This project addresses two fundamental issues in targeted drug delivery: standardization of drug uploading onto targeting proteins and monitoring the delivery process using non-invasive imaging. A generic docking device for standardizing drug uploading and an integrated docking/imaging device for non-invasive imaging will be engineered. Both devices are made of self-assembling peptide modules. A computer-aided design procedure will be developed to program self-assembling peptide modules.
The specific aims are: 1. Develop a computer-aided design procedure to program self-assembling peptide modules Modular assembly is an emerging mode for the construction of molecular devices. Polypeptides are ideal materials for constructing artificial modular devices for two reasons: the programmability of peptide sequences and the abundance of device prototypes existing in nature. To engineer self-assembling peptide modules, a computer-aided design procedure will be developed to reprogram the modules of a prototypical device to meet specifications required by an application. The design procedure will be refined based on experimental feedbacks. 2. Engineer a generic docking device to standardize drug uploading in targeted drug delivery Standardization of drug uploading onto targeting proteins is very important for advancing targeted drug delivery. A generic docking device will be developed for this purpose. The device prototype is based on nature's smallest protein dimerization domain, the heterodimeric coiled-coil, a molecular complex assembled from two complementary a-helices. The prototypical device will be modified by the aforementioned computer-aided design procedure. In vivo docking is achieved through the self-assembly of the two modules. To standardize drug uploading, the two modules of the generic device will be made entirely of canonical proteinogenic amino acids so that one of the modules can be genetically fused to the targeting protein using standard cloning technique while the other module can be conjugated with drugs using standard solid-phase synthesis. Docking characteristics of this device will be evaluated using various biophysical techniques. Biocompatibility of this device will be tested in animal models. 3. Engineer an integrated docking/imaging device to monitor targeted drug delivery process Targeted drug delivery can be optimized if the biodistribution of both the targeting and the therapeutic moieties can be monitored by non-invasive imaging. A docking device can play the dual role of docking and imaging if proper imaging reporter groups are engineered into its modules. To form such an integrated docking/imaging device, the generic docking device will be modified to incorporate fluorinated amino acids for non-invasive imaging, using 19F NMR. Modules of this device can be fused to targeting proteins using expanded genetic code or native protein ligation. Docking characteristics of this device will be evaluated using biophysical techniques. Biocompatibility of this device will be tested in animal models. Structural and imaging properties of the integrated docking/imaging device will be characterized by NMR spectroscopy. The long-term goal is to apply the engineered devices in radioimmunotherapy of solid tumors.
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| Jiang, Zhong-Xing; Yu, Y Bruce (2007) The Design and Synthesis of Highly Branched and Spherically Symmetric Fluorinated Oils and Amphiles. Tetrahedron 63:3982-3988 |
| Jiang, Zhong-Xing; Yu, Y Bruce (2007) The synthesis of a geminally perfluoro-tert-butylated beta-amino acid and its protected forms as a potential pharmacokinetic modulator and reporter for peptide-based pharmaceuticals. J Org Chem 72:1464-7 |
| Xiao, Nu; Jiang, Zhong-Xing; Yu, Y Bruce (2007) Enantioselective synthesis of (2R, 3S)- and (2S, 3R)-4,4,4-trifluoro-N-Fmoc-O-tert-butyl-threonine and their racemization-free incorporation into oligopeptides via solid-phase synthesis. Biopolymers 88:781-96 |
