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Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E10871-E10880. doi: 10.1073/pnas.1713390114. Epub 2017 Dec 5.

Effect of removing Kupffer cells on nanoparticle tumor delivery.

Tavares AJ1,2, Poon W1,2, Zhang YN1,2, Dai Q1,2, Besla R3, Ding D1,2, Ouyang B1,2,4, Li A3, Chen J5, Zheng G5,6, Robbins C3,7, Chan WCW8,2,9,10,11.

Author information

1
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
2
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
3
Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
4
MD/PhD Program, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 1L7, Canada.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
7
Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
8
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; warren.chan@utoronto.ca.
9
Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
10
Department of Chemical Engineering, University of Toronto, Toronto, ON M5S 3E5, Canada.
11
Department of Materials Science and Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.

Abstract

A recent metaanalysis shows that 0.7% of nanoparticles are delivered to solid tumors. This low delivery efficiency has major implications in the translation of cancer nanomedicines, as most of the nanomedicines are sequestered by nontumor cells. To improve the delivery efficiency, there is a need to investigate the quantitative contribution of each organ in blocking the transport of nanoparticles to solid tumors. Here, we hypothesize that the removal of the liver macrophages, cells that have been reported to take up the largest amount of circulating nanoparticles, would lead to a significant increase in the nanoparticle delivery efficiency to solid tumors. We were surprised to discover that the maximum achievable delivery efficiency was only 2%. In our analysis, there was a clear correlation between particle design, chemical composition, macrophage depletion, tumor pathophysiology, and tumor delivery efficiency. In many cases, we observed an 18-150 times greater delivery efficiency, but we were not able to achieve a delivery efficiency higher than 2%. The results suggest the need to look deeper at other organs such as the spleen, lymph nodes, and tumor in mediating the delivery process. Systematically mapping the contribution of each organ quantitatively will allow us to pinpoint the cause of the low tumor delivery efficiency. This, in effect, enables the generation of a rational strategy to improve the delivery efficiency of nanoparticles to solid tumors either through the engineering of multifunctional nanosystems or through manipulation of biological barriers.

KEYWORDS:

cancer; liver; macrophage; nanoparticle; tumor delivery

PMID:
29208719
PMCID:
PMC5754793
DOI:
10.1073/pnas.1713390114
[Indexed for MEDLINE]
Free PMC Article

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