This award to University of Washington by the Biomaterials program in the Division of Materials Research is to develop a dual-functional zwitterionic biomaterial based on carboxybetaine (CB) as an alternative to poly(ethylene glycol) for targeted drug delivery. CB is a dual-functional material, which is not only highly resistant to nonspecific protein adsorption, but also has abundant functional groups convenient for ligand immobilization. The availability of abundant functional groups in a non-fouling background is essential to the success of targeted drug delivery in complex environments. Abundant functional groups will allow one to prepare conjugates containing cocktail drugs for better drug efficiency, to introduce multiple functional groups for multiple-step drug delivery, and to immobilize small ligands for improved drug delivery kinetics. Furthermore, carboxybetaine is a smart material responsive to changes in ionic strengths and pH values, which are desirable for drug controlled release. Due to a zwitterionic nature similar to proteins, CB-coated nanoparticles (NPs) are sterically very stable under physiological conditions. Carboxybetaine is similar to glycine-betaine in structure and is thus biomimetic. The objective of this work is to demonstrate the uniqueness (i.e., dual-functional and zwitterionic characteristics) of CB-coated nanoparticles as targeted drug delivery carriers. NPs of 50-150nm will be coated with CB. The chain lengths and densities of the CB-based polymer and the number of carbon atoms between the two charged groups of the CB monomer will be varied. CB-coated NPs will be evaluated for their physicochemical properties, their steric stability under physiological conditions, and their resistance to nonspecific protein adsorption from blood plasma. CB-coated NPs will be functionalized with targeting groups for cancer cells via carbodimide chemistry and evaluated for their cell association and uptake. Ligand densities will be varied to study their effects on targeted delivery. The circulation time of these modified NPs will be evaluated. Results will be compared with those from poly(ethylene glycol)-modified NPs with or without the targeting groups.
The ability of drug carriers to target specific cell types is critical for effective drug delivery. While PEG has been widely used to improve the efficacy of drug delivery carriers, there are a very limited number of functional groups available to immobilize target-specific ligands. The dual-functional zwitterionic biomaterial proposed in this work is well suited for this purpose. The success of this work will open a new direction to build better drug delivery systems. Although CB-based materials used for drug delivery carriers will be demonstrated in this work, they have a very broad range of applications in tissue engineering, coatings for medical devices, and biomedical diagnostics. Graduate and undergraduate students will be involved in this project, particularly those from underrepresented groups. Undergraduate researchers will be recruited through well-established outreach programs at local research centers, in which the PI has been actively involved. In addition, the knowledge will be disseminated through various courses taught or under development by the PI. The proposed work will also involve international collaborations.
