Part I: Non-technical summary Recent attempts to mimic the anti-biofouling properties of the external membrane of mammalian cells on synthetic substrates are increasingly relying on the use of zwitterionic-based materials, i.e., those bearing positively and negatively charged groups. In the context of biomaterials intended for drug delivery applications, surface modification methods that preclude aggregation, precipitation or clearance of diagnostic or therapeutic nanoparticles are particularly important to extend their circulation time in the body, and allow them to accumulate at specific sites through active targeting. Despite the tremendous potential of zwitterionic-based materials, little is known regarding weak interactions between particles and cells due to the limited sensitivity of existing techniques. In this work, the PIs will measure nanometer scale interactions between cells and zwitterionic-decorated particles using non-intrusive microscopy measurements of particle trajectories and analyses that reveal weak interactions. The PIs will use this method to evaluate interactions between nanoparticles functionalized with zwitterionic polymers with well-defined molecular architectures and cell surfaces. Outreach efforts will involve participation of undergraduate students in research, and community involvement through an education-based Latino outreach program and STEM Achievement in Baltimore Elementary Schools.
Part II: Technical summary The proposed research will provide fundamental and technological insights into the molecular and processing parameters that produce zwitterionic (ZI) particles having the desired combination of specific and non-specific kT-scale interactions with various biomaterials. Non-specific repulsion between zwitterionic species and biomaterials will be understood, designed, optimized by controlling molecular architecture and structure, which will be quantitatively connected to direct sensitive measurements and models. Specific interactions to be investigated include sigma receptor-anisamide and CD44-hyaluronic acid interactions. The work proposed is divided into four tasks. The first deals with ZI polymer design, synthesis and characterization. The goal is to produce a library of materials with increasing architectural complexity that should translate into distinct surface properties. The second task is to examine ZI particle formation through either copolymer adsorption onto silica particles or self-assembly of highly branched amphiphilic macromolecules using processing conditions to affect ZI particle surface properties. The third task is to carry out diffusing probe measurements of ZI particles with model synthetic substrates, to ultimately establish the combination of polymer architecture and adsorption/self-assembly conditions that will result in desired non-specific repulsion. Having established this, the last task of this proposal is to use this knowledge to carry out diffusing probe measurements of specific interactions between ZI particles decorated with specific moieties and cancer cells. Such measurements will be performed for breast cancer cells to study interactions between hyaluronic acid and CD44 receptors, as well as, anisamide and sigma receptors. Each of the four tasks is part of an overarching plan to measure and interpret how particle-cell interactions are influenced by covalent attachment, orientation, and organization on synthetic and cell surfaces in nanobiotechnological applications.
