| Autor: |
Stapleton S; Department of Medical Biophysics , University of Toronto , Toronto , ON M5G 1L7 , Canada., Dunne M; Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON M5S 3M2 , Canada., Milosevic M; Department of Radiation Oncology , University of Toronto , Toronto , ON M5S 3E2 , Canada., Tran CW; Department of Immunology , University of Toronto , Toronto , ON M5S 1A1 , Canada., Gold MJ, Vedadi A, Mckee TD, Ohashi PS; Department of Immunology , University of Toronto , Toronto , ON M5S 1A1 , Canada., Allen C; Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON M5S 3M2 , Canada., Jaffray DA; Department of Medical Biophysics , University of Toronto , Toronto , ON M5G 1L7 , Canada.; Department of Radiation Oncology , University of Toronto , Toronto , ON M5S 3E2 , Canada.; Techna Institute , University Health Network , Toronto , ON M5G 1L5 , Canada. |
| Abstrakt: |
Nanomedicine drug delivery systems are capable of transporting significant payloads to solid tumors. However, only a modest increase in antitumor efficacy relative to the standard of care has been observed. In this study, we demonstrate that a single dose of radiation or mild hyperthermia can substantially improve tumor uptake and distribution of nanotherapeutics, resulting in improved treatment efficacy. The delivery of nanomedicine was driven by a reduction in interstitial fluid pressure (IFP) and small perturbation of steady-state fluid flow. The transient effects on fluid dynamics in tumors with high IFP was also shown to dominate over immune cell endocytic capacity, another mechanism suspected of improving drug delivery. Furthermore, we demonstrate the specificity of this mechanism by showing that delivery of nanotherapeutics to low IFP tumors with high leukocyte infiltration does not benefit from pretreatment with radiation or heat. These results demonstrate that focusing on small perturbations to steady-state fluid dynamics, rather than large sustained effects or uncertain immune cell recruitment strategies, can impart a vulnerability to tumors with high IFP and enhance nanotherapeutic drug delivery and treatment efficacy. |
