新型四氢卟吩衍生物的制备及其抗原发性肝癌作用研究

Hepatocellular carcinoma (HCC) is a life-threatening malignancy that is most prevalent in China. Recent epidemiological analysis reveals that the number of HCC patients is increasing even in developed countries. It is due to an increasing incidence of hepatitis C and B virus infection, chronic alcohol abuse, and non-alcoholic fatty liver disease. Treatment options for HCC fall into four categories: surgical interventions such as tumor resection and liver transplantation, percutaneous interventions, including ethanol injection and radiofrequency thermal ablation, transarterial interventions such as embolisation and chemoembolisation, and drug treatment, gene therapy and immunotherapy. To reduce morbidity and mortality from HCC, it is important to develop early diagnostic technologies and minimal invasive procedures to treat localized cancers. Photodynamic therapy (PDT) is a promising cancer treatment in which a photosensitizing drug accumulates in tumor tissues and is subsequently activated by visible light of an appropriate wavelength matched to the absorption spectrum of the photosensitizer. Following the absorption of light, the photosensitizer is transformed from its ground state to the excited state. The excited drug leads to cytotoxicity by way of type I and type II reactions. Type I reaction involves the production of radicals resulting from the activated sensitizer reacting with plasma membrane or other molecules. The radicals interact with oxygen to produce oxygenated products. Type II reaction involves generation of singlet oxygen upon energy transfer from the activated sensitizer to oxygen. The ratio between type I and type II reactions depends on the type of photosensitizer used, the concentrations of oxygen and target substrate. One important feature of PDT is that it provides a selective therapeutic effect sparing surrounding normal tissue by preferential accumulation of the photosensitizer in the tumor tissue and light irradiation restricted to the target tissue. Due to minimal invasiveness of PDT, it has been used to treat several types of cancers, infectious diseases, and age-related macula degeneration. With the development of new photosensitizers and the advancement of fiber optic delivery devices, substantial research has been invested in exploring their potential application in PDT of HCC. Here series of tetrahydro-porphins such as chlorophyll derivatives will be designed and synthesized. Their photodynamic anti-HCC effects in vitro and in vivo will be evaluated. The photochemical and photobiological mechanism and the structure-activity relationships will also be investigated.These work will be of great value to the development of new photodynamic drugs, and to the use of PDT in clinics.

原发性肝癌是严重危害人民健康的常见恶性肿瘤，全球55%的病例集中在我国，其确诊后6个月死亡率高达95％。目前采用的手术、化疗、放疗等方法各有局限性，亟待研究其治疗的新策略、新药物。 光动力疗法已被美国和我国等国列入肿瘤基本疗法，是目前唯一能够在细胞水平上高效、微创、选择性治疗癌症的新技术，前景极为看好。原发性肝癌的光动力治疗近年引起广泛关注，初步研究表明该法疗效确切、创伤小、恢复快，有望成为治疗肝癌的主要疗法之一。 本研究通过制备一系列新型四氢卟吩化合物，在细胞与整体动物水平测定其对肿瘤的抑制作用，用活体动物体内荧光成像技术测定其分布情况，用脉冲辐解、激光光解等方法研究其微观光化学作用机理，用基因芯片等方法在基因组水平研究其抗肿瘤作用机理，研究其定量构效关系，提供具有自主知识产权、定向、高效、价廉、无皮肤光毒作用的单体原发性肝癌治疗候选新药，促进光动力疗法在临床上的推广应用。

原发性肝癌是严重危害人民健康的常见恶性肿瘤，全球55%的病例集中在我国，其确诊后6个月死亡率高达95％。目前采用的手术、化疗、放疗等方法各有局限性，亟待研究其治疗的新策略、新药物。.光动力疗法已被美国和我国等国列入肿瘤基本疗法，是目前唯一能够在细胞水平上高效、微创、选择性治疗癌症的新技术，前景极为看好。原发性肝癌的光动力治疗近年引起广泛关注，初步研究表明该法疗效确切、创伤小、恢复快，有望成为治疗肝癌的主要疗法之一。.本研究制备了100个新型四氢卟吩化合物，在细胞与整体动物水平测定了其对肿瘤的抑制作用及光生物学抗肿瘤作用机理，用荧光成像技术测定了其分布情况，用脉冲辐解、激光光解等方法研究了微观光化学作用机理，研究了构效关系，发现了2个具有自主知识产权、定向、高效、价廉、无皮肤光毒作用的单体原发性肝癌定位成像与治疗候选新药，为光动力疗法在临床的推广应用提供了理论与技术指导。