The overall goal of the project is the development of microfluidic technology for the synthesis of biomolecule (peptide/antibody) targeted nuclear imaging probes for cancer. Currently, such probes need to be synthesized by research-level synthetic chemists experienced in radio-synthetic protocols. These methods typically require HPLC purification post-labeling which adds additional time and potential radiation exposure to the preparation. The development of an automated, reliable, and robust kit-like platform for the preparation of biomolecule based imaging probes for either Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging would greatly benefit both, preclinical research and clinical imaging. The proposed project focuses on the development of a microfluidic based platform capable of preparing three broad types of imaging probes consisting of: (1) a targeting biomolecule-bifunctional chelate conjugate which is then radio labeled with a desired radio metal, (2) a targeting biomolecule to which a pre-radio labeled bifunctional chelate can then be conjugated, and (3) a core molecule to which one or more targeting peptides (or optical imaging probes) will be conjugated along with a bifunctional chelate to complex the appropriate radio metal The ability of microfluidics to improve both chemical syntheses by using small volumes of highly concentrated reagents, and improved radio labeling in aqueous conditions with widely utilized radio metals provides the basis for a flexible, efficient, and automated platform for the combinatorial optimization of the syntheses or routine production of an expansive diversity of imaging agents which could greatly aid in the detection of tumors and their metastases.
The specific aims of the project are: 1. Develop microfluidic devices for covalently attaching the various probe components together, radio labeling the imaging probe with a desired radio metal, and purifying the molecular probe. 2. Test and validate the microfluidic devices and conjugation reactions by using them to prepare radio labeled peptides used for cancer imaging, with commonly used bifunctional chelate groups and radio metals. 3. Test and validate the radio labeled peptides in a well developed tumor bearing animal model to ensure that the probes function in vivo. 4. With the successful development of the individual devices, develop a single integrated device incorporating the optimized versions of the individual devices of the first aim.
The use of microfluidics has been shown to be beneficial in the radio labeling of peptides used as imaging probes for cancer diagnosis or as radiotherapy agents. This project seeks to develop a versatile, automated microfluidic platform for producing such imaging probes eliminating several of the drawbacks limiting wider adoption of such probes.
|Whittenberg, Joseph J; Li, Hairong; Zhou, Haiying et al. (2017) ""Click Chip"" Conjugation of Bifunctional Chelators to Biomolecules. Bioconjug Chem 28:986-994|
|Wright, Brian D; Whittenberg, Joseph; Desai, Amit et al. (2016) Microfluidic Preparation of a 89Zr-Labeled Trastuzumab Single-Patient Dose. J Nucl Med 57:747-52|
|Li, Hairong; Whittenberg, Joseph J; Zhou, Haiying et al. (2015) Development of a microfluidic ""click chip"" incorporating an immobilized Cu(I) catalyst. RSC Adv 5:6142-6150|
|Li, Hairong; Zhou, Haiying; Krieger, Stephanie et al. (2014) Triazine-based tool box for developing peptidic PET imaging probes: syntheses, microfluidic radiolabeling, and structure-activity evaluation. Bioconjug Chem 25:761-72|
|Goyal, Sachit; Desai, Amit V; Lewis, Robert W et al. (2014) Thiolene and SIFEL-based Microfluidic Platforms for Liquid-Liquid Extraction. Sens Actuators B Chem 190:634-644|
|Zeng, Dexing; Desai, Amit V; Ranganathan, David et al. (2013) Microfluidic radiolabeling of biomolecules with PET radiometals. Nucl Med Biol 40:42-51|