【Technical introduction】
The literature review shows that a large number of activated macrophages expressing the chemokine C-X-C receptor type 4 (CXCR4) will accumulate at the lesion site. In order to develop small molecule CXCR4 radiopharmaceutical, the National Atomic Research Institute(NARI) used computer simulation technology to antagonize CXCR4. Based on the agent TIQ-15, a new atherosclerosis contrast agent APD (Figure 2) was designed. The chemical structure of the drug has been patented in the United States (2024), Japan (2023), and Taiwan (2022) (the EU patent is under review). In addition to the winner of the merit award in the basic group for the oral paper at the 2021 Taiwan Nuclear Medicine Annual Conference, this research also won the 2023 National Innovation Award, and were further selected as the annual "Top Ten Highlight Technologies". The results of the toxicity pre-test found that APD did not have any toxicity at a dose exceeding 1,500 times that of the human body.


Figure 1. Process of Atherosclerotic Lesions and Current Clinical Use


Figure 2. Based on the structure of TIQ-15, a new atherosclerosis contrast agent APD is designed through computer simulation technology.

【Project Planning/Technology Application】
Using atherosclerosis model (ApoE^-/-) mice for PET angiography, APD can produce drug accumulation in the atherosclerotic lesions within 1 hour, and it is rapidly excreted from the body through the kidneys and bladder. The target/background ratio (TBR)=17.68 ± 0.71 (n=3), which is at least 5 times better than the current internationally used drug Gallium-68-Pentixafor in human clinical trials. If compared with the clinical drug Fluorine-18-FDG, it only produces a large amount of drug accumulation in the myocardium, and the diagnostic specificity of atherosclerotic lesions is not ideal. Fluorine-18-NaF is only suitable for angiographic diagnosis after calcification occurs in the middle and late stages of the lesion, so it cannot be used in diagnostic early stages of illness. (Figure 3)


Figure 3. PET angiography was performed on atherosclerosis model mice. Ga-68-APD can produce drug accumulation in the lesion site, and the image is significantly better than Ga-68-Pentixafor and F-18-FDG.

NARI has carried out research cooperation with National Taiwan University Hospital and the School of Medicine, and successfully applied APD to non-invasively diagnose the effects of diabetes medication (sGLT2i) and bromelain. Subsequently, NARI has also used APD to diagnose the effects of common cardiovascular-related biotech foods (such as Natto, red yeast rice and Lumbrokinase) to evaluate the effect (Figure 4), and cross-compared the data with the blood biochemical test (cholesterol, triglyceride...etc.) data. The results found that various biotech foods are effective in improving blood lipids and blood vessel plaques have different effects. If they are mixed and consumed, the effects will show different additive or inhibitory results. Therefore, this technology platform will be the basis for the future development of compound biotech foods or clinical therapeutic drugs as an effective tool for rapid screening.


Figure 4. Using the Ga-68-APD technology platform to evaluate the efficacy of cardiovascular-related biotech foods.

【Future layout】
Cardiovascular disease is one of the leading causes of death in the world. Fat accumulation leads to the formation of atherosclerotic plaque, which narrows or blocks arteries and causes coronary artery disease, stroke and other diseases. Currently, non-invasive treatments such as computed tomography, magnetic resonance imaging, ultrasound and commonly used nuclear medicine drugs (such as Thallium-201-TlCl, Fluorine-18-NaF, etc.) are suitable for imaging of intermediate and advanced atherosclerosis only, but not suitable for systemic vascular plaques detection.
 
APD will establish drug preclinical animal safety test evaluation data and PIC/S GMP manufacturing process and analysis validation technology, combine the absorption and metabolism of pharmacokinetics, complete the relevant eCTD documents required for clinical trial application, and implement the design of clinical trials and apply with the IRB. APD will be developed in a lyophilized kit and be able to be shipped around the world in the future, regardless of the half-life of the radioactive isotope.
 
According to data from the World Health Organization (WHO), the number of deaths from cardiovascular disease will reach 23.6 million in 2030. With the trend on aging of the population, changes in lifestyle and the increased awareness of cardiovascular disease, the global market for cardiovascular imaging is growing rapidly at 6% per year. The overall growth rate of Taiwan's biotech food market is also as high as 5.6%, among which functional foods for regulating blood lipids account for the most. APD can be used to diagnose mild to severe systemic vascular occlusion, and the radiation dose received by the human body is only 2.8% of thallium-201; this chemical structure has been patented and will be targeted at the markets in Europe and American states in the future. By carrying out the strategy in promotion and expanding the scope of application to create a more efficient business model, when early detection successfully introduce early treatment and efficacy evaluation, we can approach the substantive goal of improving the health and well-being of people around the world.


【Contact information】
Name: Chien-Chung Hsia. Researcher
Tel: 03-4711400 ext 7159
E-mail: hsiacc@nari.org.tw