Our research
is on the development of new synthetic methodologies as well as the use of biological precedents and strategies for the design of new materials. Our lab continues to take on significant new challenges in the exploration of applications of our materials for interaction with biological systems and for medicine, as well as development of new economical and scalable preparative routes to more complex and functional polypeptide architectures.

Polypeptide Synthesis
NCA Monomer Preparation and Polymerization

The building blocks of synthetic polypeptides. N-carboxyanhydrides (NCAs) can often be prepared in large scale (grams to kilograms) in a single step from amino acids.
Polypeptide Synthesis via Catalysis

catalystmeth1.png catalystmeth2.png
Our catalysis chemistry allows allows living polymerization of NCAs with significant rate enhancement over conventional initiators.
Functional Polypeptides
Introducing Biological Functionality into Polypeptides

Synthesis of Functionalized NCAs

The use of functionalized NCAs allows direct incorporation of biologically relevant functional groups in precise locations in chains, but may require multiple synthetic steps and tedious purification.
Post-Polymerization Functionalization via Methionine Modification

MethOxi.png MethAlkyl1.png
Our methodology utilizes methionine NCA, derived from the natural amino acid and readily prepared and polymerized without need of protecting groups. High yield, efficient modification of thioether groups after polymer formation provides a scalable route to highly functional, and biologically relevant polypeptides.
Polypeptides with Switchable Chain Conformations

Our lab has discovered that functional polypeptides based on poly(homocysteine) backbones can undergo reversible switching between alpha-helical and disordered conformations via mild, and reversible chemical modifications under biologically relevant conditions.
Thermoresponsive Polypeptides

Using methionine alkylation and demethylation methodology, we prepared a series of oligoethylene glycol functionalized poly(homocysteine) derivatives, all from the same parent poly(methionine) sample. These polymers undergo reversible temperature dependent solubility transitions (lower critical solution temperature behavior) in aqueous media. These and related polypeptides are being developed for use in stimuli responsive block copolypeptide assemblies.
Block Copolypeptide Assemblies
Multidomain Block Copolypeptide Self Assembly

catalystmeth1.png catalystmeth2.png
This methodology allows the synthesis of well defined block copolypeptides through sequential additions of different monomers to the growing chains. Our lab has pioneered the self-assembly of amphiphilic block copolypeptides in water into a variety of structures with tunable properties.
Applications of Polypeptides in Biology
Diblock Copolypeptide Hydrogels (DCH) for Central Nervous System Repair

In collaboration with the lab of Prof. Michael Sofroniew (Neurobiology Dept, UCLA), were are developing polypeptide hydrogels for study of biology and neural repair in central nervous system (CNS) tissues. Synthetic DCH have been designed with tunable physical properties (stiffness, porosity, chemical functionality), and can be degraded in vivo. We have shown that many DCH formulations form hydrogel deposits and are well tolerated in healthy mouse forebrain tissue. DCH are being developed to encapsulate and release both hydrophilic (e.g. protein) and hydrophobic (e.g. small molecule active agent) cargos within CNS tissues. We are also developing DCH formulations to encapsulate neural progenitor stem cells (NPSCs) to allow cell grafting within CNS tissues, and to provide biomimetic scaffolds for encapsulated cells. Recent efforts have focused on study and development of DCH formulations to facilitate neural repair after spinal cord injury.
Encapsulation of Hydrophobic Molecules within DCH

The hydrophobic domains of DCH are able to dissolve small hydrophobic molecules. These can be small molecule drugs or signalling molecules.
Tuning of Cargo Loading Capacity and Release Rate

Variation of hydrophobic segments in DCH allows adjustment of loading capacity and release rate
Encapsulation and Release of Growth Factors (proteins) in DCH

Release of nerve growth factor (NGF) from a DCH depot in healthy mouse forebrain shows biological effects on cholinergic neurons (ChAT) in vivo, where they respond to NGF by increasing in size. DCH provide prolonged release of NGF compared to injection of NGF in saline.
Encapsulation and Release of Small Molecules in DCH

Release of Tamoxifen from a DCH depot in the lesion core of a spinal cord injury model in mouse shows biological effects on scar forming astrocytes. In the astrocytes (also identified using GFAP), Tamoxifen activates reporter gene expression of green fluorescent protein (GFP) in transgenic mice.
Non-Ionic DCH for Cell Grafting

To improve cell compatibility, non-ionic DCH were developed. In the initial design, oligoethylene glycol functionalized polypeptide segments were used to replace cationic lysine segments found in original DCH. These DCH were able to support encapsulated NPSCs, which could then be grafted into CNS tissue with high viability and integration with host tissue.
Poly(Methionine Sulfoxide) based Non-Ionic DCH

MOXhydrogel.png MOXhydrogel2.png
As we continue to develop and optimize our DCH formulations, we have switched from unnatural oligoethylene glycol based hydrophilic segments in non-ionic DCH to use of natural poly(methionine sulfoxide) segments (DCHMO). The sulfoxide functionality in these hydrogels possesses non-fouling properties (similar to PEG), but gives DCH that are degradable and resorbable, in addition to being less expensive and easier to synthesize. DCHMO is currently being used for a variety of NPSC grafting studies in mice.
Polyion Complex DCH (DCHPIC)

PIChydrogel.png PIChydrogel1.png
Another recent development has been the design of DCH that can assemble via polyion complexation as opposed to hydrophobic interactions. By taking advantage of the ability of enantiomerically pure poly(lysine) and poly(glutamate) segments to form beta-sheet structured polyion complexes, we were able to form DCH that retain the functionality of DCHMO, but are assembled via stronger electrostatic and H-bonding interactions. The result is DCHPIC that are significantly more resistant to dissolution compared to DCHMO, and can be prepared with much greater stiffness as two-component formulations while retaining cell and tissue compatibility.