Photodynamic therapy (PDT) traces its origin to Germany in 1900. The first significant observation was made by Oscar Raab, a medical student in University of Munich, no noticed that paramecium thrived in culture medium containing acridine and similar dyes in dark condition, but died exposed to light. Further investigation indicated that the phenomenon was influenced not only by the concentration of acridine, but also by the illumination intensity. This marked the first PDT research that verified the cytotoxic effect of the combined application with light and chemical substances, laying the groundwork for photodynamic research.
1. The History of PDT in China
Traditional Chinese medicine has long used Fructus Psoraleae and Radix Angelica, which contain compounds like psoralen and propionin that, when activated by ultraviolet rays, can induce erythema, edema, and hyperpigmentation in sun-exposed areas. Chlorophyll and other plant-based substances in traditional Chinese herbs also serve as photosensitizers for photodynamic therapy (PDT). Silkworm rearing, a traditional practice in China, has contributed to PDT research. Silkworm excreta, known as silkworm sand, is a traditional medicine used to promote blood circulation and has photosensitive properties, with Chlorophyll Derivative 4 (CPD4) being isolated from it.
Between 1980 and 1981, Chinese scholars, including Jin Zou, Xianwen Ha, and Junheng Li, started basic and clinical studies on PDT. In 1981, Chinese researchers successfully isolated hematoporphyrin and its sodium salt (HpD) for the first time. Beijing Tongren Hospital then treated a basal cell carcinoma patient with HpD-PDT, marking the first application of PDT in China. Following this, the Beijing Area PDT Treatment Collaboration Group was formed with eight participating hospitals. From 1982 to 1984, 421 patients with various tumors were treated with PDT, achieving an effective rate of 86.7%. In 1984, PDT was listed as a key scientific research project in China's Sixth and Seventh Five-Year Plans, leading to significant national collaboration in the development of photosensitizers and laser devices. It organized nationwide cooperation in four aspects: photosensitizer R&D, laser R&D, basic research and clinical treatment. In just a few short years, Beijing and Yangzhou have successfully developed domestically produced HpD photosensitizers, which have shown good clinical efficacy in clinical applications; Domestic laser sources such as argon ion pumped dye lasers, copper vapor pumped dye lasers, gold vapor lasers, and high-power helium neon lasers have also been successfully developed. The country has invested a large amount of manpower and resources, and has conducted extensive research on drugs, equipment, infrastructure, and clinical practice, achieving remarkable achievements that have attracted worldwide attention. At the same time, it also accelerates the construction of the PDT professional team and the cultivation of related talents, greatly promoting the development and popularization of China's PDT industry.
In the 1980s, there were three types of mixed porphyrin preparations used in clinical trials in China, namely cancer porphyrin (HpD), cancer porphyrin (PsD-007), and photoporphyrin (HpD). In 2001, Hematoporphyrin Injection (HpD) developed by Beijing Institute of Pharmacy and produced by Chongqing Huading Biopharmaceutical Company became the photosensitizer approved for market by the National Food and Drug Administration, with the trade name Xipofen ®. By the mid-1990s, the use of domestic photosensitizers and laser light sources to treat thousands of cancer patients, including esophageal cancer, lung cancer, bladder cancer, cervical cancer and other types of malignant tumors, have achieved remarkable results. Unfortunately, in the late 1990s, due to the limitation of photosensitizer available for clinical use, and the shortcomings of HpD requiring 8 weeks of strict light protection, PDT was gradually neglected, many units and personnel have changed careers, and the work of PDT was almost stagnant.
Fortunately, since the beginning of the new century, many knowledgeable individuals in the Chinese medical, academic, and business communities have vigorously promoted the development of PDT. In 1994, professor Deyu Xu from the Second Military Medical University developed a second-generation hematoporphyrin monomethyl ether (HMME), also known as Hemoporfin. It is a monomeric porphyrin with a chemical purity of 99.8%, fast metabolism in vivo, and can be used in the treatment of tumors. After that, professor Junheng Li and academician Ying Gu used HMME in the clinical treatment of port-wine stains (PWS). After years of theoretical research and clinical practice, academician Ying Gu's team summarized the empirical treatment plan of HMME-PDT in the treatment of PWS. After 2000, professor Xu De transferred HMME patent to Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. The latter organized and carried out CMC research, preclinical and series GCP clinical research, standardized clinical protocols and solved the problems of industrial GMP production. Finally, HMME was marketed as a class I new drug in 2016, and its trade name was Fumeida®. Hemoporfin is the first first-in-class photodynamic drug approved by regulatory authorities for the treatment of port wine stains in the world. It has been tested by randomized controlled clinical trials and has clear evidence-based medical evidence, which represents a unique innovation in the field of photodynamic therapy in China.
2. The Development of ALA-PDT in China
In 1996, professor Shizheng Xu introduced the 5-aminolevulinic acid (ALA)-PDT concept into China. Under his leadership, professor Xiuli Wang established a photodynamic therapy room at Wuhan University People's Hospital (formerly the First Hospital of Hubei Medical University) / Hubei Provincial People's Hospital to conduct clinical research on ALA-PDT treatment for skin tumors. In 1999, ALA-PDT was first reported in the Chinese Journal of Laser Medicine for the treatment of Bowen's disease, and in the same year, ALA-PDT was first reported in the Chinese Journal of Dermatology for the treatment of basal cell carcinoma and cutaneous squamous cell carcinoma of the skin. Based on the pathological manifestation of papillomatous hyperplasia in condyloma acuminatum (CA), professor Xiuli Wang explored the use of ALA-PDT in the treatment of non-malignant tumor related urethral CA in 1997, achieving satisfactory results. In 1999, Shizheng Xu and Xiuli Wang held the first domestic ALA-PDT training course in Wuhan (Figure 1).
Figure 1. The first domestic "ALA photodynamic therapy training course" was held in Wuhan in 1999
In 2000, professor Xiuli Wang completed research on the fluorescence kinetics, treatment related parameters, and mechanism of action of ALA-PDT for the treatment of CA in China and Germany. Her innovative research results were first systematically reported in the journal of “British Journal of Dermatology” in 2004, attracting attention from the international photodynamic and dermatological fields. Afterwards, ALA-PDT was comprehensively extended to the treatment and basic research of CA and high-risk HPV infection in the cervix. In 2006, professor Xiuli Wang held the first national level continuing medical education course on ALA-PDT in Shanghai (Figure 2), inviting professor Reinhold Baumgartner, professor Herbert Stepp, and professor Peter Hillemans from the University of Munich in Germany, as well as professor Rolf Markus Szeimies from the University of Regensburg in Germany. The course covered the basics of photodynamic physics and the clinical applications of photodynamic technology in dermatology, urology, and obstetrics and gynecology, The trainees come from the backbone and backbone of tertiary hospitals across the country.
Figure 2. Clinical application and development of photodynamic therapy in China reported by the International Society for Photodynamic Therapy in 2008
In 2006, a comparative study was conducted between ALA-PDT and CO2 laser treatment for CA, and it was found that the "surface clearance" effect of ALA-PDT was superior to the "point clearance" effect of CO2 laser, which can effectively reduce the recurrence rate; Assisting in the production of domestic and topical ALA hydrochloride powder (from Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., trade name: 艾拉®); Indications focus on CA, completed the Phase III clinical trial of ALA-PDT treatment for CA. CA have become the only non-tumor related indication approved for ALA-PDT globally. The research team led by Xiuli Wang began to study the application time and drug concentration, explore treatment parameters, develop a series of standards, draft expert consensus and guidelines, and standardize ALA-PDT treatment. In 2008, professor Xiuli Wang was interviewed by the official communication of the International Society for Photodynamic Therapy to introduce the clinical application and development of photodynamic therapy in China (Figure 3). On November 15, 2014, with the strong support of professor Jianzhong Zhang, then Chairman of the Dermatology and Sexuality Branch of the Chinese Medical Association, professor Xiuli Wang and professor Heng Gu were appointed as the chief experts to establish the Photodynamic Therapy Research Center of the Dermatology and Sexuality Branch of the Chinese Medical Association (Figure 4). Shanghai Dermatology Hospital and the Dermatology Hospital of the Chinese Academy of Medical Sciences were the group leaders, and the first batch of 25 famous tertiary hospitals in China became the central units, In 2016, 7 additional hospitals were added, with a total of 32 central units. ALA-PDT treatment has shown a new trend of vigorous development in China. The Expert Consensus on the Clinical Application of Aminolevulinic Acid Photodynamic Therapy, led by professor Xiuli Wang and professor Gu Heng in 2015, pointed out that ALA-PDT is the preferred treatment for urethral genital warts and has also been included in the Chinese Clinical Diagnosis and Treatment Guidelines for CA.
Figure 3. Clinical application and development of photodynamic therapy in China reported by the International Society for Photodynamic Therapy in 2008
Figure 4. The Establishment Conference of Photodynamic Therapy Research Center in 2014
In 2006, Xiuli Wang's team applied ALA-PDT for the first time in China to treat acne vulgaris. They further explored the optimal ALA concentration, application time, and red light measurement, and proposed the corresponding treatment principle of "first short time, low energy, gradually increasing thereafter". The indication was moderate to severe acne, and the related results were cited in the 2016 American Acne Treatment Guidelines. Successfully isolated human sebaceous gland cell lines (XL-i-20) from Chinese acne patients, providing an important cell model for the study of ALA-PDT treatment mechanism for acne. In the field of skin tumor research, Xiuli Wang's team has transitioned from clinical research to basic research. SKH-1 hairless mice were introduced from Jackson Laboratory in the United States, and the first UV induced skin photoaging and skin tumor mouse model was established in China. The mouse skin squamous cell carcinoma cell line (XL50) was successfully cultured and isolated, revealing that ALA-PDT can not only kill tumor cells but also induce anti-tumor immune effects, has tumor vaccine and dendritic cell (DC) vaccine effects. It is also proposed that graded preprocessing is crucial for photodynamic therapy of skin tumors. Xiuli Wang's team continuously explores and expands new indications for ALA-PDT dermatology, such as skin aging, refractory HPV infection, fungal infection, androgenic hair loss, etc; Taking the lead in proposing and initiating clinical prospective research on new painless photodynamic and sunlight photodynamic technologies in China, improving and innovating light source equipment, and winning the first prize of the "Top Ten Most Transforming Potential Scientific and Technological Achievements" of Tongji University in 2020, opening a new chapter in the innovation and transformation of photodynamic therapy for skin diseases.
In 2017, professor Xiuli Wang and her team participated in the 16th International Photodynamic World Conference held in Coimbra, Portugal. As a Chinese expert in this field, Xiuli Wang applied to the conference to hold the 18th International Photodynamic Association World Congress in Shanghai, China, but failed to meet her expectations. In 2019, professor Xiuli Wang led her team to once again apply to host the International Photodynamic Association World Congress in China at the 17th International Photodynamic Congress in Boston, USA. She successfully won the right to host the 19th International Photodynamic Congress in Shanghai, China (Figure 5). At the same time, she was elected as the executive director of the International Photodynamic Association.
Figure 5. Successfully obtained the right to host the 19th International Photodynamic Congress in Shanghai, China in 2019
In 2021, in order to further standardize, guide, and promote the application of ALA-PDT in dermatology clinical practice, the Dermatology and Sexuality Branch of the Chinese Medical Association, the Dermatology Rehabilitation Professional Committee of the Chinese Rehabilitation Medicine Association, and the Photomedical Treatment Equipment Group of the Dermatology and Dermatology Beauty Branch of the Chinese Medical Equipment Association revised and updated the "Guidelines for the Clinical Application of Aminolevulinic Acid Photodynamic Therapy in Dermatology (2021 Edition)" based on the 2015 consensus. In the same year, the guide was published in English in the journal of “Photodiagnosis and Photodynamic Therapy”, showcasing the application and research achievements of China's photodynamic technology. In 2021, professor Xiuli Wang led the establishment of the China Rehabilitation Medicine Association Skin Photodynamic Therapy Rehabilitation Technology Special Training Base and a total of 15 hospitals in the first batch of training bases were approved, providing technical demonstrations and personnel training for the application and development of ALA-PDT in China.
PDT has thrived in China and has been widely applied and developed in various fields and disciplines, including obstetrics and gynecology, stomatology, oncology, neurosurgery, ophthalmology, pulmonology, gastroenterology, urology, and otolaryngology. In the meanwhile, multiple professional organizations dedicated to PDT have been established successively, such as the "Photodynamic Therapy Specialized Committee of the Chinese Anti-Cancer Association", the "Photodynamic Therapy Specialized Committee of the Chinese Clinical Oncology Society", and the "Photodynamic Therapy and Rehabilitation Specialized Committee of the Chinese Rehabilitation Medicine Association".