Spatio-temporal analysis of nanoparticles in live tumor spheroids impacted by cell origin and density

Aria Ahmed-Cox; Elvis Pandzic; Stuart T Johnston; Celine Heu; John McGhee; Friederike M Mansfeld; Edmund J Crampin; Thomas P Davis; Renee M Whan; Maria Kavallaris

doi:10.1016/j.jconrel.2021.12.014

Spatio-temporal analysis of nanoparticles in live tumor spheroids impacted by cell origin and density

J Control Release. 2022 Jan:341:661-675. doi: 10.1016/j.jconrel.2021.12.014. Epub 2021 Dec 13.

Authors

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Center, UNSW Sydney, NSW 2031, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Australian Center for NanoMedicine, UNSW Sydney, NSW 2031, Australia; School of Women and Children's Health, Faculty of Medicine and Health, UNSW Sydney, NSW 2031, Australia.
² Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Center, UNSW Sydney, NSW 2031, Australia.
³ ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Systems Biology Laboratory, School of Mathematics and Statistics, and Department of Biomedical Engineering, University of Melbourne, Parkville, Victoria 3010, Australia.
⁴ ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Australian Center for NanoMedicine, UNSW Sydney, NSW 2031, Australia; 3D Visualisation Aesthetics Lab, UNSW Art & Design, UNSW Sydney, NSW 2021, Australia.
⁵ Children's Cancer Institute, Lowy Cancer Research Center, UNSW Sydney, NSW 2031, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Australian Center for NanoMedicine, UNSW Sydney, NSW 2031, Australia; School of Women and Children's Health, Faculty of Medicine and Health, UNSW Sydney, NSW 2031, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, 3052, Australia.
⁶ ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Systems Biology Laboratory, School of Mathematics and Statistics, and Department of Biomedical Engineering, University of Melbourne, Parkville, Victoria 3010, Australia; School of Medicine, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia.
⁷ Precision Medicine, Australian Institute of Bioengineering & Nanotechnology, University of Queensland, QLD, 40679, Australia.
⁸ Children's Cancer Institute, Lowy Cancer Research Center, UNSW Sydney, NSW 2031, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Australian Center for NanoMedicine, UNSW Sydney, NSW 2031, Australia; School of Women and Children's Health, Faculty of Medicine and Health, UNSW Sydney, NSW 2031, Australia. Electronic address: m.kavallaris@ccia.unsw.edu.au.

PMID: 34915071
DOI: 10.1016/j.jconrel.2021.12.014

Abstract

Nanoparticles hold great preclinical promise in cancer therapy but continue to suffer attrition through clinical trials. Advanced, three dimensional (3D) cellular models such as tumor spheroids can recapitulate elements of the tumor environment and are considered the superior model to evaluate nanoparticle designs. However, there is an important need to better understand nanoparticle penetration kinetics and determine how different cell characteristics may influence this nanoparticle uptake. A key challenge with current approaches for measuring nanoparticle accumulation in spheroids is that they are often static, losing spatial and temporal information which may be necessary for effective nanoparticle evaluation in 3D cell models. To overcome this challenge, we developed an analysis platform, termed the Determination of Nanoparticle Uptake in Tumor Spheroids (DONUTS), which retains spatial and temporal information during quantification, enabling evaluation of nanoparticle uptake in 3D tumor spheroids. Outperforming linear profiling methods, DONUTS was able to measure silica nanoparticle uptake to 10 μm accuracy in both isotropic and irregularly shaped cancer cell spheroids. This was then extended to determine penetration kinetics, first by a forward-in-time, center-in-space model, and then by mathematical modelling, which enabled the direct evaluation of nanoparticle penetration kinetics in different spheroid models. Nanoparticle uptake was shown to inversely relate to particle size and varied depending on the cell type, cell stiffness and density of the spheroid model. The automated analysis method we have developed can be applied to live spheroids in situ, for the advanced evaluation of nanoparticles as delivery agents in cancer therapy.

Keywords: Fluorescence imaging; Mathematical modelling; Microscopy; Nanoparticles; Tumor spheroids; Uptake kinetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Nanoparticles*
Neoplasms*
Particle Size
Spatio-Temporal Analysis
Spheroids, Cellular