Abstract:
The present invention relates to a series of new drugs which refer to chemical series capable of catalyzing the decomposition of H 2 O 2  to generate singlet oxygen ( 1 O 2 ). The drugs relate to therapeutic mechanisms, different from traditional photodynamic therapy, in which the specific affinity of photofrin to focus, such as tumors, vascular plaques and skin diseases is utilized. The activation of photofrin is carried out by specific protein binding or by electron beam, x-ray, r-ray, or other means, to focus, catalyze the decomposition reaction of H 2 O 2  to generate  1 O 2  in the focus,  1 O 2  further induces apoptosis and necrosis of cells with pathological changes. The drugs are useful in tumors, vascular plaques and skin diseases, and cosmetic effects on skin are prompted. The drugs obtained via the screening and studying of the present invention are used for chemodynamic therapy (CDT), or for radiochemodynamic therapy (RCDT) carried out via radioactive rays.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This Application is a Continuation of U.S. patent application Ser. No. 13/734,442, “SERIES OF DRUGS USING PHOTOFRIN TO CATALYZE DECOMPOSITION OF HYDROGEN PEROXIDE,” filed Jan. 4, 2013, and claims priority to and the benefit of Chinese Patent Application No. 201210390725.7 filed Oct. 16, 2012. Both of these applications are incorporated herein by reference in their entirety. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a series of drugs using a photofrin to catalyze in vivo decomposition of hydrogen peroxide (H 2 O 2 ) to generate singlet oxygen ( 1 O 2 ) for treatment of diseases or for cosmetology, which can be used for Chemodynamic Therapy (CDT), or used for Radiochemodynamic Therapy (RCDT), “Radiodynamic Therapy (RDT)” in which radioactive rays directly activate photofrin to fulfill the treatment. 
       BACKGROUND OF THE INVENTION 
       [0003]    In traditional photodynamic therapy (PDT), the specific affinity of photofrin to focus, such as tumors, vascular plaques, skin diseases, is utilized, then a visible light with a specific wavelength capable of being absorbed by photofrin is used to irradiate the focus, after the focus absorbs the light energy, O 2  converts into  1 O 2 , and  1 O 2  further induce apoptosis or necrosis of cells with pathological changes, so as to achieve therapeutical effects. However, PDT usually could not achieve desired effects in clinic due to the poor penetrability of visible light, difficulty in therapeutical quantitation, and the deficiency of O 2 . In the same time, traumatic or non-traumatic intervention means have to be used to introduce light source to the diseased regions in many situations, so that both doctors and patients feel difficulty to accept PDT. 
         [0004]    In order to overcome the drawbacks of PDT, PDT should be modified and improved in abstracto. It is known H 2 O 2  can be catalytically decomposed under weak alkaline condition, the reaction almost stoichiometrically produce  1 O 2 , the reaction formula is as follows: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   
                       
                   
                    
                   
                     
                       M 
                       o 
                     
                      
                     
                       O 
                       4 
                       
                         2 
                         - 
                       
                     
                   
                    
                   
                       
                   
                 
               
               
                 OH 
                 - 
               
             
              
             
               
                 2 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                 
                     
                 
                   
                 
                     
                 
                 1 
               
             
           
         
       
     
         [0005]    However, this reaction is of low efficiency, uncontrollable, poor specificity to focus, unable to be used in clinic treatment of diseases. In order to use this chemical reaction model in clinic, the following five basic requirements have to be met: 1) the reaction must be performed at focus of disease; 2) the reaction must be carried in high efficiency; 3) the reaction must be controllable; 4) the reaction must be quantitative; 5) the catalyst should not directly participate the reaction and no new compound is generated. Hence, the present invention develops a series of creative new drugs of chemical reactions catalyzed by photofrin on the basis of proposal and discussion of the following assumptions, which can decompose H 2 O 2  to generate singlet oxygen ( 1 O 2 ) without using oxygen and visible light. These series drugs are useful in Chemodynamic Therapy (CDT) and Radiochemodynamic Therapy (RCDT). 
         [0006]    Assumptions for CDT and RCDT 
         [0007]    It is assumed that photofrin can catalyze the decomposition reaction of H 2 O 2  to generate  1 O 2  with high efficiency under certain condition, and the decomposition reaction of H 2 O 2  catalyzed by photofrin is limited to focus of diseases due to the specific affinity of photofrin to focus, such as tumors, vascular plaques, skin diseases. 
         [0008]    It is assumed that photofrin can be activated by physical and/or chemical binding energy to prompt the decomposition reaction of H 2 O 2  catalyzed by photofrin to generate  1 O 2  with higher efficiency, so that when specific means (such as radiation, biochemistry, heating, etc.) is applied to quantitatively generate  1 O 2  at site of focus, the decomposition reaction of H 2 O 2  would be further limited to the focus. 
         [0009]    It is assumed photofrin is a key factor for catalyzing the decomposition reaction of H 2 O 2  to generate  1 O 2 , and the decomposition reaction of H 2 O 2  can rapidly start or stop by changing conformation or energy level. 
         [0010]    It is assumed in the presence of an amount of photofrin and H 2 O 2 , its physical quantity of stoichiometric amount is in proportion with the generated  1 O 2 . Hence, the irradiation dose of electron beam, x-ray, r-ray and ion beam is in proportion with the measurable amount of the generated  1 O 2 , so that the quantitative determination of RCDT can be fulfilled. 
         [0011]    It is assumed photofrin only acts as catalyst to catalyze the decomposition reaction of H 2 O 2  to generate  1 O 2 . Photofrin does not directly participate the reaction and does not generate new derivatives of photofrin. 
         [0012]    Experimental Demonstration of CDT and RCDT 
         [0013]    Under weak alkaline condition, the catalytic decomposition reaction of H 2 O 2  has a relatively low efficiency even in the presence of .OH free radicals, the reaction formula is as follows: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   • 
                    
                   OH 
                 
               
               
                 OH 
                 - 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0014]    When the content of H 2 O 2  is 0.15%, the generation of  1 O 2  free radicals cannot be detected after reaction for 6 h. 
         [0015]    When photofrin is added under weak alkaline condition, the reaction rate increases significantly: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   
                     
                       
                         photo 
                         - 
                       
                     
                   
                   
                     
                       sensitizers 
                     
                   
                 
               
               
                 OH 
                 - 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0016]    However, the generation of a large amount of  1 O 2  is detected until the concentration of H 2 O 2  is 1% or more, and the reaction is performed for 8 h. This reaction can hardly be carried in vivo environment, because: 1) such a high concentration of H 2 O 2  cannot be maintained in vivo for a long term; 2) hydrogen peroxidase can rapidly eliminated H 2 O 2  in vivo; 3) there is not an alkaline environment in vivo. 
         [0017]    When photofrin is activated by radiation or protein binding simultaneously, it can catalyze the decomposition reaction of H 2 O 2  rapidly with high efficiency: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   
                     
                       
                         photo 
                         - 
                       
                     
                   
                   
                     
                       sensitizers 
                     
                   
                 
               
               •OH 
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0018]    When the concentration of H 2 O 2  is 0.03% or less,  1 O 2  can be formed quickly. 
         [0019]    X-ray irradiation can electrolyze H 2 O to generate .OH, or the generation of .OH can be achieved by adding metal ions and Vit-C, which can rapidly start the decomposition reaction of H 2 O 2  to generate  1 O 2 ; once X-ray irradiation stops, or .OH free radical scavenger is added, the decomposition reaction of H 2 O 2  will stop quickly. 
         [0020]    When the contents of photofrin and H 2 O 2  are fixed, the irradiation dose of X-ray is in proportion with the yield of  1 O 2 . 
         [0021]    Fluorescence spectrophotometer is used to analyze the structure of photofrin before and after being used to catalyze the decomposition reaction of H 2 O 2 , it is found that the content and structure of photofrin do not change before and after the reaction. 
         [0022]    The above important findings bring the theory of Chemodynamic Therapy (CDT) and Radiochemodynamic Therapy (RCDT), which is the basis for developing these series drugs. 
         [0023]    Photofrin is used as catalyst for decomposing H 2 O 2  in vivo to finally generate  1 O 2 , and in the present invention, this therapeutic model is called as Chemodynamic Therapy (CDT), while the CDT carried out by radioactive rays is called as Radiochemodynamic Therapy (RCDT). Both CDT and RCDT are promising in overcoming the drawbacks of traditional photodynamic therapy (PDT), especially when combining to radiotherapy or pharmacotherapy,  1 O 2  therapeutic model is more suitable in clinical application. 
         [0024]    At this time, the mechanism, use and therapeutic effects of photofrin are totally different from those of traditional photodynamic therapy, thus an independent series of new drugs are developed for use in combination with H 2 O 2 , and activation via hydroxyl free radicals. The present invention is to seek intellectual property protection for the series of drugs. 
         [0025]    Advantages of CDT and RCDT 
         [0026]    No Need for Light Source: 
         [0027]    in traditional photodynamic therapy (PDT), light source is the most important factor, the quality of light source directly determine the therapeutical effects. In addition, photofrin used for PDT should be designed according to light source to maximize the absorption of light, and for lights with different wavelengths, the used photofrin should have different chemical structure. CDT and RCDT do not need light source. In the presence of an amount of photofrin, electron beam, x-ray, r-ray or ion beam, or protein binding can activate the photofrin, start the decomposition reaction of H 2 O 2  to generate  1 O 2 . The therapeutical effect of photofrin is not determined by the ability of absorbing light, but determined by the ability of catalyzing the decomposition of H 2 O 2 . 
         [0028]    No Need for Oxygen: 
         [0029]    many tumors are at O 2  deficient state, while the reaction substrate of traditional PDT is O 2 , i.e., when there is not oxygen,  1 O 2  cannot be generated and therapeutical effect cannot be achieved. CDT and RCDT do not need O 2 , their reaction substrate is H 2 O 2 , while a low concentration of exogenous or endogenous H 2 O 2  would meet the therapeutical requirement. 
         [0030]    Good Therapeutical Effects: 
         [0031]    (1) Visible light has poor tissue penetrability, and poor therapeutical effect in PDT for large focus or deep focus. CDT and RCDT do not need light source, so that CDT and RCDT can act in whole range of focus of disease whatever the size of depth of focus. (2) In therapeutical procedure of PDT, photofrin content decreases rapidly, and therapeutical effect becomes weak accordingly. CDT and RCDT use photofrin as reaction catalyst, and the structure of photofrin would not be destroyed and its content would not be reduced during the therapeutical procedure, so that therapeutical effects are maintained. (3) CDT and RCDT generate .OH and  1 O 2  at the same time, increasing the killing effects of free radicals. (4) When electron beam, X-ray, r-ray or ion beam are used to carry out RCDT, these radioactive rays per se have function of killing cells with pathological changes, thereby bring about double effects. (5) When electron beam, X-ray, r-ray or ion beam are used to carry out RCDT, target regions can be designed by three-dimensional stereotaxis, together with the specific affinity of photofrin to target regions, forming double target effects, which not only improves therapeutical effects, but also reduces side-effects. (6) photofrin per se has a certain effects on enhancing sensitivity in radiotherapy. (7) H 2 O 2  can also be decomposed by hydrogen peroxidase in tumors to generate O 2 , thereby improving oxygen deficient condition of tumors and enhancing therapeutical effects. 
         [0032]    Less Side-Effects: 
         [0033]    Since two conditions, presence of photofrin and activation of photofrin, are required to start decomposition reaction of H 2 O 2  to generate  1 O 2 , photofrin is concentrated at focus and activated in target region of focus, so that the decomposition reaction of H 2 O 2  is limited in the region of focus, and rarely occurs at sites around focus and at other sites of body, wherein the decomposition reaction of H 2 O 2  even does not occur. In addition, H 2 O 2  can be rapidly decomposed in vivo by hydrogen peroxidase to form H 2 O and O 2 . 
         [0034]    Capable of being Quantitated: 
         [0035]    One of the serious drawbacks of traditional PDT is difficulty in determining therapeutical dose, which directly influences therapeutical effects and evaluation thereof. RCDT can totally fulfill quantitation, because the amount of  1 O 2  generated in RCDT is in proportion with the irradiation dose of x-ray, r-ray and so on. With the great progress in current precise radiotherapy, precise RCDT can be fully fulfilled. 
         [0036]    No Need for Intervention Means: 
         [0037]    Since visible light has poor tissue penetrability, traumatic or non-traumatic intervention means are usually used in traditional PDT to introduce light source into focus of disease. These means may not be accepted by many doctors and patients, so that many patients lose an opportunity to be treated. Since x-ray, r-ray and the like have a tissue penetrability significantly higher than visible light and can reach any sites of body, RCDT does not need any intervention means. 
         [0038]    Simple Operation: 
         [0039]    Even for superficial lesions, traditional PDT still requires light source to irradiate focus, which operation is complex and difficult in popularization. CDT is very simple to therapy superficial lesions, comprising separately coating photofrin, H 2 O 2  or H 2 O 2 -containing preparation in order on the lesions, directly activating photofrin to start decomposition reaction of H 2 O 2 , generating  1 O 2 . At the end of therapy, the activation of photofrin stops, to terminate the decomposition reaction of H 2 O 2 . In combination with radiotherapy, the relevant technology is well developed, and the operations thereof are highly automatized. 
         [0040]    Capable of being Continuous and Repeated Therapy: 
         [0041]    Traditional PDT destroys photofrin, usually requires interventional means, and thus can hardly be used for continuous and repeated therapy. However, continuous and repeated therapy is very important in many conditions, for example, for patients with tumors, tumor vessels are targets for immediate therapy after intravenous injection of photofrin, and tumor cells are targets for delay therapy. CDT and RCDT do not destroy photofrin, do not need intervention means, and thus are competent enough for segmented repeated therapeutic protocols. 
         [0042]    Easy for Popularization and Application: 
         [0043]    Due to the above advantages, CDT and RCDT are easier for popularization and application in clinic. 
       SUMMARY OF THE INVENTION 
       [0044]    Mechanism of CDT and RCDT 
         [0045]    Traditional photodynamic therapy (PDT) is a method of using a visible light with certain wavelength to irradiate photofrin, converting O 2  into  1 O 2  by energy conversion to treat diseases. 
         [0046]    The present invention relates to therapeutical mechanism, means and series drugs totally different from PDT, in which the specific affinity of photofrin to focus, such as tumors, vascular plaques and skin diseases, is utilized, and a certain means is used to activate photofrin in the focus, rapidly start (or stop) the decomposition reaction of H 2 O 2  to generate  1 O 2  in the focus,  1 O 2  further induces apoptosis and necrosis of cells with pathological changes, the purpose of treating tumors, vascular plaques and skin diseases is achieved, and cosmetic effects on skin are prompted. On this theoretical basis, the present invention develops a series of new drugs for this kind of therapeutical model. These drugs can be used for Chemodynamic Therapy (CDT), or be used for CDT carried out via radioactive rays, which is so-called as Radiochemodynamic Therapy (RCDT). The action mechanism of the drugs is as follows: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               → 
               
                 
                   
                     
                       photo 
                       - 
                     
                   
                 
                 
                   
                     sensitizers 
                   
                 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0047]    In the formula, photofrin can be endogenous (e.g., 5-ALA synthetic endogenous porphyrin), or exogenous; H 2 O 2  can be exogenous, or can be endogenous H 2 O 2  generated by means of hydrogen peroxidase inhibitor; the activation of photofrin is carried out by specific protein binding or by electron beam, x-ray, r-ray, or other means. 
         [0048]    The series of drugs of the present invention can overcome the drawbacks of photodynamic therapy (PDT), do not use visible light source, do not rely on oxygen. 
         [0049]    Photofrin Catalysts Used for CDT and RCDT 
         [0050]    Different from the purpose and function of photofrin used in PDT, PDT uses photofrin to perform photo energy conversion, while CDT and RCDT use photofrin as catalyst for decomposition reaction of H 2 O 2 , under certain physical and chemical conditions, this kind of photofrin has high efficiency in catalyzing the decomposition reaction of H 2 O 2 , to rapidly generate  1 O 2 . 
         [0051]    Different from the action effects of photofrin used in PDT, the photofrin used in PDT should be designed according to light source to maximize absorption of light, and as for lights with different wavelengths, the chemical structure of the used photofrin should be different. The therapeutical effects of photofrin in CDT and RCDT do not depend on its absorption of light, while depend on its ability of catalyzing decomposition of H 2 O 2 . The photofrin having good therapeutical effects in PDT may not catalyze the decomposition reaction of H 2 O 2  with high performance, and thus may not be suitable for CDT and RCDT, vice versa. 
         [0052]    Different from the chemical structure of photofrin used in PDT, the photofrin used in PDT is designed and developed according to the absorptivity of visible light with certain wavelengths, while the photofrin used in CDT and RCDT is designed and developed according to the catalytic efficiency for decomposition reaction of H 2 O 2    
         [0053]    Different from the fate of photofrin used in PDT, the photofrin is destroyed by visible light in PDT, while the photofrin is merely used as reaction catalyst in CDT and RCDT, which chemical structure is not destroyed. 
         [0054]    Methods for Researching and Developing a Series Drugs Useful in CDT and RCDT 
         [0055]    Photofrins with different structures and same molar concentration are taken, and separately mixed with H 2 O 2  solutions with different concentrations in vacuum reaction bottles away from light. Then a suitable amount of  1 O 2  free radical indicator (e.g., 9,10-dimethylanthracene, etc.) is added. The decomposition reaction of H 2 O 2  starts and stops according to the following methods, and the content of  1 O 2  free radicals is finally measured directly or indirectly by a fluorescence spectrophotometer. 
         [0056]    The mixture solutions of photofrin and H 2 O 2  in vacuum reaction bottles away from light are irradiated by quantitative (Gy) x-ray, r-ray or other methods, to start the decomposition reaction of H 2 O 2  catalyzed by photofrin, and the decomposition reaction of H 2 O 2  catalyzed by photofrin is terminated by stopping the irradiation.  1 O 2  can be quantitatively analyzed. 
         [0057]    A photofrin-binding protein in a quantitative amount is added to the vacuum reaction bottles containing a mixture solution of photofrin and H 2 O 2  away from light, to start the decomposition reaction of H 2 O 2  catalyzed by photofrin, and the decomposition reaction of H 2 O 2  catalyzed by photofrin is terminated by destroying protein function (e.g., by ethanol). 
         [0058]    Thus, photofrin catalysts with high performance can be screened out. 
         [0059]    Experimental Methods for CDT and RCDT 
         [0060]    Cell Tests 
         [0061]    Various kinds of cells are cultivated, for performing relevant researches of CDT and RCDT. 
         [0062]    Tumor Models and Therapeutical Researches 
         [0063]    Various tumor-bearing animal models are prepared, for performing treatment of tumors by CDT and RCDT, treatment of tumor vessels by CDT and RCDT, and immunotherapy researches relevant to tumors by CDT and RCDT. 
         [0064]    Vascular Plaques and Therapeutical Researches 
         [0065]    Various animal models with vascular injury or vascular plaques are prepared, for performing treatment of vascular plaques by CDT and RCDT, including treatment of plaques of small vessels (eye ground vessels) and large vessels (aorta) by CDT and RCDT. 
         [0066]    Other Animal Models and Therapeutical Researches 
         [0067]    Various animal models with skin diseases are prepared, for performing local treatment by CDT and RCDT. 
         [0068]    Treatment of Tumors by Series of Drugs for RCDT 
         [0069]    Step 1, positioning tumors by images, completing the sketch of RCDT tumor targets and the protocol of RCDT by radio-therapeutical planning system; 
         [0070]    Step 2, administering photofrin or photofrin prodrug (e.g., 5-ALA) systematically or topically to tumor part, utilizing the specific affinity of photofrin to tumor tissues to concentrate photofrin at tumor cells; 
         [0071]    Step 3, administering exogenous H 2 O 2  (e.g., injection of carbamide peroxide, or H 2 O 2 ) systematically or topically to tumor part, or using hydrogen peroxidase inhibitor to generate endogenous H 2 O 2  in vivo; 
         [0072]    Step 4, after administering exogenous H 2 O 2  systematically or topically to tumor part, using an instrument for radiotherapy, immediately carrying out the RCDT plan, using electron beam, x-ray, r-ray or ion beam to activate photofrin to catalyze the decomposition reaction of H 2 O 2  to generate  1 O 2 . The administration of H 2 O 2  is for early treatment by killing tumor vessels, and for delay treatment by killing tumor cells; 
         [0073]    Step 5, stopping the irradiation of electron beam, x-ray, r-ray or ion beam, thus immediately terminating the decomposition reaction of H 2 O 2 , the residual H 2 O 2  can be decomposed by hydrogen peroxidase to form harmless H 2 O and O 2 . 
         [0074]    If necessary, RCDT can be repeatedly carried out according to a reasonable time schedule. 
         [0075]    Treatment of Tumor Vessels by Series of Drugs for RCDT 
         [0076]    Step 1, positioning tumors by images, completing the sketch of RCDT tumor targets and the protocol of RCDT by radio-therapeutical planning system; 
         [0077]    Step 2, preparing fresh photofrin and exogenous H 2 O 2  or H 2 O 2 -containing preparations; 
         [0078]    Step 3, administering photofrin and exogenous H 2 O 2  or H 2 O 2 -containing preparations to tumor topical control vessels or whole body vessels; 
         [0079]    Step 4, after administering photofrin and exogenous H 2 O 2  or H 2 O 2 -containing preparations, using an instrument for radiotherapy, immediately carrying out the RCDT plan, using electron beam, x-ray, r-ray or ion beam to activate photofrin in vascular endothelial cells of tumor or vascular interstitial tissue to start the decomposition reaction of H 2 O 2  catalyzed by photofrin to generate  1 O 2 , so as to destroy tumor vessels; 
         [0080]    Step 5, stopping the irradiation of electron beam, x-ray, r-ray or ion beam, thus immediately terminating the decomposition reaction of H 2 O 2 , the residual H 2 O 2  can be decomposed by hydrogen peroxidase to form harmless H 2 O and O 2 . 
         [0081]    If necessary, RCDT can be repeatedly carried out according to a reasonable time schedule. 
         [0082]    Treatment of Vascular Plaques by Series of Drugs for RCDT 
         [0083]    Step 1, positioning vascular plaques by images, completing the sketch of RCDT vascular plaque targets and the protocol of RCDT by radio-therapeutical planning system; 
         [0084]    Step 2, administering photofrin or photofrin prodrug (e.g., 5-ALA) systematically, utilizing the specific affinity of photofrin to vascular plaques to concentrate photofrin at vascular plaques; 
         [0085]    Step 3, administering exogenous H 2 O 2  (e.g., injection of carbamide peroxide, or H 2 O 2 ) systematically, or using hydrogen peroxidase inhibitor to generate endogenous H 2 O 2  in vivo; 
         [0086]    Step 4, after administering H 2 O 2  systematically, using an instrument for radiotherapy, immediately carrying out the RCDT plan, using electron beam, x-ray, r-ray or ion beam to activate photofrin in vascular plaques to start the decomposition reaction of H 2 O 2  catalyzed by photofrin to generate  1 O 2 , so as to ablating vascular plaques; 
         [0087]    Step 5, stopping the irradiation of electron beam, x-ray, r-ray or ion beam, thus immediately terminating the decomposition reaction of H 2 O 2 , the residual H 2 O 2  can be decomposed by hydrogen peroxidase to form harmless H 2 O and O 2 . 
         [0088]    If necessary, RCDT can be repeatedly carried out according to a reasonable time schedule. 
         [0089]    Treatment of Other Diseases by Series of Drugs for RCDT 
         [0090]    The therapeutical procedure is similar to the aforementioned, suitable for topical disease in deep sites of body, for example, benign diseases such as topical intractable inflammations, ophthalmic diseases, vascular tumors in organs, prostatic hyperplasia, etc. 
         [0091]    Treatment of Skin Diseases by Series of Drugs for CDT 
         [0092]    It is useful in treatment of all kinds of skin diseases suitable for PDT. 
         [0093]    Step 1, administering photofrin or photofrin prodrug (e.g., 5-ALA) systematically or topically, utilizing the specific affinity of photofrin to skin lesions to concentrate photofrin at skin lesions; 
         [0094]    Step 2, administering H 2 O 2  or H 2 O 2 -containing preparations to the skin lesions; 
         [0095]    Step 3, when administering a specific activator to the skin lesions, starting the decomposition reaction of H 2 O 2  catalyzed by photofrin to generate  1 O 2 , so as to achieve the purpose of treating skin diseases; 
         [0096]    Step 4, washing the skin lesions with activator scavenger (e.g., mannitol, ethanol, etc.) to terminate the decomposition reaction of H 2 O 2 . 
         [0097]    This method is simple in operation, needs no light source, and can be repeated as external application drugs. 
         [0098]    Treatment of Tumor Cells and Tumor Vessels by Series of Drug for CDT 
         [0099]    An intervention means is required as assistant. 
         [0100]    Step 1, administering photofrin or photofrin prodrug (e.g., 5-ALA) systematically, utilizing the specific affinity of photofrin to tumor tissues to concentrate photofrin at tumor cells; 
         [0101]    Step 2, selectively incubating tumor blood supplying vessels, or directly injecting tumor body; 
         [0102]    Step 3, preparing fresh photofrin and exogenous H 2 O 2 ; 
         [0103]    Step 4, injecting freshly prepared photofrin and exogenous H 2 O 2  into tumor bed separately via vessel cannula, or directly slowly injecting into tumor bed; 
         [0104]    Step 5, after injection, using a physical or chemical method to activate the decomposition reaction of H 2 O 2  catalyzed by photofrin to generate  1 O 2 , so as to kill tumor cells and destroy tumor vessels. 
         [0105]    Treatment of Other Disease by Series Drugs for CDT 
         [0106]    For example, drug-resistant infections, topical intractable inflammations, ophthalmic diseases, vascular tumors in organs, prostatic hyperplasia, etc. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0107]      FIG. 1  shows irradiation of 5Gy x-ray in grey histogram, metal ion induction reaction in colorless histogram, the results show when the concentration of H 2 O 2  is lower than or equal to 0.15%, both of these two methods do not exhibit obvious generation of  1 O 2 . 
           [0108]      FIG. 2  shows when the concentration of H 2 O 2  is lower than or equal to 0.15%, haematoporphyrin cannot significantly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 . When the concentration of H 2 O 2  is 1.5%, haematoporphyrin can slowly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 . 
           [0109]      FIG. 3  shows haematoporphyrin can rapidly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 , in comparison with the catalytic reaction using merely haematoporphyrin, the reaction time is shortened from 480 min to about 1 min, the reaction rate is elevated by near 500 times. In addition, the used concentration of H 2 O 2  is only 1/20 to 1/50 of that of the catalytic reaction using merely haematoporphyrin, and the catalytic efficiency increases by 20 to 50 times. 
           [0110]      FIG. 4  shows an acidified porphyrin PpIX can rapidly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 , in comparison with the catalytic reaction using merely haematoporphyrin, the reaction time is shortened from 480 min to about 1 min, the reaction rate is elevated by near 500 times. In addition, the used concentration of H 2 O 2  is only 1/20 to 1/50 of that of the catalytic reaction using merely haematoporphyrin, and the catalytic efficiency increases by 20 to 50 times. 
           [0111]      FIG. 5  shows when using DMSO, ethanol and mannitol to eliminate .OH, the decomposition reaction of H 2 O 2  catalyzed by haematoporphyrin is rapidly suppressed, even under condition of high concentration of H 2 O 2 . 
           [0112]      FIG. 6  shows to a mixture solution of haematoporphyrin (15 uM) and 1.5% H 2 O 2 , 0.5 mM FeCl3 (FeCl3.6H2O) and 0.5 mM Vit-C are added, sufficiently mixed, H 2 O 2  is decomposed to generate .OH, starting the decomposition of H 2 O 2  to produce  1 O 2 . In comparison with the catalytic reaction catalyzed using only haematoporphyrin, the reaction time is shortened from 480 min to 5 min. 
           [0113]      FIG. 7  shows under condition of low concentration of H 2 O 2 , the contents of photofrin and H 2 O 2  are fixed, x-ray is used to start the decomposition reaction of H 2 O 2 , and the amount of the generated  1 O 2  is in proportion with the irradiation dose. 
           [0114]      FIG. 8  shows PpIX in violet histogram, HPD in orange histogram. Under the same conditions, the catalytic effect of PpIX is higher than HPD by 50 times or more. When the concentration of H 2 O 2  is 0.03%, PpIX and X-ray catalyze the decomposition reaction of H 2 O 2 , so that 90% or more of DMA is bound by  1 O 2  free radicals; even when the concentration of H 2 O 2  is 0.01%, PpIX and X-ray can catalyze the decomposition reaction of H 2 O 2 , so that near 40% (background subtraction) of DMA is bound by  1 O 2  free radicals. 
           [0115]      FIG. 9  shows plaques of thoracic aorta of New Zealand rabbit (indicated by upper arrows), in which contrast media is blocked. After radiodynamic therapy for once for one week, the plaques disappear (indicated by lower arrows), in which contrast media pass smoothly. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Example 1 
     Weak Alkali and .OH Free Radical Catalyzing the Decomposition Reaction of H 2 O 2    
       [0116]    Experimental Methods: 
         [0117]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0118]    (2) H 2 O 2  solutions (in DMF: H 2 O=1:5) with different concentrations were added to the sealed vacuum bottles. 
         [0119]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0120]    (4) 50 MeV X-ray was used to irradiate the vacuum bottles, with dose of 5Gy, to start the decomposition reaction of H 2 O 2 ; the reaction was terminated by stopping x-ray irradiation. 
         [0121]    (5) or 0.1 mM FeCl 3  (FeCl 3 .6H 2 O) and 0.1 mM Vit-C were added, to start the decomposition of H 2 O 2 , after decomposition of H 2 O 2  for 5 min, 20% was used to terminate the reaction. 
         [0122]    Experimental Results: 
         [0123]    The results show that when the concentration of H 2 O 2  is lower than or equal to 0.15%, whether ionizing H 2 O with high energy X-ray or generating .OH by chemical method cannot reduce DMA fluorescence degree, on the contrary, the DMA fluorescence degree even increases slightly (but showing no statistics significance). This indicates when the concentration of H 2 O 2  is relatively low, the decomposition reaction of H 2 O 2  cannot be started by using only .OH, and  1 O 2  free radical cannot be generated (see:  FIG. 1 ). 
         [0124]    Reaction Formula: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   • 
                    
                   OH 
                 
               
               
                 OH 
                 - 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
       Example 2 
     Weak Alkali and Photofrin Catalyzing the Decomposition Reaction of H 2 O 2    
       [0125]    Experimental Method: 
         [0126]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0127]    (2) H 2 O 2  solutions (in DMF: H 2 O=1:5) with different concentrations were added to the sealed vacuum bottles. 
         [0128]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0129]    (4) 15 uM Haematoporphyrin derivative was added, and reacted at 25° C. for 8 h. 
         [0130]    Experimental Results: 
         [0131]    The results show that similar to the decomposition reaction of H 2 O 2  catalyzed by .OH, when the concentration of H 2 O 2  is lower than or equal to 0.15%, the decomposition reaction of H 2 O 2  cannot be catalyzed by haematoporphyrin derivative, to generate  1 O 2 . When the concentration increases to 1.5%, haematoporphyrin can catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 . This reaction is very slow, needs about 8 h of reaction time, and this reaction can be carried out only under condition of high concentration of H 2 O 2  (see:  FIG. 2 ). 
         [0132]    Reaction Formula: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   
                     
                       
                         photo 
                         - 
                       
                     
                   
                   
                     
                       sensitizers 
                     
                   
                 
               
               
                 OH 
                 - 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0133]    The above 5-1 and 5-2 experimental results show that when merely using .OH or photofrin as catalyst, the catalytic decomposition reaction of H 2 O 2  in vivo, because 1) H 2 O 2  concentration cannot be maintained at high level in body for a long time period (8 h); 2) H 2 O 2  can be rapidly eliminated in vivo by hydrogen peroxidase; 3) there is not an alkaline environment in body. 
       Example 3 
     Catalyzing the Decomposition Reaction of H 2 O 2  Using Photofrin and Physical Method (RCDT Method) 
       [0134]    Experimental Method: 
         [0135]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0136]    (2) H 2 O 2  solutions (in DMF: H 2 O=1:5) with different concentrations were added to the sealed vacuum bottles. 
         [0137]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0138]    (4) 15 uM Haematoporphyrin derivative (HPD) was added, or 15 uM acidified porphyrin (Protoporphyrin IX, PpIX) was added. 
         [0139]    (5) The vacuum bottles were irradiated with 10 MeV X-ray for about 1 min, dose of 5Gy, to start the decomposition reaction of H 2 O 2 . The reaction was terminated by stopping irradiation. 
         [0140]    Experimental Results: 
         [0141]    (1) Haematoporphyrin and x-ray activation could rapidly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 , in comparison with the reaction catalyzed by using merely haematoporphyrin, the reaction time is shortened from 480 min to about 1 min, and the reaction rate increased by near 500 times (see:  FIG. 3 ). 
         [0142]    (2) Haematoporphyrin and x-ray activation could rapidly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 , the used concentration of H 2 O 2  was 1/20 to 1/50 of the concentration (1.5% H 2 O 2 ) used for the reaction catalyzed by merely using haematoporphyrin, the catalytic efficiency increased by 20 to 50 times (see:  FIG. 3 ). 
         [0143]    (3) PpIX and X-ray activation could rapidly catalyze the decomposition reaction of H 2 O 2 , to generate  1 O 2 , in comparison with the reaction catalyzed by using merely haematoporphyrin, the reaction time is shortened from 480 min to about 1 min, and the reaction rate increased by near 500 times (see:  FIG. 4 ). 
         [0144]    (4) PpIX and x-ray activation could rapidly catalyze the decomposition reaction of 0.01% H 2 O 2 , to generate  1 O 2 , the used concentration of H 2 O 2  was 1/150 of the concentration (1.5% H 2 O 2 ) used for the reaction catalyzed by merely using haematoporphyrin, the catalytic efficiency increased by 150 times (see:  FIG. 4 ). 
         [0145]    (5) When using 20% DMSO, 15% ethanol, or 5% mannitol to eliminate .OH, the decomposition reaction of H 2 O 2  catalyzed by haematoporphyrin and .OH was rapidly suppressed. Even under condition of high concentration of 1.5% H 2 O 2 , 20% DMSO, 15% ethanol and 5% mannitol could still inhibit 75.1%, 43.0% and 17.7% of  1 O 2  yield, respectively (see:  FIG. 5 ). 
         [0146]    The decomposition reaction of H 2 O 2  catalyzed by photofrin and .OH together has formula and pharmaceutical mechanism as follows: 
         [0000]    
       
         
           
             
               2 
                
               
                 H 
                 2 
               
                
               
                 O 
                 2 
               
             
              
             
               
                 → 
                 
                   
                     
                       
                         photo 
                         - 
                       
                     
                   
                   
                     
                       sensitizers 
                     
                   
                 
               
               
                 • 
                  
                 OH 
               
             
              
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   H 
                   2 
                 
                  
                 O 
               
               + 
               
                 O 
                 2 
                   
                   
                   
                 1 
               
             
           
         
       
     
         [0147]    This reaction has the following features: (1) rapid catalyst reaction rate, in comparison with the reaction catalyzed by using merely haematoporphyrin, the reaction rate increases by near 500 times. (2) high catalytic efficiency, in comparison with the reaction catalyzed by using merely haematoporphyrin, even a very low concentration of H 2 O 2  (0.01%) can still generate  1 O 2 , the catalytic efficiency increased by 150 times. (3) the catalysis of reaction is irrelevant to OH − , because PpIX has a higher catalytic efficiency than haematoporphyrin. (4) .OH plays an crucial role in the catalysis reaction, can rapidly start or stop the decomposition reaction of H 2 O 2 , .OH scavenger can rapidly inhibit the catalysis reaction. 
         [0148]    The above results show that both of photofrin and .OH are necessary conditions for highly efficient catalysis of the decomposition reaction of H 2 O 2  to generate  1 O 2 . Since the life of .OH is transient (10 −6  s), it can be used for quickly starting and stopping the decomposition reaction of H 2 O 2 . 
       Example 4 
     Catalyzing the Decomposition Reaction of H 2 O 2  Using Photofrin and .OH Free Radical (CDT Method) 
       [0149]    Experimental Method: 
         [0150]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0151]    (2) H 2 O 2  solution (in DMF: H 2 O=1:5) with concentration of 1.5% was added to the sealed vacuum bottles. 
         [0152]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0153]    (4) 15 uM Haematoporphyrin derivative was added. 
         [0154]    (5) 0.5 mM FeCl 3  (FeCl 3 .6H 2 O) and 0.5 mM Vit-C were added, sufficiently mixed, H 2 O 2  was decomposed to generate .OH, so as to start the decomposition reaction of H 2 O 2  to generate  1 O 2 . 
         [0155]    (6) It was 5 min after the reaction started, .OH scavenger (20% ethanol) was added, to terminate the reaction, DMA fluorescence degree was measured. 
         [0156]    Experimental Results: 
         [0157]    In the mixture solution of haematoporphyrin (15 uM) and 1.5% H 2 O 2 , 0.5 mM FeCl 3  (FeCl 3 .6H 2 O) and 0.5 mM Vit-C were added, mixed sufficiently, H 2 O 2  was decomposed to generate .OH, so as to start the decomposition of H 2 O 2  to generate  1 O 2 . In comparison with the reaction catalyzed by using merely haematoporphyrin, the reaction time was shortened from 480 min to 5 min. This indicates the .OH generated by chemical method can also rapidly start the decomposition reaction of H 2 O 2  to generate  1 O 2  (see:  FIG. 6 ). 
       Example 5 
     Using RCDT Method to Quantitatively Analyze and Measure  1 O 2    
       [0158]    Experimental Method: 
         [0159]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0160]    (2) H 2 O 2  solution (in DMF: H 2 O=1:5) with concentration of 0.075% was added to the sealed vacuum bottles. 
         [0161]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0162]    (4) 15 uM acidified haematoporphyrin (Protoporphyrin IX, PpIX) was added. 
         [0163]    (5) X-ray in different doses were used to irradiate the vacuum bottles. 
         [0164]    Experimental Results: 
         [0165]    Under condition of low concentration of H 2 O 2 , the contents of photofrin and H 2 O 2  were fixed, X-ray started the decomposition reaction of H 2 O 2 , and the amount of the generated  1 O 2  was in proportion with the irradiation dose. Using EXCEL correlation analysis CORREL function to calculate coefficient correlation of the  1 O 2  amount and the irradiation dose, r=0.91302, which indicated the correlation between the  1 O 2  amount and the irradiation dose was very significant (see:  FIG. 7 ). 
         [0166]    The traditional clinical PDT cannot be used for direct quantitative analysis of therapy and cannot measure  1 O 2 , which is one of the main factors preventing PDT from clinical application. 
         [0167]    The above results show that the contents of photofrin and H 2 O 2  were fixed, X-ray started the decomposition reaction of H 2 O 2 , and the amount of the generated  1 O 2  was in proportion with the irradiation dose. This indicates that the therapeutical dose of RCDT (i.e.,  1 O 2  yield) can fully analyzed and measured by using the irradiation dose of electron beam, x-ray, or ion beam. 
       Example 6 
     Screening and Studying and Developing a Series of Drugs for CDT or RCDT 
       [0168]    Experimental Method: 
         [0169]    (1) 10 ml vacuum bottles were used, and the vacuum bottles were totally sealed with Kodak photographic film light protecting paper. 
         [0170]    (2) H 2 O 2  solutions (in DMF: H 2 O=1:5) with different concentrations were added to the sealed vacuum bottles. 
         [0171]    (3) 5 uM 9,10-dimethylanthracene (DMA) was added. DMA was a kind of  1 O 2  specific indicator (probe), DMA had intensive fluorescence property, after binding to  1 O 2 , endorperoxide without fluorescence property was formed, so that the amount of the generated  1 O 2  is in inverse proportion with the content of DMA. 
         [0172]    (4) 15 uM Haematoporphyrin derivative (HPD), or 15 uM acidified porphyrin (Protoporphyrin IX, PpIX) was added. 
         [0173]    (5) The vacuum bottles were irradiated with 10 MeV X-ray, dose of 5Gy, to start the decomposition reaction of H 2 O 2 . The reaction was terminated by stopping irradiation. 
         [0174]    Experimental Results: 
         [0175]    Since PDT is totally different from CDT or RCDT in therapeutical mechanism, a photofrin suitable for PDT may not be suitable for CDT or RCDT. For example, it is found in the present example, the haematoporphyrin widely used in clinical PDT is far less efficient in catalyzing the decomposition reaction of H 2 O 2  to generate  1 O 2  than PpIX. 
         [0176]    Under the same conditions, the catalytic effect of PpIX is higher by 50 times or more than HPD. When H 2 O 2  concentration is 0.01%, PpIX and X-ray activation can catalyze the decomposition reaction of H 2 O 2 , so that near 40% (background subtraction) of DMA binds to  1 O 2  free radicals; when the concentration of H 2 O 2  is 0.03%, PpIX and X-ray catalyze the decomposition reaction of H 2 O 2 , so that 90% or more of DMA binds to  1 O 2  free radicals. However, even the concentration of H 2 O 2  reaches 1.5%, such effects cannot be achieved by haematoporphyrin and x-ray in catalyzing the decomposition reaction of H 2 O 2  (see:  FIG. 8 ). 
         [0177]    The above results show that photofrins with different structures have different efficiencies in catalyzing the decomposition reaction of H 2 O 2 , and photofrins with higher efficiency and practicality for CDT and RCDT could be obtained by further studying and developing. 
       Example 7 
     Example of Treatment of Vascular Plaques by RCDT Method 
       [0178]    Experimental Method: 
         [0179]    (1) Male New Zealand rabbits, bodyweight 3-4 kg, were fed with diet containing 1% cholesterol and pork fat, raised for 11 weeks, until atherosclerotic plaques occurred at vessels of eye ground at both sides and artery. 
         [0180]    (2) The rabbits were anesthetized with ketamine and thiopental sodium. 
         [0181]    (3) Target regions of plaques at artery to be treated were determined by total body CT plain scanning and CTA enhancing. 
         [0182]    (4) Target regions of plaques at artery to be treated were sketched by a therapy planning system, to formulate a therapeutical plan suitable for RCDT, using GTV dose of up to 5.0Gy, irradiated once. Normal feeding was restored during the procedure. 
         [0183]    (5) It was 2 h before the irradiation that 5-ALA (80 mg/kg in saline 5 ml) was intraperitoneally injected, carbamide peroxide (injection containing H 2 O 2 , 80 mg/kg) in 5 ml of saline was slowly injected via ear vein immediately before the irradiation, and the therapeutical plan was carried out immediately after the injection of carbamide peroxide. 
         [0184]    (6) It was 5-7 days after irradiation the CTA was reexamined, and the situations of elimination of vascular plaques were recorded. 
         [0185]    The New Zealand rabbit models of vascular plaques are common animal models. New Zealand rabbits are fed with high-cholesterol for 3 months, and CTA visualization and MR show the formation of plaques in thoracic aorta. The plaques are used as target regions, positioned, and radiotherapy plan is formulated. It is 1.5 h after intraperitoneal injection of 5-ALA (80 mg/kg of body weight) that a substrate is intravenously dripped, the vascular plaques are irradiated with 5Gy once. The New Zealand rabbits are continuously fed for one week. On the 7 th  day after therapy, CTA visualization and MR examination are performed again, and the results show that the plaques in thoracic aorta completely disappeared (see:  FIG. 9 ).