/MS data were used to estimate peak plasma concentrations, exposure (AUC0-24), volume of distribution, clearance and half-life in plasma and the tumor. Simulations suggested that the CNOB-GDEPT can be a successful therapy without large increases in the prodrug dosage. MCHB fluorescence quantifies this drug, and CNOB can be effective at relatively low doses. MCHB fluorescence characteristics will expedite further development of CNOB-GDEPT by, for example, facilitating specific gene delivery to the tumor, its prolonged expression, as well as other attributes necessary for successful gene-delivered enzyme prodrug therapy. The online version of this article (doi:10.1186/s12885-016-2508-6) contains supplementary material, which is available to authorized users.