Understanding the pharmacokinetics and distribution of nanoparticles has always been challenging. Researchers can quantify accumulation at the organ level, but at the expense of cellular detail. Or they can quantify accumulation at the cellular level, but at the expense of 3D tissue architecture detail. Given that nanomedicine is a delivery-based therapy, it’s important to know the delivery destinations of nanoparticles. As the field of nanomedicine shifts towards understanding cell-nanoparticle interactions, this gap needs to be addressed: where exactly are the nanoparticles going?
Researchers in Dr. Warren Chan’s lab at the University of Toronto have developed a method to create whole tissue maps to answer this question. They adapted a technique that makes tissues transparent (CLARITY), and used it to visualize nanoparticle distribution deep inside tissues. They take advantage of the layer of proteins that form around nanoparticles and cross-linked it to hold the nanoparticles in place. Additionally, they created a high-throughput system that can process 48 tissues simultaneously. In a proof-of-concept paper published in ACS Nano, they used quantum dots as a model nanoparticle and showed its distribution in the liver, kidney, and spleen. They observed most of the particles to be inside or on the blood vessels, indicating potential endothelial cell or macrophage uptake. Further, they developed algorithms to quantify the distribution by assessing how far the particles could penetrate past the blood vessels into tissues; in the liver, the limit seems to be 20 μm (a few cells thick).
“This paper represents a tour-de-force in uncovering how nanoparticles distribute themselves in tissues and tumors,” said Teri Odom, a professor of Materials Science & Engineering at Northwestern University who was not involved in the study. “The scope and depth of the project required great patience, and those of us who work in targeted nano-therapeutics will certainly benefit from this massive undertaking. Direct visualization of how nanoparticles interact in native environments will surely aid in nanoparticle design.”
“We wanted to have a Google Earth kind of view of nanoparticle distribution with the ability to zoom into every street and house to find what the nanoparticle is doing and zoom back out again,” said Shrey Sindhwani, co-lead author on the study.
“The biggest challenge was to create a robust method that can do this for a large number of samples and developing algorithms to report the “GPS” location of nanoparticles with respect to other biological structures,” said Abdullah Syed, another co-lead author on the study. “We envision this method to become a standard way to analyze any tissue, especially tumors, to find answers to nano-bio questions from the lack of 3D information of current techniques.”
The researchers were also able to visualize tumor microenvironment, so the next logical step is to look at nanoparticle distribution inside a tumor. This could tell us why nanoparticles, hailed for their potential as homing missiles for tumors, have yet to translate into a clinically-effective cancer therapeutic.
Here are a few videos demonstrating the capabilities of this new technology:
Article in ACS Nano: Three-Dimensional Optical Mapping of Nanoparticle Distribution in Intact Tissues