The Study On The Structure-Effect Relationship Of Small-Molecule Targeting PTKs Photosensitizer

Photosensitizer acts as a key role in PDT,and the enhancing of photosensitizer targeting has become a hot spot of recent research.Small molecular targeting agent can specially inhibit the necessary signal transduction pathway during the growth and proliferation of tumor.In recent years,the strategy that using the targetment of small molecular targeting agent to enhance the targeting of photosensitizer has obtained great achievements.It can provide a new strategy to design novel high efficient and lower toxicity anti-cancer drug by studying the structure-effect relationship.Based on the previous work of our group,here we choose small molecular targeting agent,such as gefitinib,erlotinib which are used as the target structure and zinc phthalocyanine as the photosensitiser,Small molecule targeted agents-zinc phthalocyanine conjugate was selected as the objection of study.By evaluating the ability of its targeting in vivo/vitro and Inactivation of the tumor cells in vitro to explore its structure-activity relationship.The main content and results are shown as following:1.Vitro targeting:Targeted uptake of tumor cells about conjugates showed a positive correlation with the expression of EGFR in different cancer cells.The introduction of gefitinib structure could increase the sensitivity of zinc phthalocyanine to the expression of EGFR in tumor cells.The targeting unit will affect the uptake amount of zinc phthalocyanine conjugate in tumor cells,compared with erlotinib,the uptakes of gefitinib-phthalocyanine conjugate was in the higher level in tumor cells.The differences in binding sites have no significant effect on the targeting of the conjugates,but it do affect the uptake of conjugates in tumor cells which are positive with EGFR.The binding of the erlotinib structure to the phthalocyanine zinc structure using UiO-66 as the linker can significantly improve the targeting of the phthalocyanine to tumor cells,showing that MOFs provide a novel strategy to small molecule targeting drug conjugated with a photosensitizer.The introduction of zinc phthalocyanine did not significantly affect the targeting of gefitinib which is sensitive to non-small cell lung cancer cell lines.2.Vivo targeting:After administration of the tail vein,ZnPc-EU was first distributed through the blood to the mice.After a certain period of time,the drug was gradually enriched in the tumor site.The 3D tomography showed that the drug was highly enriched in the EGFR overexpression region which has a good targeting for BXPC-3 tumors,which is consistent with the results of in vitro targeting studies.3.Anticancer activity study in vitro:we found that the introduction of phthalocyanine zinc structure not only improved the cytotoxicity of gefitinib to tumors,but also reduced its sensitivity on EGFR expression.While the photodynamic activity of phthalocyanine was not significantly changed.The study on subcellular location showed that the conjugate could be distributed in the lysosomes and mitochondria while there was no distribution in the nucleus.The erlotinib-phthalocyanine conjugate Er-UiO-66-Pc also showed a dual effect of chemotherapy and photodynamic therapy.In summary,we have designed a proper linker that combines small molecule target drugs and photosensitizers,which might be expected to be a new strategy for designing highly efficient and low toxicity anticancer drugs.