NSF Award
2217474
Research in drug delivery by polymeric carriers is still in its infancy. The demanding challenge in this field is to find the right carrier architecture and the optimum polymer chemistry that can facilitate controlled delivery and release of therapeutic agents (drugs) to their targets. A unique carrier is invertible polymer micellar assemblies, which are formed by the rapid self-organization/assembly of polymers with alternated and repeated hydrophobic (water-hating) and hydrophilic (water-loving) segments in a rod-like shape (tens of nanometers long). Drugs and polypeptides/nucleic acids which can treat various diseases but cannot be directly introduced to human body can be incorporated into invertible micellar assemblies. Once the environmental conditions are changed (i.e., when the assemblies from water “arrive” to the cellular membrane), the invertible micellar assemblies reverse their dimensions and geometry (shape) in a smart way to effectively deliver and release cargo molecules to the targets (biological membranes) and, thus, treat relevant diseases. Although the structure and dynamics of invertible micellar assemblies have been understood to a certain level, the key questions that still need to be answered are (i) what properties of cargo-loaded invertible micellar assemblies make them efficient in treating diseases (ii) how significant is a fact of unique change of shape (called “inversion” in this project) for efficient delivery performance. Answering these questions require an in-depth understanding on the interactions between drug cargos and invertible micellar assemblies under varied environments at the molecular level, which is a challenging task because most commonly seen techniques do not have a sufficiently high resolution to “penetrate” the assemblies and probe biopolymer cargos therein. In this project, researchers from the North Dakota State University bridge this knowledge gap by labelling biopolymers and studying the behavior of the labeled sites using a unique technique known as Electron Paramagnetic Resonance spectroscopy. The obtained data will provide details on how invertible micellar assemblies interact with the solvent environment and the biopolymer cargos as well as how the cargos move and/or aggregate within the interior of invertible micellar assemblies. This information not only answers aforementioned questions but also assists in the rational design of new delivery vehicles that better adapt/deliver biopolymers and/or drugs, broadening the application of invertible micellar assemblies as general drug carriers to treat various diseases. The research team will provide training to underrepresented students including Native American students and local undergraduate and high school students on nanotechnology and chemistry. The team will also offer scientific educational opportunities for youths whose parents are deployed as soldiers through the Operation Military Kids program in the state of North Dakota.<br/><br/>This project aims to understand the interactions among the invertible micellar assemblies, cargo, and environment (solvent) at the nanoscale, in order to reveal the mechanistic details in the interior of invertible micellar assemblies when biopolymer cargos are loaded and released due to environment polarity changes. This goal will be achieved via three steps: (i) revealing the changes in the morphology, crowding, and polarity of invertible micellar assemblies under varied solvent conditions, (ii) depicting the impact of biopolymer cargo loading on the morphology, crowding, and polarity of invertible micellar assemblies in water, and (iii) elucidating the movement and aggregation state (if any) of the biopolymer within invertible micellar assemblies upon environment polarity change. The key to acquiring this knowledge is to covalently place an Electron Paramagnetic Resonance spin probe/tag at specific locations/positions within the invertible micellar assemblies and on biopolymers, followed by Electron Paramagnetic Resonance spectroscopy study of (bio)polymer structure and dynamics. This research will provide maps of the local crowding and polarity within the invertible micellar assemblies under various solvent conditions and locate various segments of biopolymer cargos (connecting which lead to cargo conformation) in the invertible micellar assemblies based on the local crowding and polarity of the cargo. The obtained knowledge offers a direct connection between the microenvironment of invertible micellar assemblies and cargo structure/hydrophobicity/polarity to assess and rationalize the relative strength of the interactions between invertible micellar assemblies and cargos. This work will also use the information of cargo location and cargo movement to depict the relative position of cargos upon interacting with the invertible micellar assemblies. Lastly, this research will elucidate the possible structural changes of cargos, if any, caused by the interactions between invertible micellar assemblies and cargos. All of these efforts will result in an in-depth understanding of the cargo uptake/release performance and the interactions between invertible micellar assemblies and cargos. This project will also provide training to students at various educational levels (high school, undergraduate) from diverse backgrounds by offering hands-on research experience in cutting-edge nanotechnology, biopolymer engineering, and spectroscopy. The obtained knowledge and experimental approaches from research activities will be disseminated through scientific peer-review journal publications, national/international conferences, and local science fairs.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
