Therapy Of Brain Tumor By Ultra-small Nanoparticles Combined With Focused Ultrasound

Brain tumor,which represents a deadly disease that has been difficult to be identified and treated,is one of the most challenging diseases due to its particularity and complexity.The Blood-Brain Barrier(BBB)plays an important role in maintaining the stability of central nervous system(CNS).The unique structure of BBB is the most stringent barrier in the human body.On one hand,it prevents harmful substances from entering the CNS and maintains the normal physiological microenvironment in the brain,on the other hand,it prevents about 98%of small molecule drugs and all of the macromolecular drugs entering the CNS.The existence of BBB affects the therapeutic effect of brain diseases seriously.Therefore,how to safely,non-invasively and targeted transport the therapeutic agents across the BBB and reach the target site is an urgent problem to be solved at present.The work of this thesis mainly focuses on the focused ultrasound-assisted opening of the BBB,using the ultra-small Cu2-xSe NPs as therapeutic agent for noninvasively monitoring the opening and recovery of the BBB.The ultra-small Cu2-xSe NPs loaded with chemotherapeutic drugs were developed for photodynamic therapy and chemotherapy of orthotopic brain tumor under the irradiation of 1064 nm laser with the assistance of focused ultrasound.The main results of the study are as follows:Chapter 1:A brief overview of the research progress of the BBB.Firstly,the imaging methods of brain diseases diagnosis are summarized systematically,and then the various ways of therapeutic reagents to enter the CNS are outlined.The strategies to enhance the permeability of the BBB and the basis and research content of this dissertation are introduced at last.Chapter 2:PA imaging of different size Cu2-xSe nanoparticles in brain with the assistant of focused ultrasound.Cu2-xSe NPs with the different sizes of 3 nm,20 nm and 100 nm were synthesized.After the BBB opening mice were administrated with Cu2-xSe NPs(3 nm,20 nm and 100 nm),The PA imaging of the BBB opening mice were captured after treatment with various size of Cu2-xSe NPs.The results showed that the size of 3 nm Cu2-xSe NPs were the best for PA imaging of the opening BBB.Chapter 3:Monitoring the opening and recovery of the BBB with noninvasive molecular imaging by biodegradable ultra-small Cu2-xSe NPs.Dual-modal PA and SPECT/CT imaging based on ultra-small Cu2-xSe NPs(3 nm)were used to noninvasively monitor the opening and recovery of the BBB induced by focused ultrasound.The ultra-small Cu2-xSe NPs exhibited a long blood circulation time.Both small size and long blood circulation time enable them to efficiently penetrate into the brain with the assistance of ultrasound,which resulted in a strong signal at the sonicated site and allowed for PA and SPECT/CT imaging monitoring the recovery of the opened BBB.The results of biodistribution,histological staining and blood routine examination indicate that the accumulated Cu2-xSe NPs could be excreted from the brain and other major organs after 15 days without causing side effects.By the combination of the advantages of noninvasive molecular imaging and focused ultrasound,the ultra-small biocompatible Cu2-xSe NPs hold great potential for the diagnosis and therapeutic treatment of brain diseases.Chapter 4:Second near-infrared window photodynamic therapy and chemotherapy of orthotopic brain tumor with ultra-small Cu2-xSe NPs.Ultra-small Cu2-xSe NPs possess a strong absorbance in the NIR-? window.Their strong NIR-? absorbance and the deeper-tissue penetration of NIR-? light ensure excellent photodynamic therapy performance under irradiation by a 1064 nm laser.We also demonstrate that ultra-small Cu2-xSe NPs can produce vast amounts of reactive oxygen species via electron transfer(for ·OH generation)and energy transfer(for 1O2 generation)mechanisms under irradiation.In addition,these NPs can be effectively and locally transported into orthotopic brain tumor with the assistance of focused ultrasound.The results show that the tumor growth can be significantly suppressed.This work demonstrates the great potential of drug-loaded ultra-small Cu2-xSe NPs as a promising therapeutic agent for treatment of orthotopic brain tumor.