Radiochemical biology · nuclear pharmaceuticals

 

          Research in the Liu group focuses on the development of novel radiochemistry for Positron Emission Tomography (PET) and radiotherapy. We seek to discover molecular structure and activity that can contribute to interdisciplinary solutions for long-standing challenges in clinics. The lab focuses on synthetic organic/bioconjugate chemistry, late-stage radiolabeling, PET imaging and mechanistic studies to pursue the molecules of interest in the early diagnosis, patient selection and tailored treatment.

1. Develop new radionuclides and liquid target system for nuclear molecular imaging, cancer therapy and radiochemistry

                                                            

          As the core of nuclear medicine, new radionuclides give infinite possibilities for new PET/SPECT tracer and molecular radiotherapy strategy. Besides, high energy nuclide can be used to generate more Cherenkov photons (1.33 for one F-18 decay, 33.9 for Ga-68 and 47.3 for Y-90) to improve the efficiency of biomolecular regulation.

    Equipped with one of the few cyclotrons at Chinese universities, we can produce various radionuclides for different demands. In May 2017, we succeeded in producing Zr-89, which has not been produced since the 1990s in China. Zr-89 is the isotope of choice for antibody labeling, and it has been applied for radiolabeling PD-L1 antibody in our laboratory and is planning for preliminary clinical study for patient screening. In addition, Ac-225 was proposed as the next generation nuclide for radiotherapy, but it was never produced in China. Using 100 MeV cyclotron, we are planning to produce Ac-225 through Th-232(p, x) Ac-225 reaction.

           Most cyclotrons for metal nuclide use solid target, which needs a complicated delivery system and technological process. To meet this challenge, we are developing a liquid target so as to offer a practical and broadly applicable way for the various clinical cyclotron to obtain different metal nuclides.

2. Boron–Fluorine Bond Formation: A Broadly Applicable 18F-Labeling for Positron Emission Tomography

                                                                  

           A long-term goal of our research is to investigate the mimics of carboxylate (-COO-) to develop small-molecule tracers for positron emission tomography (PET), a powerful imaging technique to study biological processes in vivo. We radiolabel amino acids, fatty acids, peptides and other molecules based on the boron-fluorine bond formation at the very last step. Ultimately, we envision engaging in translational research through new and existing collaborations with physicians and imaging experts to affect the broadest possible impact of our science.

    Cancer is inextricable from inflammation. When cancer initiates, inflammation is a key promoter to stimulate neoplastic progression; while cancer growths, tumor cells produce an abundance of pro-inflammatory cytokines can lead to a level of inflammation, that potentiates angiogenesis for further cancer development. Cancer, especially at early stage, is morphological and functional similar to chronic inflammation, resulting a long-standing challenge to differentiate inflammation from cancer for early cancer detection. To assess the malignancy of a questionable lesion, an invasive and costly operation such as biopsy or surgery is often required. In last decade, positron emission tomography (PET) with 18F-FDG opens an opportunity to non-invasively diagnose abnormal metabolic activity in patients. However, because 18F-FDG accumulation in tumor cells depends on glucose metabolism, in addition to accumulating in fast-growing tumors, FDG highlights any tissue with high energy consumption, such as brain and inflammation. Contradictory to the urgent need for early cancer diagnosis, no non-invasive imaging probe is virtually available that can be generally useful to identify cancer from inflammation.

    Previously, a head-to-head comparison is performed between 18F-FDG and 18F-boramino acid (BAA) within same animals, and we found that radioactive BAA exhibits equal if not higher uptake in xenografts tumors, but almost negligible uptake in inflammatory tissues. We conclude that boron-derived amino acid coordinates a superiority over FDG from both endogenously high metabolic stability and exogenously high tumor selectivity, and we hypothesize that this boron-deriving strategy is broadly applicable to other amino acids and their derivatives, and may contribute to identifying next-generation chemotherapy drugs through LAT-1 targeting.

3. Boron Neutron Capture Therapy (BNCT)
  Boron neutron capture therapy (BNCT) is a binary, biochemically-targeted radiotherapy which provided excellent tumor control over locally invasive malignant tumors such as melanoma, glioblastoma and recurrent head and neck cancer. The damage of BNCT to cancer cells is based on the reactions that occur when irradiating low energy thermal neutrons to non-radioactive boron-10 to yield high linear energy transfer (LET) and high relative biological effectiveness (RBE) radiations, including alpha particles and recoiling lithium-7 nuclei, within the radius of one single cell, thereby resulting in the death of cancer cells. Currently, BNCT is suffering from lacking high-efficient tumor-selective boron delivery agent, and consequently, the progress of clinical translation is rather slow. We are trying to develop novel theranostic boron delivery agents to solve those problems mentioned above.

    Figure 1A. A schematic illustration of the mechanism of boron neutron capture therapy (BNCT). A beam of thermal neutrons is required to reach the malignancy after penetrating the normal tissue. Once there the thermal neutrons slow down and these low-energy neutrons combine with boron-10 (delivered in advance to the cancer cells by tumor targeting drugs) to form metastable boron-11, then releasing lethal radiation (alpha particles and lithium ions) that can kill the tumor precisely.

    Figure 1B. Compared with other groups, mice pre-injected with drug followed by neutron-irradiation have been shown effective local tumor control without exhibiting systemic toxicity.

4. Radionuclide as a depth-independent Photon Emitter for regulation of biomolecular in vivo

    The poor tissue penetration of light has been a long-standing challenge for in vivo optical imaging, photoactivatable conversions, and photodynamic therapy. In general, light from outside can hardly go beyond several millimeters. Radionuclides have been used in the diagnosis and treatment of cancer through its targeting and energy release from nuclear decay. We noticed that the energy from nuclear decay (e.g. Cherenkov radiation) can ignite certain chemical reactions. We hope to use the radiation to trigger some biomolecular and biological processes in vivo so as to break the depth limitation of traditional photo-regulation in living animals.