Utilizing native fluorescence imaging, modeling and simulation to examine pharmacokinetics and therapeutic regimen of a novel anticancer prodrug
| Autor: | Jing-Hung Wang, Carol E. Green, Abdul Matin, Aaron N. Endsley |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Cancer Research Fluorescence-lifetime imaging microscopy media_common.quotation_subject Modeling and simulation Mice Nude Antineoplastic Agents Gene delivery Pharmacology Fluorescence Drug Administration Schedule Imaging Mice 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Cell Line Tumor Oxazines Genetics Animals Humans Medicine Prodrugs Prodrug Cancer media_common Volume of distribution business.industry Optical Imaging medicine.disease 3. Good health Regimen 030104 developmental biology Oncology 030220 oncology & carcinogenesis CNOB business Neoplasm Transplantation Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-016-2508-6 |
| Popis: | Background 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. Methods 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. Results 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. Conclusion 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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2508-6) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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