³ÉÈËVRÊÓƵ

Abstract:

We have developed a family of selective organic catalysts for ring-opening polymerization reactions,¹ and have integrated these catalysts into flow reactors for the programmed synthesis of block copolymer libraries.² In parallel efforts, we have developed aerobic alcohol oxidation catalysts³ that generate new monomers which were then enchained using organocatalytic polymerization⁴ to generate functional materials that proved useful agents for the delivery of messenger RNA into living animals.^4-7 Functional delivery of messenger RNA (mRNA) in-vivo is key to implementing potentially transformative strategies for vaccination, protein replacement therapy and genome editing. The step-economical synthesis and evaluation of a new, tunable and effective class of synthetic biodegradable materials: Charge-Altering Releasable Transporters (CARTs) will be described for mRNA delivery. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect and deliver mRNA, and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein expression.

(1) Lin, B.; Waymouth, R. M. "Urea Anions: Simple, Fast, and Selective Catalysts for Ring-Opening Polymerizations" J. Am. Chem. Soc., 2017, 139(4), 1645–1652

(2) Lin, B.; Hedrick, J. L.; Park, N. H.; Waymouth, R. M. "A Programmable High-Throughput Platform for the Rapid and Scalable Synthesis of Polyester and Polycarbonate Libraries" J. Am. Chem. Soc, 2019, 141,8921-8927.

(3) Ho, W. C., Chung, K.; Ingram, A. J., Waymouth, R. M. "Pd-Catalyzed Aerobic Oxidation Reactions: Strategies to Increase Catalyst Lifetimes", J. Am. Chem. Soc., 2018, 140, 748-757

(4) Blake, T.; Waymouth, R. M. " Organocatalytic Ring Opening Polymerization of Morpholinones: New Strategies to Functionalized Polyesters " J. Am. Chem. Soc., 2014, 136, 9252-9255.

(5) McKinlay, C. J.; Vargas, J. R.; Blake, T. R.; Hardy, J. W.; Kanada, M.; Contag, C. H.; Wender, P. A.; Waymouth, R. M. "Charge-altering Releasable Transporters (CARTs) for the delivery and release of messenger RNA in living animals" Proc. Natl. Acad. Sci., 2017, 114, E448-E456.

(6) Haalbeth, O.; Blake, T.; McKinlay, C. J.; Waymouth, R. M.; Wender, P. A.; Levy, R.; "Vaccination with Charge-Altering Releasable Transporters of mRNA Cures Established Experimental Tumors" Proc. Nat. Acad. Sci., 2018, 115(39) E9153-E9161

(7) Haabeth, O. A. W.; Blake, T. R.; McKinlay, C. J.; Tveita, A.; Sallets, A.; Waymouth, R.M.; Wender, P. A.; Levy, R. "Local OX40L, CD80, and CD86 mRNA delivery kindles global anti-cancer immunity." Cancer Res 2019, 79 (7), 1624-1634.

Bio:

Robert Waymouth is the Robert Eckles Swain Professor of Chemistry at Stanford University. He received B.S. in Mathematics and B.A. in Chemistry from Washington and Lee University and his Ph.D. in Chemistry at the Caltech in 1987 with Professor R.H. Grubbs. He was a postdoctoral fellow with the late Professor Piero Pino at the ETH in Zurich in 1987 and joined the faculty at Stanford as an Assistant Professor in 1988. He received the Alan T. Waterman Award from the NSF in 1996, the Cooperative Research Award in Polymer Science in 2009, and EPA's Presidential Green Chemistry Challenge Award in 2012 with Dr. James Hedrick. He has won several university teaching awards, including the Walter J. Gores Award, the Phi Beta Kappa Teaching Award, and is currently a Bass Fellow in Undergraduate Education. His research interests are at the interface of Inorganic, Organic and Polymer Chemistry, in particular the development of new concepts in catalysis for the selective synthesis of both macromolecules and fine chemicals. Particular areas of interest include catalytic polymerization reactions, selective oxidation catalysis the development of organocatalytic polymerization strategies and the design of functional macromolecules for applications in biology and medicine.