Study On The Photodynamic Anticancer Activities Of Novel Phthalocyanines And Their Doxorubicin Conjugates

Photodynamic therapy(PDT)is a novel method for cancer treatment.Essentially,it takes advantage of reactive oxygen species produced when photosensitizer under the excitation of light to damage cancer cells.Therefore,photosensitizer is a vital factor which can influence the efficience of PDT.Phthalocyanines,as a new generation of photosensitizer,have attracted much attention in the field of anticancer reaserach due to their good properities as follows:the maximum absorption wavelength located in near infrared region which can easily pass through the body tissues,low toxicity and favourable light&heat stability etc.On the basis of previous studies of our group,this thesis is going to the photophysical,photochemical properties and biological activities of novel phthalocyanines and their doxorubicin conjugates.It is expected to provide beneficial reference in the development of novel efficient anticancer photosensitizers and chemotherapy conjugates.The main research work of this thesis can be summarized as follows:1.The photodynamic activities of eight silicon phthalocyanines(SiPcs)axially symmetrically substituted with amino acids,nucleosides or carboxylic acid esters have been compared against malignant liver cancer HepG2 cells in vitro.The results show that the eight compounds all have photodynamic activities.Especially,three silicon phthalocyanines substituted with amino acids and one silicon phthalocyanine substituted with adenosine show high photodynamic antitumor activities with IC50 values<5 nM.These results can be attributed to their high cell uptake rate and high singlet oxygen yield.Meanwhile,SiPcs symmetrically substituted methyl salicylates exhibits selective photocytotoxicity towards HepG2 and human normal liver cells L02.Its IC-50 value against HepG2 is 30 μM,while its IC50 value towards L02 is 125 μM.2.Four novel silicon phthalocyanines axially asymmetrically substituted with tyramine and low polyethylene glycol have been synthesized and characterized.The photophysical,photochemical and photobiological properties of four asymmetric SiPcs and two corresponding symmetric SiPcs were further studied.The results are summarized as follows:(1)the maxlimum absorption wavelength of six compounds range from 674 nm to 681 nm and their maximum emission wavelength are 681-689 nm,they all exist in the form of monomer in the solution of DMF and cell medium.(2)Compared with corresponding symmetric silicon phthalocyanine,the photodynamic anticancer activities of four asymmetrical SiPcs are better due to their high cell uptake rate.(3)Z42,the SiPc asymmetrically substituted with tyramine and tetraethylene glycol has a very high photodynamic activity with an IC50 value as low as 3 nM aganist malignant gastric cells BGC-823.(4)The pharmacokinetic study of mice bearing a hepatoma H22 tumor indicates that the compound Z42 reaches a maximum distribution at the tumor location after 24 h post-injection by tail vein injection(2 mg/kg).And then irradiated with a 685±4 nm laser(0.1 w/cm2)for 5 min at the tumor location,the inhibition rate was found to be 60%and no significant skin phototoxicity was observed.3.Z42 liposome has been prepared by hand-cranking combined with ultrasonic dispersion technology.The particle size and potential distribution of Z42 liposome are 139.2 nm and 11.3 mV,respectively.The encapsulation efficiency of Z42 liposome is 95%.Besides,Z42 liposome shows preferable photodynamic effect on BGC-823 cells than Z42 itself,its IC50 value as low as 0.17 nM.4.The enzymolysis release of dipeptide-doxorubicin and zinc phthalocyanine-depeptide-doxorubicin prodrug under the action of FAPa have been studied.It’s found that both compounds have a certain degree of enzymolysis under the specific effect of FAPα,leading to the release of doxorubicin.At the same time,the cytotoxicity effect of four zinc phthalocyanine-doxorubicin conjugates and corresponding zinc phthalocyanine on malignant breast cancer cells MCF-7 have also been studied.The main results are summarized as follows:(1)The chemotherapy toxicities of doxotubicin conjugates are lower than that of doxorubicin.(2)In the condition of illumination,disubstituted lactone hydrolysis zinc phthalocyanine-doxorubicin DETZ1 showed a stronger photodynamic inhibition effect on MCF-7 cells than the corresponding ZnPcZ1.