【Technical Introduction】
Cardiovascular diseases caused by atherosclerosis are the leading cause of death worldwide. According to literature, activated macrophages that can express chemokine C-X-C receptor type 4 (CXCR4) gather in large numbers at the site of atherosclerotic lesions. In order to develop small molecule CXCR4 nuclear medicine diagnostic drugs, the National Atomic Research Institute has designed a novel atherosclerotic PET Diagnosis (APD) (Figure 1) based on the CXCR4 antagonist TIQ-15 through artificial intelligence computer simulation technology. The chemical structure of the drug has been patented in the European (2025), United States (2024), Japan (2023) and Taiwan (2022). In addition to winning the Excellence Award in the basic group of the oral paper at the 2021 Taiwan Nuclear Medicine Annual Meeting. The research and development results also won the 2023 National Innovation Award's "Top Ten Highlight Technologies" and the 2024 National Innovation Award, and were invited to give speeches at related large-scale conferences in Taiwan. The results of Good Laboratory Practice (GLP) toxicity tests showed that APD did not show any toxicity even at a dose 220 times that of the human body. This drug has completed three batches of trial production under PIC/S GMP control and has been compiled into Modules 1 to 4 and the investigator brochure in the eCTD format.
Figure 1. Based on the TIQ-15 structure, a new APD chemical structure of atherosclerosis contrast agent was designed through AI computer simulation technology.
【Project Planning/Technical Applications】
In PET/CT image of atherosclerotic mice (ApoE-/-) (Figure 2), 68Ga-APD can produce accumulation in atherosclerotic lesions within 1 hour and is rapidly excreted through the kidneys and bladder. The lesion target/background ratio TBR>10, which is better than 68Ga-Pentixafor, a drug currently being used in human clinical trials internationally. Compared with the clinical drug 18F-FDG, 18F-FDG only produces a large amount of drug accumulation in the myocardium. 18F-NaF is currently only used in clinical trials for the diagnosis of calcification in mid- and late-stage lesions, so it cannot be used for the examination of non-calcified and unstable plaques.
Figure 2. Mice image of 68Ga-APD and compare with 68Ga-Pentixafor
Our study has successfully applied 68Ga-APD to non-invasively diagnose the efficacy of diabetes medications (sGLT2i) and bromelain. Subsequently, we have evaluated the effects of common cardiovascular-related health supplements on the market (natto-kinase, red yeast rice, and lumbrokinase). After cross-comparison with the data of biochemical tests in the blood (cholesterol, triglycerides, etc.), we found that various health supplements have different effects on improving blood lipids and vascular plaques. This technology platform will be an effective tool for the development of health supplements or rapid screening of clinical therapeutic drugs in the future.
This study also cooperated with the engineering institute, industry, academia, and medical teams to develop an artificial intelligence-assisted atherosclerosis lesion location and grading decision support system (ADSS). The system core program was developed using Taiwan's open source WEB medical imaging browser system (Bluelight), which has clinical experience in domestic medical institutions. In conjunction with the cardiology medical team, the atherosclerosis imaging data of different sclerosis programs were used by experts to mark the lesion area, and at the same time, the sclerosis degree grading index was defined to provide reference samples for artificial intelligence learning. After AI training, an accurate and effective model will be established and built into the system to provide AI identification of atherosclerotic lesions in original images. The identification results will be able to accurately mark the atherosclerosis area, 3D positioning, and expert recommended indicators for the degree of atherosclerosis. This system will be designed with relevant modules that can be linked to the hospital system, provide report printing functions, and print reports based on relevant chart information identified by AI in combination with patient data, providing them to the medical team for evaluation. This system uses the latest global commercial 3D MR technology to display the AI training recognition results through a head-mounted display and present the 3D images of the atherosclerotic lesions through a 3D MR display platform, providing the medical team with preoperative communication, intraoperative assistance, and postoperative tracking. (Figure 3)
Figure 3. Medical AI development functional interface and process 3D MR display
【Future Development】
Atherosclerotic vulnerable plaques formed by fat accumulation can cause narrowing or blockage of arteries, easily leading to coronary artery disease, stroke and other diseases. Currently, non-invasive CT, MRI, ultrasound and commonly used radiopharmaceuticals (such as Tl-201, etc.) are only suitable for image mid- to late-stage atherosclerosis, and are not suitable for the detection of systemic vascular plaques.
Ga-68-APD has completed GLP toxicology testing, chemical manufacturing and control (CMC) documentation, PIC/S GMP process and analytical technology, and pharmacokinetic absorption and metabolism analyses. It has also completed the relevant eCTD documents required for clinical trial applications. It is expected that formal application for human trial ethics committee (IRB) and TFDA review will be submitted in September 2025. Once approved, the phase I human clinical trials will be arranged.
Taking into account the convenience of international transportation, the APD kit has been developed in a liquid dosage form that has undergone terminal sterilization. It can then be labeled with Ga-68 washed out from a Ge-68 generator and used clinically by hospitals around the world. This way, it will not be limited by the half-life of radioactive isotopes.
In the future, we will establish a knowledge database on atherosclerosis symptom classification exclusively for the people and apply it to longitudinal studies related to atherosclerosis to achieve the effects of intelligent diagnosis and preventive warning. We will also complete the product registration and technology transfer procedures for the artificial intelligence-assisted atherosclerosis lesion location and classification decision support system (ADSS), and complete the TFDA artificial intelligence medical device inspection and registration application. We expect that the introduction of AI-assisted decision support system will improve the technical level and service quality of medical institutions, increase market competitiveness, attract outstanding medical talents, improve the level of medical teams, apply this system to the diagnosis of various types of cardiovascular diseases, expand the service scope of medical institutions, and create more business opportunities.
According to the World Health Organization (WHO), the number of deaths from cardiovascular diseases will reach 23.6 million in 2030. Due to the aging population, changes in lifestyle and increased awareness of cardiovascular diseases, the global market for cardiovascular angiography is growing rapidly at 6% per year. APD can be used to diagnose mild to severe systemic unstable plaques that cause vascular obstruction, and the radiation dose received by the human body is only 2.8% of that of Tl-201. This chemical structure has been patented and will be promoted mainly in European and American countries with larger markets in the future to expand the scope of application and create a more efficient business model. We look forward to early detection, early treatment and efficacy tracking, so as to achieve the substantive goal of improving the health and well-being of people around the world.
【Contact Information】
Name： Chien-Chung Hsia Ph.D
Tel：03-4711400 Ext. 7159
E-mail：hsiacc@nari.org.tw
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