Dual-channel near-infrared fluorescent thiol-activatable theranostic prodrug for in vivo real-time tracking chemotherapy

Event Abstract Back to Event Dual-channel near-infrared fluorescent thiol-activatable theranostic prodrug for in vivo real-time tracking chemotherapy Jianbin Tang1, Minghzou Ye1, Xiaohang Wang2, Zhiqian Guo2, Youqing Shen1 and Weihong Zhu2 1 Zhejiang University, College of Chemical and Biological Engineering, China 2 East China University of Science and Technology, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, China Introduction: Chemotherapy is one of the most important arsenals against cancer, but always results in undesired purgatorial side-effects such as hair loss, bone marrow suppression and organ damage. Tumor-activatable prodrugs that are selectively activated in tumors were developed to reduce off-target toxicity and improve the therapeutic index. Real-time monitoring when, where, and how the prodrugs are activated in vivo is critical for their development, but it remains as a great challenge since we lack capable theranostic prodrugs to track their behavior in vivo. The reported fluorescent theranostic prodrugs were plagued by their mono-channel fluorescence and short wavelength, which were insufficient for simultaneously tracking their biodistribution and activation in vivo[1],[2]. To solve the problem, we developed a novel theranostic prodrug (Cy-S-CPT) from cyanine dye and anticancer drug CPT, which were covalently connected with a disulfide bond linkage. The cleavage of the disulfide bond by GSH and the successive cyclization reaction produced the activated anti-cancer drug CPT and induced remarkable fluorescent shift from 825 to 650 nm, making a breakthrough with switchable dual-channel near-infrared (NIR) fluorescence to real-timely scrutinize the activation process of prodrugs with disulfide bond linker in vivo (Figure. 1). Figure. 1 Design and activation mechanism of dual-channel fluorescent theranostic prodrug Results and Discussion: The prodrug release process was tested at different conditions by using spectrometer, flow cytometer and confocal laser scanning microscopy, which verified the activation sensitivity and thiol-specificity in vitro. The in vivo fluorescent imaging of mice after the intravenous injection of the prodrug loaded in PEG-PLA nanoparticles was performed with different fluorescence channels (λex = 750 nm and λem = 825 nm vs λex = 530 nm, λem = 650 nm ) (Figure. 2B). Clearly, the NIR fluorescence of intact prodrug (represented in green) was quickly distributed in the whole body of mice soon after the injection, and then slowly faded out, demonstrating a quick distribution and gradual activation of Cy-S-CPT. Simultaneously, the red fluorescence of cyanine dye (represented in red) became stronger as time increased, and reached its peak at 4 h post injection, which indicated the highest prodrug activation level occurred at this time point. Intriguingly, even though red fluorescence dispersed broadly in the mice, indicating a comprehensive activation occurred in all organs, the tumor bestowed the strongest red fluorescence at 24 h post injection, which revealed a preferential prodrug accumulation and activation in tumor. Additionally, the in vivo antitumor studies performed on xenografted BCap-37 tumor model indicated that Cy-S-CPT loaded nanoparticles displayed significantly improved therapeutic efficacy than the clinical used drug CPT-11(Figure. 2B). Figure. 2 In vivo imaging (A) and antitumor activities (B) of the theranostic prodrug on BCap-37 tumor xenografted nude mice. Note: green signal represents the fluorescence from the intact prodrugs (λex = 750 nm, λem = 825 nm), indicating prodrug biodistribution; while red signal represents the fluorescence from CyA-K (λex = 530 nm, λem = 650 nm), indicating drug activation. Yellow represents the mix. Conclusion: A theranostic prodrug with a disulfide bond linkage possessing switchable NIR fluorescent from 825 to 650 nm was prepared and used to investigate GSH-responsive drug activation in vivo. The dual-channel fluorescent imaging indicated that although the prodrug with disulfide could be activated comprehensively in all the organs and tissues with a relatively high speed, tumor demonstrated the strongest prodrug activation at 24 h post injection. Moreover, Cy-S-CPT exhibited significant therapeutic efficacy which overwhelmed clinical used drug CPT-11. The theranostic prodrug with switchable dual-channel near-infrared (NIR) fluorescence provided a new strategy to real-time monitor the distribution and activation of prodrugs in vivo. National Basic Research Program (2014CB931900and 2013CB733700); NSFC for Creative Research Groups (21421004) and Distinguished Young Scholars (21325625), NSFC/ChinaReferences:[1] Yang, Z.; Lee, J. H.; Jeon, H. M.; Han, J. H.; Park, N.; He, Y.; Lee, H.; Hong, K. S.; Kang, C.; Kim, J. S. Journal of the American Chemical Society 2013, 135, 11657[2] Wu, X. M.; Sun, X. R.; Guo, Z. Q.; Tang, J. B.; Shen, Y. Q.; James, T. D.; Tian, H.; Zhu, W. H. Journal of the American Chemical Society 2014, 136, 3579 Keywords: Molecular Imaging, in vivo, Drug delivery, Environmental response Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: New Frontier Oral Topic: Imaging with biomaterials Citation: Tang J, Ye M, Wang X, Guo Z, Shen Y and Zhu W (2016). Dual-channel near-infrared fluorescent thiol-activatable theranostic prodrug for in vivo real-time tracking chemotherapy. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02368 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jianbin Tang Minghzou Ye Xiaohang Wang Zhiqian Guo Youqing Shen Weihong Zhu Google Jianbin Tang Minghzou Ye Xiaohang Wang Zhiqian Guo Youqing Shen Weihong Zhu Google Scholar Jianbin Tang Minghzou Ye Xiaohang Wang Zhiqian Guo Youqing Shen Weihong Zhu PubMed Jianbin Tang Minghzou Ye Xiaohang Wang Zhiqian Guo Youqing Shen Weihong Zhu Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.