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Organic Chemistry Proposal Seminar – Aaron Hendricksen
November 3, 2020 @ 12:30 pm - 2:30 pm
Oral Prelim Exam Announcement
Tuesday, November 3rd @ 12:30 pm; ZOOM ONLY
Aaron Hendricksen (Mancini Group)
Title: Multivalent Immunostimulant Glycopolymers as Novel Adjuvants and Immunotherapeutics
Abstract: The development of rationally designed adjuvants is critical for the efficacy of purified antigens used in modern vaccine formulations including those developed for cancer immunotherapy. Few adjuvants are licensed for use in human vaccines at this time, however recent advances in the understanding of immune activation allow for development of discrete motifs targeting Pattern Recognition Receptors (PRRs) to the desired clinical benefit. Of these PRRs, the Macrophage Inducible C-Type Lectin receptor (MINCLE) has become an attractive target for adjuvant design. Despite this, only one experimental adjuvant CAF01 has been formulated for human use with trehalose dibehenate, a synthetic analogue of the glycolipid responsible for pathogenicity of Mycobacterium tuberculosis, whereby multivalent agonism is exploited for effective signaling. Furthermore, aryl derivatives of trehalose including the natural product brartemicin have demonstrated anti-invasive properties by inhibition of key proteins involved in tumor metathesis, highlighting the promising role of C-type lectin receptor agonists as anti-cancer therapeutics. In this work, we will investigate the molecular parameters for multivalent MINCLE agonism with a trehalose-based glycopolymer scaffold constructed via controlled/living radical polymerization for precise control of agonist density and macromolecular architecture. In addition, we propose the development of a hydrophilic tri-block polymer scaffold that retains MINCLE-specific immunogenicity and expands the platform to include aryl trehalose subunits for application in cancer immunotherapy. We propose a hydrophilic A-block for improved solubility and passive targeting of tumor tissue, a lipidated trehalose B-block to exploit multivalent MINCLE agonism, and an aryl trehalose C-block for delivery of anti-invasive therapeutics to the tumor microenvironment. The proposed work will elucidate the discrete molecular parameters of multivalent agonism for improvement of adjuvant design and subsequent control of immune response, while combined properties of MINCLE dependent immunogenicity and metathesis inhibition in tandem with the in vivo benefits of macromolecular carriers will serve to broaden their potential in cancer immunotherapy.
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Date & Time: Nov 3, 2020 12:30 PM Pacific Time (US and Canada)
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