Preparation Of Functional D-A-D Structured Organic Small Molecules Based On NIR-Ⅱ Photoexcitation And Its Synergistic Therapy Of Breast Cancer Bone Metastases

Breast cancer is the most common cancer in women worldwide,and more than half of breast cancer patients will develop bone metastasis symptoms at an advanced stage.Chemotherapy is the main method to inhibit the growth and bone metastasis of breast cancer,but it still cannot effectively improve the clinical outcome of patients due to the disadvantages such as poor drug resistance,non-specific biodistribution and clinical complications.Therefore,it is necessary to develop new tumor treatment methods to improve the therapeutic effect.At the same time,the heat shock proteins secreted by tumor cells also limit its therapeutic effect,so it is necessary to combine PTT with other treatment methods to solve the disadvantages of single treatment.In this thesis,catechole-modified functional D-A-D NIR-Ⅱ organic small molecules（BBT-TF-DA）were synthesized and fabricated into nanoparticles BTZ/Fe²⁺@BTF-DA and BTZ/Fe²⁺@BTF/ALD.The synergistic treatment of breast cancer bone metastases by NIR-Ⅱ fluorescence/photoacoustic dual-mode imaging guided NIR-Ⅱ PTT/chemotherapy/chemical kinetics（CDT）was realized respectively.The specific research content of this paper is as follows:（1）Preparation of NIR-Ⅱ photostimulated dopamine-modified D-A-D type organic small molecules:In the work of this chapter,6,7-bis（4-（hexyloxy）phenyl）-4,9-di-（thiophen-2-yl）-[1,2,5]thiadiazolo[3,4-g]quinoxaline（TTQ）and(4,8bis(5-bromo-4-（2-octyldodecylthiophe-2-yl）-benzo[1,2-c:4,5-c’]bis[1,2,5]thiadiazole（BBT）were selected as electron acceptors,and 9-bis（6-bromo-hexyl）-9-fluorene（F）and 2-(9,9-bis（6-bromo-hexyl）-9-fluoren-2-tributyl（2-thienyl）tin（FT）were selected as electron donors,and then D-A-D type organic molecules TTQ-F and BBT-FT were synthesized by stille coupling and Suzuki coupling.Through optical properties testing and analysis,when the organic solution of BBT-FT was prepared with tetrahydrofuran（THF）,the BBT-FT exhibited stronger NIR-Ⅱ absorption and NIR-Ⅱ fluorescence emission.Therefore,BBT-FT was selected as the conjugate backbone structure applied to NIR-Ⅱ photodiagnosis and treatment agent,and it was functionalized by sodium azide（Na N₃）substitution and click reaction to obtain the final product catecholol（DA）modified BBT-FT-DA.It has the potential to be applied to NIR-Ⅱ fluorescence imaging-guided combination therapy.（2）Multimodal combined treatment of NIR-Ⅱ photoexcited photodiagnosis and treatment agents for breast cancer:In this thesis,BTZ/Fe²⁺@BTF-DA nanoparticles were prepared by coating a small organic molecule（BBT-FT-DA）with bortezomib（BTZ）in DSPE-m PEG 2000 by covalent bonding force,and then coordinating Fe²⁺through ionic bonding force.The particle size of BTZ/Fe²⁺@BTF-DA is 246 nm,which shows excellent biocompatibility and particle size stability.Under 1064 nm laser irradiation,the absorption spectrum is 900-1200 nm,the emission spectrum is 1100-1300 nm,and the photoacoustic intensity is linear with the concentration,which has excellent NIR-Ⅱ fluorescence signal intensity,NIR-Ⅱ photoacoustic signal intensity and good photostability.Under 1064 nm laser irradiation with a power of 1.0 W cm^-2,the photothermal conversion efficiency is 34.95%,which has excellent NIR-Ⅱ PTT effect and can accelerate the release of BTZ drug and Fe²⁺,thereby enhancing the therapeutic effect.The in vivo results of the4T1 breast cancer mouse model showed that BTZ/Fe²⁺@BTF-DA had bright in vivo NIR-Ⅱ fluorescence and NIR-Ⅱ photoacoustic signals under 1064 nm laser irradiation.In acidic and hydrogen peroxide（H₂O₂）-overexpressing tumor microenvironment,BTZ/Fe²⁺@BTF-DA will release BTZ to achieve chemotherapy,and Fe²⁺ions will be released to trigger Fenton reaction to produce free radicals to achieve chemokinetic treatment.Through the comparison of multiple treatment groups,NIR-Ⅱ PTT/chemotherapy/CDT combination therapy has a more obvious therapeutic effect on breast cancer tumors.（3）Multimodal combined treatment of NIR-Ⅱ photoexcited photodiagnosis and treatment agents for bone metastases of breast cancer:Based on the excellent combined therapeutic effect of BTZ/Fe²⁺@BTF-DA in the previous chapter,we used the bone-affinity property of alendronate to modify alendronate（ALD）on the surface of nanoparticles to obtain BTZ/Fe²⁺@BTF/ALD nanoparticles to improve the enrichment ability of nanoparticles for bone metastases.The in vivo test results of the 4T1 breast cancer bone metastasis mouse model showed that BTZ/Fe²⁺@BTF/ALD could be effectively enriched at the bone metastasis tumors and realize the NIR-Ⅱ fluorescence and NIR-Ⅱ photoacoustic guided NIR-Ⅱ PTT/chemotherapy/CDT synergistic treatment under 1064 nm laser irradiation.