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1)Transition metal catalysis in polypeptide synthesis
The goal of this research has been to use transition metal chemistry to produce synthetic block copolypeptide materials with precise control over comonomer sequence and composition and polymer molecular weight. The lack of well-defined synthetic polypeptides has limited their use in materials applications. We believe that the ability to prepare well-defined block copolypeptides will tremendously increase their potential as biomolecular materials. We have successfully developed organonickel initiators for the living polymerization of α-aminoacid-N-carboxyanhydrides (NCAs) into complex polypeptide sequences and architectures.
The mechanistic details of this polymerization system have been studied in detail and have led to the development of initiator systems based on other metals such as cobalt and iron. We continue to study the organometallic chemistry of this system in order to develop new initiators that will allow even greater control over polypeptide formation. The development of chiral, enantioselective initiators and chain-end functionalization chemistry are examples of accomplishments in this area. We also have pursued the formation of block copoly(β-peptides) from β-lactams using transition metal inititors. Recent work is focused on stereochemical control of NCA polymerizations and the metal-mediated synthesis of branched copolypeptides. Additionally, progress has been made using transition metal initiators to polymerize N-thiocarboxyanhydrides (NTAs).
Researchers: Allison Rhodes
Select Publications:
“Synthesis of AB Diblock Copolymers via Controlled/”living” Radical Polymerization (ATRP) and Living Polymerization of a-Amino Acid-N-Carboxyanhydrides” Brzezinska, K. R.; Deming, T. J. Macromolecular Biosci. 2004, 4, 566-569.
“Use of Chiral Ruthenium and Iridium Amido-Sulfonamidate Complexes for Controlled, Enantioselective Polypeptide Synthesis”. Seidel, S. W.; Deming, T. J. Macromolecules , 2003, 36, 969-972.
"Cobalt and Iron Initiators for the Controlled Polymerization of alpha-Amino Acid-N-Carboxyanhydrides". Deming, T. J. Macromolecules 1999, 32, 4500-4502
"Facile Synthesis of Block Copolypeptides of Defined Architecture". Deming, T. J. Nature ,1997, 390, 386-389.
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2)Polypeptide hydrogels for biomedical applications
Protein-based hydrogels are used for many applications, ranging from food and cosmetic thickeners to support matrices for drug delivery and tissue replacement. These materials are usually prepared using proteins extracted from natural sources, which can give rise to inconsistent properties detrimental for medical applications. We have recently synthesized diblock copolypeptide amphiphiles containing charged and hydrophobic segments. Rather than forming micelles, dilute solutions of these copolypeptides surprisingly were found to form hydrogels with useful and unique properties, including high temperature stability and rapid healing after stress. The use of synthetic materials allows adjustment of copolymer chain length and composition, which we can vary to study their effect on hydrogel formation and properties. In addition to the amphiphilic nature of the polypeptides, their chain conformations, either α-helix, β-strand or random coil, were found to play key roles in gelation. This shape-specific supramolecular assembly was found to be integral to the gelation process, and provides new peptide-based hydrogels with potential for applications in biotechnology. We are currently exploring the assembly mechanisms in these materials, and also exploring the properties of the materials for a number of applications, including axon regeneration.
Collaborators: Prof. Michael Sofroniew (UCLA)
Researchers: Jennifer Yang, Alyse Hurd
Lysine-Leucine diblock copolymer hydrogel (3.0 wt% in water)
Left: Cryo-TEM image (bar = 0.5 μm)
Right: schematic showing self-assembly
Gel Deposit K180L20-3%
Injection into Striatum (Caudate/putamen)
Blue channel = polypeptide gel Merged image = polylpeptide/tissue (red)
Fluorescence images of 3 wt.% AMCA-X (blue) labeled R180L20
Select Publications:
“Biocompatibility of Amphiphilic Diblock Copolypeptide Hydrogels in the Central Nervous System”. Yang, C.-Y.; Song, B.; Ao, Y.; Nowak, A. P.; Abelowitz, R. B.; Korsak, R. A.; Havton L. A.; Deming, T. J.; Sofroniew, M. V. Biomaterials, 2009, 30, 2881-2898.
“SANS and Cryo-TEM Study of Self-Assembled Diblock Copolypeptide Hydrogels with Rich Nano- through Microscale Morphology”. Pochan, D. J.; Pakstis, L.; Ozbas, B.; Nowak, A. P.; Deming, T. J. Macromolecules , 2002, 35, 5358-5360.
“Rapidly Recovering Hydrogel Scaffolds From Self-Assembling Diblock Copolypeptide Amphiphiles”. Nowak, A. P.; Breedveld, V.; Pakstis, L.; Ozbas, B.; Pine, D. J.; Pochan, D.; Deming, T. J. Nature , 2002, 417, 424-428.
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3)Self-assembly of block copolypeptides in aqueous solution
We are examining the self-assembly of copolypeptides containing different combinations of uncharged hydrophilic, charged, and hydrophobic domains in aqueous environments. Beyond the usual types of aggregated structures (e.g. micelles, vesicles, and lamellar phases), we hope to identify new structures that result from the secondary structures found in the polypeptide domains. By varying the placement of these discrete domains along a polymer chain, we plan to prepare new structures for biomedical applications (including drug/gene delivery, artificial membranes, and bioactive surface coatings).
Collaborators: Prof. Dan Kamei(UCLA), Prof. Lily Wu(UCLA), Prof. Tom Mason(UCLA), Prof. Darrin Pochan (U. Delaware)
Researchers: Dr. Jarrod Hanson, April Rodriguez, Jessica Kramer, Shuwen Koh, and Dr. Zhibo Li
Confocal of 1.0 wt. % FITC-R60L20 100nm FITC-labeled R60L20 vesicles,
loaded with Texas Red-labeled
dextran, incubated with and taken up
into T84 cells.
Select Publications:
“Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery” Holowka, E. P.; Sun, V. Z.; Kamei, D. T.; Deming, T. J. Nature Materials, 2007, 6, 52–57.
“Charged Polypeptide Vesicles with Controllable Diameter” Holowka, E. P.; Pochan, D. J.; Deming, T. J. J. Am. Chem. Soc. , 2005, 127, 12423 - 12428.
Uncharged Polypeptide Vesicles
(diethylene glycol-Lysine)-Leucine (KPmLn) block copolypeptide vesicles in aqueous suspension
Left: KP100L20, Right: KP150L40
Select Publication:
“Stimuli Responsive Polypeptide Vesicles via Conformation Specific Assembly” Bellomo, E.; Wyrsta, M. D.; Pakstis, L.; Pochan, D. J.; Deming, T. J. Nature Materials, 2004, 3, 244-248.
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4)block copolypeptide stablized nanoscale double emulsions
Double emulsions contain two immiscible phases (such as water and oil) within each droplet. For example, a typical double emulsion is an water in oil in water emulsion or WOW. They can incorporate multiple cargos within the same carrier making them very attractive for drug delivery and cosmetic applications. However, this complex emulsion morphology is very difficult to stabilize. Multiple steps and surfactants are needed which typically result in an unstable product. We have recently demonstrated that block copolypeptide surfactants can stabilize nanometer scale double emulsion droplets in one step with a single component surfactant. This greatly simplifies the procedure and leads to droplets with small diameters that are much better suited for a variety of biomedical applications.
Collaborators: Prof. Tom Mason(UCLA)
Researchers: Dr. Jarrod Hanson
20% PDMS in H2O
Select Publication:
"Nanoscale Double Emulsions Stabilized by Single Component Block Copolypeptides." Hanson, J.A.; Chang, C.; Graves, S.; Li, Z.; Mason, T.G.; and Deming, T.J. Nature, 2008, 455, 85-88.
For more information e-mail us at demingtATseasDOTucla.edu
