A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways
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Author(s)
Morton, Stephen Winford
Lee, Michael J.
Deng, Zhou J.
Siouve, Elise
Shopsowitz, Kevin
Shah, Nisarg J.
Dreaden, Erik
Yaffe, Michael B
Hammond, Paula T
Date Issued
May 2014
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Morton, S. W., M. J. Lee, Z. J. Deng, E. C. Dreaden, E. Siouve, K. E. Shopsowitz, N. J. Shah, M. B. Yaffe, and P. T. Hammond. “A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways.” Science Signaling 7, no. 325 (May 13, 2014): ra44–ra44. p.1-11.
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Author's final manuscript
Abstract
Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.
MIT Department
Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1126/scisignal.2005261
