The ability to target imaging agents or drugs specifically to diseases has been a major medical goal for decades. Targeting is attractive because it would direct more of the agent to the disease site, which improves potency, while also reducing concentrations in normal tissues, which prevents detrimental side effects. Nanoparticle carriers have received considerable attention for targeting applications due to numerous attributes including high-loading capacity, protection of the agent, facile attachment of targeting molecules, and favorable pharmacokinetics. Another advantage of nanoparticles is that they are large enough to serve as a scaffold for forming multiple bonds with target cells, which is referred to as multivalent adhesion. It is well known that multivalent adhesion can enhance binding strength, but little is known about how this effect can be controlled. A major reason that a high level of control is necessary is because disease biomarkers are often present on both normal and diseased cells, but at different levels. Ideally the nanoparticle would display a switch-like change in binding such that there was no adhesion to normal cells and maximal adhesion to diseased cells to maximize targeting selectivity. However, achieving this type of behavior has remained elusive. Thus, entirely new strategies and technologies are needed that go beyond basic adhesion concepts, and instead enable adhesion to be tailored in a dynamic manner. If successful, molecular targeting of diseases inside the body would dramatically change diagnostic and treatment paradigms, enabling early detection and personalized medical practices. Concepts underlying this work will be conveyed in educational outreach programs focused toward K-12, undergraduate, and graduate students to spur interest in biomedical engineering. The educational plan involves: (1) developing new course content, (2) mentoring student researchers at various education levels, and (3) developing K-12 outreach programs to encourage young students to pursue science and medicine.
The ultimate goal of this proposal is to develop a versatile and robust computational design platform for controlling multivalent nanoparticle binding and achieving super selective adhesion. This will be accomplished by significantly advancing the novel experimental and computational simulation methods developed by the research team in previous work. The researchers will use vascular inflammation and the target molecule ICAM-1 as a model system. ICAM-1 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. The PIs will first add new simulation capabilities, including the phase of initial attachment from free solution and extension of the methods to nanorods. The PIs will then focus on experimentally testing new molecular bond properties. Finally, the PIs will adapt the simulation to live cells and design and test prospective affinity molecule-nanoparticle formulations that can exhibit super selective targeting behavior. This complex behavior is currently unprecedented, and thus will require the new tools to understand. At the conclusion of the work, the simulation will be positioned to serve as a predictive tool for designing nanocarriers that possess unique and powerful adhesive properties. Concepts underlying this work will be conveyed in educational outreach programs focused toward K-12, undergraduate, and graduate students to spur interest in biomedical engineering. The educational plan involves: (1) developing new course content, (2) mentoring student researchers at various education levels, and (3) developing K-12 outreach programs to encourage young students to pursue science and medicine.
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.
