Study On The Carborane-modified Boron Tyrosine L-B

Boron Neutron Capture Therapy was first used in clinical trials in the 1950 s.As a new type of radiotherapy,compared with traditional cancer treatments,BNCT’s duality,targeting and treatment accuracy are its outstanding advantages.However,BNCT has many difficulties in becoming a routine therapy for cancer.The biggest problem is that boron-containing drugs,one of the two components of BNCT,fail to meet the necessary requirements.Therefore,this paper designed a new type of boron-containing drugcarborane modified boron tyrosine.The design with tyrosine as the parent body makes the boron-containing drug have the potential for selective uptake by tumor cells,which can make the boron-containing drug be transported and enriched in tumor tissues by amino acid transporter.The introduction of o-carborane can increase the amount of boron on a single molecule and increase the amount of boron in tumor cells.In addition,since the boron trifluoride group and the carboxyl group are isosteres,the introduction of the boron trifluoride group will not affect the transport and uptake of the amino acid transporter,and it also makes the boron-containing drug easy to use for 18 F labeling.Thus,PET can be used to accurately control the concentration of boron drug.The thesis is mainly divided into the following four parts:In chapter 1,the basic principles of boron neutron capture therapy are introduced,and the basic requirements and development process of boron-containing drugs used in boron neutron capture therapy are introduced in detail.The relevant ideas and current research status of improving the specific uptake of boron-containing drugs in tumor cells are discussed,and the potential application and research status of boron-containing drugs in vivo tracing are also discussed.In chapter 2,the synthetic route of the small molecule boron-containing drug carborane modified boron tyrosine was described in detail,and the successful synthesis of the compound was proved by proton nuclear magnetic resonance analysis.As a result,a suitable and feasible synthetic route was selected for multiple synthetic routes.In chapter 3,the cytotoxicity,cell uptake ability and distribution in mice of the prepared carborane-modified boron tyrosine were studied.Experiments show that carborane-modified boron tyrosine is much less toxic to normal cells than tumor cells,and its IC50 values for HL7702,4T1 and B16-F10 are 228.2 ± 12.65,66.09 ± 10.03 and 74.43 ± 23.92 μM.Respectively;carbon The boron content of borane-modified boron tyrosine in tumor cells is 6 to 8 times higher than that in normal cells,and it has better tumor selectivity;and its boron content in tumor cells is comparable to that of BPA,a commonly used boron-containing drug in clinical practice.It is 4 to 5 times higher than that,which can significantly increase the boron content in tumor cells;carborane-modified boron tyrosine in the B16-F10 tumor-bearing mouse model makes the boron content in tumor tissues reach 22 μg B/g,and the ratio of boron content in tumor tissue to blood reaches 3.5,which meets the parameters that must be achieved by boron-containing drugs in BNCT.Finally,summarize the paper,point out the innovations and shortcomings of this paper,and point out the direction for the next step to continue to improve the research of this topic.