Multiscale Photoacoustic Imaging-guided Diagnosis And Treatment Of Glioblastoma And The Central Nervous System Microenvironment

Glioblastoma is a common primary brain tumor in human central nervous system,characterized by heterogeneous growth,highly proliferative tumor vasculature and a complex microenvironment.At present,the clinical diagnosis and treatment of glioblastoma are challenging,and the key factor limiting the diagnosis and treatment of glioblastoma is the blood-brain barrier that naturally exists in the central nervous system.Almost all existing tumor-targeted diagnostic probes and chemotherapeutic drugs have difficulty in actively crossing the complete blood-brain barrier,and therefore have difficulty in playing their role in the diagnosis and treatment of the disease.To overcome these challenges,we propose a novel photoacoustic imagingguided NBs/HPPH-targeted photodynamic combined with nano-bubble burst composite diagnosis and treatment strategy,which enables early detection and efficacy assessment of tumors under the guidance of photoacoustic molecular imaging technology,as well as long-term visualization and monitoring of the microenvironment of tumor-associated CNS-like lymphatic system-blood-brain barrier.The research contents and innovations of this thesis are as follows.The particle size of microbubbles was reduced to the nanoscale by in vitro synthesis technique and loaded with photosensitizers inside to form NBs/HPPH complexes.Since NB is a good ultrasound contrast agent and HPPH has good optical absorption properties in the visible wavelength band,the NBs/HPPH complexes can be tracers for both ultrasound and photoacoustic imaging.The circulatory pathway of NBs/HPPH complex in vivo is observed under the monitoring of dual-modality imaging,and when the complex reaches the tumor region,the detonation of the complex is realized under the action of exogenous ultrasound to precisely release the drug in the tumor region.The bursting of NBs/HPPH complex not only provides signal enhancement for diagnostic sensitivity,but also brings great mechanical impact to surrounding cancer tissues,while improving the biological synergistic blastphotodynamic treatment of deep subcutaneous tumors.Enhancing the photodynamic treatment effect of deep tumors by improving the efficiency of light transmission in tissues.We then constructed a mouse glioblastoma in situ and achieved controlled opening of the blood-brain barrier in mice under the action of focused ultrasound and NBs/HPPH,while accomplishing precise drug delivery and release,which solved an important problem for drug delivery in the central nervous system,based on which the strategy was applied to the diagnosis and treatment of intracranial glioma in situ.In the next step,we designed and synthesized organic small molecule probes that can cross the blood-brain barrier autonomously,and with the help of the probes,we used the advantages of radiation-free,high-resolution and in situ in vivo optical imaging technology to realize the dynamic correlation monitoring of early in situ glioma in time and space,and to monitor the metabolic pathways of exogenous substances in the brainlike lymphatic system-blood-brain barrier of mice with in situ glioma,and to elucidate their metabolic pathways in the central nervous system.The pathways were monitored at the holistic-cellular-molecular level.We also observed the changes of CNS-micro vessel/blood-brain barrier in glioma mice at different growth stages at the holisticcellular-molecular level to reveal the stage-specific effects of glioma on the CNS.Based on this,this thesis achieved precise diagnosis and treatment of deep subcutaneous and intracranial glioblastoma in situ,enhanced the sensitivity of early tumor detection to sub-millimeter level.It also enhanced the depth of photodynamic therapy to centimeter level,achieves long-term monitoring of CNS microenvironment under the guidance of cross-scale photoacoustic molecular imaging,discovers the difference of blood-brain barrier permeability in different periods of glioblastoma.We proposed a method of blood-brain barrier permeability assessment based on photoacoustic imaging,it was proposed to monitor the pathways and mechanisms of central lymphoid-blood-brain barrier-immune system clearance of exogenous substances with the intervention of small molecular probes.This thesis provided an important reference for the analysis of the spatial and temporal dynamic correlation of central lymphoid-blood-brain barrier in glioblastoma.