Institute of Biomedical Engineering (BME)

Polymer Nanoparticle Design and Delivery Strategies to Resolve Vascular Inflammation
2023-07-11 10:00 - 11:00 (America/Toronto) | Donnelly Centre for Cellular and Biomolecular Research, Red Room, 160 College Street, Toronto, Ontario, M5S 3E1, Canada
Dr. Laura Bracaglia, PhD Villanova University
Polymer nanoparticles (NPs) can provide a safe and efficient delivery mechanism for therapy directly at specific tissues and cells, but achieving sufficient levels of NPs and therefore therapeutics in target tissues in humans has remained a barrier to the translation of this technology. The in vivo efficacy of polymeric NPs is dependent on their pharmacokinetics, including time in circulation and resulting tissue tropism, as well as intracellular trafficking and behavior. In this work, we examine tunable chemical and molecular characteristics of polymer NPs to tailor the design for an intended therapeutic delivery – both to and within the target cell. We are particularly interested in designing NPs and delivery strategies which can direct therapeutics to endothelial cells to correct dysfunctional inflammation in the vasculature. I will present several approaches for nucleic acid and small molecule delivery using polymeric NPs in vitro, in vivo, and in ex vivo models of human tissue, and show the impact of design changes on reducing inflammatory signaling. Our goal is to optimize NP design to combat dysfunctional inflammation locally and with more impact than globally administered therapies.
Biography
Dr. Bracaglia joined the faculty at Villanova University in the fall of 2022 as an Assistant Professor in the Department of Chemical and Biological Engineering. She is continuing her research into NP-based therapeutic delivery to human vasculature and integrating these strategies with tissue-engineering to create tools for long-term immune
modulation. Specifically, materials that provide support for tissue regrowth while temporarily inhibiting inflammation-related injury, thus reducing the burden of chronic inflammation. This work was born out of work that Dr. Bracaglia conducted as a Postdoctoral Fellow in Biomedical Engineering at Yale University as part of Dr. W. Mark Saltzman’s research group, as well as her graduate work, where she developed vascular, tissue engineered constructs using a combination of biological and synthetic materials at the University of Maryland with Dr. John Fisher in Bioengineering.

Hosted by Dr. Molly Shoichet Snacks and refreshments will be served

Carbon nanomaterials for cardiac regenerative medicine
2023-07-13 14:00 - 15:00
Dr. Sanjiv Dhingra, PhD
University of Manitoba
Abstract: Donor derived allogeneic stem cells including mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) are being tested in animal studies and clinical trials for cardiac regeneration and repair. The outcome of initial studies was very encouraging and transplanted cells were safe in the recipient heart. However, poor survival of transplanted stem cells in the infarcted heart has impaired the clinical translation of stem cells-based therapies. We have performed investigations to understand the mechanisms of poor survival of implanted stem cells in the heart. We found that allogeneic stem cells after transplantation in the ischemic heart turned immunogenic and were subsequently rejected by host immune system. In our ongoing studies we are focusing on understanding the mechanisms of increase in immunogenicity of allogeneic stem cells. We are also developing biomaterials-based strategies to prevent rejection of transplanted cells in the heart. We synthesized and characterized MXene quantum dots (MQDs). MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of CD4+IFN-γ+ T-lymphocytes and promote expansion of immunosuppressive CD4+CD25+FoxP3+ regulatory T-cells in an activated lymphocyte population. We also incorporated MQDs into a chitosan-based hydrogel to create a 3D platform for stem cell delivery to the heart. This composite immunomodulatory hydrogel-based platform improved survival of stem cells and mitigated allo-immune responses. We also found that MQDs have potential to mitigate allograft vasculopathy and prevent rejection of transplanted organs. These studies highlight the potential of MXene based next generation biomaterials for cardiac regenerative medicine.
About the speaker: Dr. Sanjiv Dhingra is a Professor at the University of Manitoba, Director of Canada Italy Tissue Engineering Program Institute of Cardiovascular Sciences and a researcher at St. Boniface Hospital Research Regenerative Medicine Program. He is a Professor at the Department of Physiology and Pathophysiology, Biomedical Engineering Program Max Rady College of Medicine, Rady Faculty of Health Sciences University of Manitoba.

Following the Rabbit into Chemical Space
2023-07-14 10:00 - 11:00
Dr. Brian K. Shoichet, PhD
University of California, San Francisco
https://utoronto.zoom.us/j/86086638773
Meeting ID: 860 8663 8773
Passcode: [REDACTED]
Structure-based docking can be used to screen compound libraries for novel ligands. Recently, docking libraries have expanded from three million “in-stock” to over four billion make-on-demand (“tangible”) molecules. Docking these new libraries versus the dopamine, melatonin, and 2 receptors have revealed novel scaffolds with nM and sub-nM potencies directly from the docking. I will discuss recent applications to the alpha2a-adrenergic, serotonin, and cannabinoid receptors, and the serotonin transporter, where in vivo active leads have been developed for analgesia, depression, and opioid withdrawal.
Methods questions will also be considered: the effect of bias toward bio-like molecules in the virtual libraries, how and if docking score improves as the libraries grow, how number tested affects the quality of the experimental actives, and whether we have reached a plateau in the results we can expect from large library docking, or if bigger remains better.
Biography
Brian Shoichet received a B.Sc. in Chemistry and a B.Sc. in History in 1985, from MIT. MIT appears to have no record of this. He received his Ph.D. for work with Tack Kuntz on molecular docking in 1991, from UCSF. Shoichet’s postdoctoral research was largely experimental, focusing on protein structure and stability with Brian Matthews at the Institute of Molecular Biology in Eugene, Oregon, as a Damon Runyon Fellow. Colleagues from Eugene have only sketchy
memories of his time there. One recalls, “He seemed to travel a lot.” Matthews himself was unavailable for comment. Shoichet joined the faculty at Northwestern University in the Dept.of Molecular Pharmacology & Biological Chemistry as an Assistant Professor in 1996. No record of this Department’s existence can be found outside of one locked filing cabinet in Gene Silinsky’s office. Silinsky was unavailable for comment. In a fit of absent-mindedness, Shoichet was promoted to a tenured Associate Professor in 2002, only one year after his younger sister, Molly Shoichet, received tenure at the University of Toronto. Shoichet denies any sensitivity around this issue. Around that time he was recruited back to UCSF, where he is now a Professor in the Department of Pharmaceutical Chemistry. We confused him with Kevan Shokat, admits a member of the recruiting committee at UCSF. A charismatic speaker, he is recalled as giving ‘the best talk at the worst Keystone Conference I ever attended,’ by a senior NIH Program Officer.
Research in the Shoichet Lab seeks to bring chemical reagents to biology, combining computational simulation and experiment. An unanticipated observation emerging from the theory/experiment cycle was the colloidal aggregation of organic molecules. This phenomenon has great effects in early and late drug discovery, and we continue to investigate it. More broadly, we adopt a protein-centric approach that seeks new ligands to complement protein structures. This involves new docking methods, model experimental systems to test them. Using a ligand-centric approach, we seek new targets for established drugs and reagents. Whereas this lacks the physical foundation of the structure-based research program, it returns to an older, pharmacological view of biological relationships, bringing to it a quantitative model. A focus for both approaches is ligand discovery against G Protein-Coupled Receptors (GPCRs).

Hosted by Dr. Molly Shoichet Snacks and refreshments will be served.
