Multifunctional Magnetic Resonance Imaging Nanoprobes For Gastric Cancer Imaging And Therapy

Nanoprobes can deliver functional drugs to tumor tissues and realize precise tumor location.Magnetic resonance imaging?MRI?features unlimited depth of penetration and high resolution.Ultrasound imaging?US?is a convenient,cost-effective real-time imaging method that can effectively monitor the structural changes of soft tissues.Fluorescence imaging?FL?possesses sensitive imaging and realizes multi-channel fluorescence signal detection.Therefore,drug delivery nanoprobes with multi-modal imaging functions are of great significance.The tumor microenvironment has unique characteristics such as EPR effect,acid pH environment,hypoxia,high expressed H₂O₂ and GSH,therefore,it is important to design drug-loaded nanomaterials with smart-responsive drug release capacity based on tumor microenvironment.Based on this,this thesis mainly designed and developed three kinds of MRI-based nanoprobes.1.An"all-in-one"drug-loaded nanobubbles were prepared via dubble-emulsion method,using for gastric cancer FL/US/MR imaging and chemo-photothermal therapy.Photosensitizer IR-780 and oleylamine loaded positive-charged nanospheres with gadolinium-labeled bovine serum albumin?BSA?,anticancer drug5-FU and folate are assembled by electrostatic adsorption.Nanobubbles?120.41±18.30 nm?have a hollow structure and a 10 nm thick shell,and the r1 relaxation rate reached 16.56 s-1/mM,indicating that the feature as T1-weighted MRI contrast agent.Importantly,nanobubbles exhibited charge-switchable and drug-release behavior in response to pH stimulation,which helps to increase their penetration depth to the tumor tissue and accelerate drug release rate.In vivo tri-modal imaging results show that folate contributes to selective accumulation and long aggregation time of nanobubbles in the tumor site.Consequently,nanobubbles achieved tumor ablation under 808 nm laser irradiation.2.Drug-loaded copper ions-protein nanoprobes?C-m-ABs?were prepared for gastric cancer FL/photoacoustic?PA?/MR imaging and enhanced chemo-photo therapy.Folate-conjugated and Gd³⁺-labeled BSA loaded with anticancer drug doxorubicin?DOX?and photosensitizer indocyanine green?ICG?are self-assembled into nanobelts?length?110.5 nm,width?26.8 nm?via metal coordination effect of Cu²⁺.Cu²⁺of C-m-ABs can effectively consume intracellular glutathione?GSH?and catalyze intracellular H₂O₂ into O₂,which enhanceed the photodynamic therapy?PDT?of ICG.After Cu²⁺reduced to Cu⁺by GSH,more amount of toxic·OH production was significantly generated triggered by the photosensitizer ICG and laser irradiation,thus,C-m-ABs exhibited Photo-Fenton-like activity.Furthermore,C-m-ABs simultaneously exhibited high photothermal conversion effects,enhanced r1 relaxation rate?21.416 s-1/mM?,and stimuli-responsive drug release behavior?acid pH,GSH-,external light irradiation?.In vitro experiments showed that C-m-ABs presented excellent cytotoxicity against gastric cancer MGC-803 cells.Cm-ABs can be effectively enriched in tumor regions mediated by folate,which was observed by FL/PA/MR imaging.Thus,enhanced chemo/PDT/photothermal therapeutic effects achieved.3.Ultrasmall iron oxide nanoparticles?UIONPs?were prepared by co-precipitation method,in which[Fe³⁺]:[Fe²⁺]was set 2:1 in molar ratio,and polyacrylic acid was used as surface stabilizer of UIONPs.Results of r1,r2 relaxation and T1-,T2-weighted MR imaging in vitro determined that UIONPs prepared at 90°C can be used as T1,T2 dual-enhanced MRI contrast agents.Furthermore,UIONPs presented catalase-like and peroxidase-like activity in vitro,which catalyze the decomposition of H₂O₂ to produce O₂ and catalyze H₂O₂ into toxic·OH under acidic conditions?pH 5.0?,thus,UIONPs showed high cytotoxicity due to·OH generation capacity.In vivo MR imaging experiments show that UIONPs performed a certain degree of T2-weighted contras MR imaging;UIONPs can also achieve specific negative imaging of liver blood vessels and gallbladder under T1 test sequence while enhanced T1-weighted MR imaging in tumor site.UIONPs can accumulate in the MGC-803 tumor observed by MR imaging,and showed a certain degree of antitumor effect.