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Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system

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Abstract

The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we developed a quantitative mathematical model describing the intracellular trafficking. Dynamics of the prodrug and the model predictions were verified with experimental data using human cancer cells in vitro. The sensitivity analysis suggested that parameters related to extracellular concentration of released PTX, prodrug uptake, target engagement, and target abundance are critical in determining the combined killing efficacy of the prodrug. We found that released PTX cytotoxicity was most sensitive to the retention time of the drug in extracellular space. Modulating drug internalization and conjugating the agents targeted to abundant receptors may provide a new strategy for maximizing the killing capacity of the far-red light-activatable prodrug system. These results provide guidance for the design of the PDT combination study in vivo and have implications for other stimuli-responsive drug delivery systems.

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Acknowledgements

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM113940, Department of Defense Breast Cancer Research Program under Award Number W81XWH-09-1-0071, and the Presbyterian Health Foundation.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA

    Mengjie Li, Pritam Thapa, Pallavi Rajaputra, Moses Bio, Youngjae You & Sukyung Woo

  2. Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Cody J. Peer & William D. Figg

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  1. Mengjie Li
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  2. Pritam Thapa
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Correspondence to Youngjae You or Sukyung Woo.

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Li, M., Thapa, P., Rajaputra, P. et al. Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system. J Pharmacokinet Pharmacodyn 44, 521–536 (2017). https://doi.org/10.1007/s10928-017-9543-z

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