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This week we profile a recent publication in Nature Communications from the laboratory of Dr. Jay
Kizhakkedathu
(pictured, back row, seventh from right) at the UBC Centre for Blood Research.

Can you provide a brief overview of your lab’s current research focus?

The focus of Kizhakkedathu lab at the Centre for Blood Research, Life Sciences Centre and Department of Pathology at UBC, is to innovate therapeutics to treat blood disorders, develop tools and technologies that can address immunological rejection, develop technologies needed for new drug delivery vehicles, develop tools for understanding various biomarkers to aid in precision medicine, and technologies for smart antithrombotic/antibiofilm devices to combat nosocomial infection and blood storage. The research program is based on a singular focus of biomaterial innovation by a common foundation in applied hematology and translational medicine. We use a complementary array of techniques including advanced polymer synthesis, organic synthesis, biochemical analysis, imaging/microscopy, cell culture, blood analysis, in vivo models examining tolerance, pharmacokinetics, biodistribution & disease specific mouse models.

What is the significance of the findings in this publication?  

In this work, we describe a fundamental understanding on potential pathways by which nanomaterials can reside in blood circulation for long periods of time. This research is highly relevant to nanomedicine and nanomaterial toxicity. Towards this, we initially developed new drug delivery vehicles (mega polyglycerols) with ultra-long blood circulation mice (up to 65 hour circulation half-life), and utilized proteomic techniques to understand the fate of these nanoparticles in circulation. We collected the nanoparticles that were circulation in mice for up to 48 hours and investigated the proteins bound to these systems using quantitative proteomics. Formation of the protein corona has been described as the phenomenon in which foreign materials or nanomedicines immediately form a layer of adsorbed proteins upon introduction to biological milieu, such as blood. The composition of protein corona has been suggested to dictate the fate of materials in blood. We found that protein corona formation on these nanoparticles in vivo is a highly dynamic process, and those nanoparticles, which can release some of opsonizing proteins, can stay in circulation while others get cleared by the immune system. This is the first report on insights to such a process happening. A better understanding of this phenomenon would allow us to take steps toward harnessing this to develop novel nanomedicine with improved circulation profiles and minimal toxicity for diverse applications.

What are the next steps for this research?

While this nanomedicine platform can allow us to study protein corona formation under a long time-course, there remains many more questions to answer. These include better understanding on which specific proteins on nanoparticle surface contribute to long-circulation profiles and which contribute to rapid clearance profiles, and how material properties can be optimized to “exploit” long circulation profiles. In the Kizhakkedathu lab, we are putting our efforts toward understand how these protein binding in vivo differs between tissue-targeted and non-targeted (systemic) nanotherapeutics. Further, we are highly interested in exploring how different disease conditions can affect the dynamic protein corona formation observed in normal mice, and thus may be helpful to draw more conclusions on immune recognition to different nanomedicine.

This work was funded by:

The Kizhakkedathu lab is supported by the Canadian Institutes for Health Research, the Michael Smith Foundation for Health Research (MSFHR), Natural Sciences and Engineering Council of Canada and Canada Foundation for Innovation. Trainees for this work: Dr. Srinivas Abbina was funded by MSFHR postdoctoral fellowship, and Lily Takeuchi was funded by NSERC CGS-M award and Nanomaterials Science and Technology CREATE program.

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