Nanomaterials-based therapeutics and imaging agents are promising for disease treatment and diagnosis. Several nanomedicines have been approved by the U.S. Food and Drug Administration, and more are under rigorous clinical studies. However, nearly all synthetic nanomaterials are quickly cleared in the bloodstream of patients after systemic administration, limiting their biomedical applications. In the blood, plasma proteins immediately adsorb onto nanomaterial surfaces. Some of the adsorbed proteins mark nanomaterials as foreign invaders, like bacteria, and this results in their clearance by the host cells. The rational design of long circulating nanomaterials depends on a thorough understanding of the interactions among nanomaterials, proteins, and cells. Currently, there is a dearth of systematic study of these interactions. The research team will establish a comprehensive understanding of nanomaterial-protein-cell interactions for developing a new generation of polymers. When grafted onto nanomaterials, these polymers are expected to dramatically extend the blood circulation of nanomaterials by minimizing protein adsorption and controlling the kinetics of nanomaterial-cell interactions in the blood flow. Ultra-long circulating nanomaterials may have tremendous societal benefits by improving the delivery of therapeutics. The polymer may also be used as an antifouling coating for insulin pump catheters, dialysis membranes, neural electrodes, and materials in direct contact with microbial environments. The knowledge gained through this research will be integrated with educational and outreach activities to inspire students to pursue high-level education in science, technology, engineering and math. Furthermore, the research team will engage kindergarten children in the use of materials science as an investigative tool and thereby explore the impact of early scientific education on students.
Cloaking nanomaterials with a grafted polymer layer is the most widely used approach to extend nanomaterials blood circulation. However, the circulation half-lives of nearly all synthetic nanomaterials are less than a few hours, restricting their applications. A new generation of stealth cloaks that enable ultra-long circulation of nanomaterials will open the door for new applications. The objectives of this proposal are to (i) achieve an in-depth understanding of nanomaterial-protein-cell interactions and (ii) develop an innovative zwitterionic polyether cloak with controlled dynamic surface morphology to efficiently reduce protein adsorption and complement activation on nanomaterials, and interfere with nanomaterial-cell interactions for generating ultra-long circulating nanomaterials. These objectives cannot be fully achieved using existing zwitterionic polymers. The rationale of this proposal is based on the novel findings that liver sinusoidal endothelial cells can be as important as Kupffer cells in clearing some types of nanomaterials, and that the fluctuation of grafted chains kinetically affect nanomaterial-protein interactions, decreasing nanomaterial clearance by cells in the liver, especially liver sinusoidal endothelial cells. To demonstrate the broad application of the dynamic cloak, representative organic and inorganic nanomaterials grafted with hierarchical flexible zwitterionic polymers will be investigated. The proposed study will advance the understanding of interactions between nanomaterials and biological systems at a molecular level, which is critical for applying nanomaterials in healthcare and environmental safety.
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.
