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Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors

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Abstract

Conventional drug delivery systems for solid tumors are composed of a nano-carrier that releases its therapeutic load. These two-stage nanoparticles utilize the enhanced permeability and retention (EPR) effect to enable preferential delivery to tumor tissue. However, the size-dependency of the EPR, the limited penetration of nanoparticles into the tumor as well as the rapid binding of the particles or the released cytotoxic agents to cancer cells and stromal components inhibit the uniform distribution of the drug and the efficacy of the treatment. Here, we employ mathematical modeling to study the effect of particle size, drug release rate and binding affinity on the distribution and efficacy of nanoparticles to derive optimal design rules. Furthermore, we introduce a new multi-stage delivery system. The system consists of a 20-nm primary nanoparticle, which releases 5-nm secondary particles, which in turn release the chemotherapeutic drug. We found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug. Our results also indicate that multi-stage nanoparticles are superior over two-stage nano-carriers provided they have a faster drug release rate and for high binding affinity drugs. Furthermore, our results suggest that smaller nanoparticles achieve better treatment outcome.

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Acknowledgments

Simulations were performed at the high performance computer systems of the Cancer Biophysics laboratory at the University of Cyprus and of the Partners Healthcare System at Massachusetts General Hospital. This work was supported by the European Commission with a Marie-Curie Reintegration Grant (FP7-PIRG08-GA-2010-276894) to TS and the National Cancer Institute (P01-CA080124, R01-CA126642, R01-CA115767, R01-CA096915, R01-CA085140, T32-CA073479, Federal Share Income Grant), and a DoD Breast Cancer Research Innovator award (W81XWH-10-1-0016) to RKJ.

Conflict of interest

R.K.J. received research grants from Dyax, MedImmune and Roche; consultant fees from Enlight, Ophthotech, SynDevRx, and Zyngenia; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit, serves on the Board of Directors of XTuit and Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors and Tekla Healthcare Opportunities Fund. No reagents or funding from these companies was used in these studies. Therefore, there is no significant financial or other competing interest in the work.

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Authors and Affiliations

  1. Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678, Nicosia, Cyprus

    Triantafyllos Stylianopoulos & Eva-Athena Economides

  2. Department of Biomedical Engineering, Bucknell University, Lewisburg, PA, 17837, USA

    James W. Baish

  3. Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Dai Fukumura & Rakesh K. Jain

Authors
  1. Triantafyllos Stylianopoulos
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  2. Eva-Athena Economides
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  4. Dai Fukumura
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  5. Rakesh K. Jain
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Correspondence to Triantafyllos Stylianopoulos or Rakesh K. Jain.

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Associate Editor Konstantinos Konstantopoulos oversaw the review of this article.

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Stylianopoulos, T., Economides, EA., Baish, J.W. et al. Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors. Ann Biomed Eng 43, 2291–2300 (2015). https://doi.org/10.1007/s10439-015-1276-9

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  • DOI: https://doi.org/10.1007/s10439-015-1276-9

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