Disease Evaluation And Theranostics Of Rheumatoid Arthritis Based On Multimodal Photoacoustic/Ultrasound Imaging

Aims and backgroundFor patients with rheumatoid arthritis(RA),accurate assessment and effective treatment are essential.Ultrasound(US)is a useful diagnostic tool for RA,but its role in clinical utilization for RA management is still controversial.It is necessary to develop novel imaging methods to assist ultrasound in assessing RA.On the other hand,conventional treatment of RA is ineffective for refractory arthritis.And side effects and drug resistance of the conventional drugs pose difficulties in the management of RA.The design of local treatment strategies for severe arthritis as a supplement to systemic therapy is therefore of clinical value.Photoacoustic imaging(PAI)possesses the ability of detecting optical properties in relatively greater depth.It allows the visualization of local structures and the calculation of tissue oxygen saturation by measuring haemoglobin and deoxyhaemoglobin levels.PAI can also detect PA exogenous agents.The integration of photoacoustic imaging into conventional ultrasound instruments for multimodal PA/US imaging,is more suitable for clinical scenarios.The feasibility of PAI in RA assessment has been initially investigated by previous studies,but PA measurement of tissue oxygenation and its supplementary role for US has not yet been validated.Novel materials,including nanomaterials or micromaterials,show great potential in treating RA.Combining and connecting multiple functional groups,these theranostic materials can be used to treat RA arthritis with multiple therapeutic methods guided by multimodal imaging.Also,PA and US can be integrated into these inflammation-inhibiting materials,as important imaging-guided strategies.Based on the above background of RA,PA and nanomaterials,the main objectives of this study are(1)to investigate the associations among PA-oxygenation,US parameters,and disease activity,and to further explore the value of combined PA/US assessment of RA disease activity;(2)to design PA-induced and anti-inflammatory theranostic nanomaterials or micromaterials,and to realize the combination of multimodal imaging and synergistic therapy for RA.MethodsThe study was divided into three parts.The first part was to recruit RA patients for multimodal PA/US imaging examination.We measured the tissue oxygen saturation(SO2),and evaluated the association among tissue oxygenation,ultrasound results and clinical scores.The second and third part were the design of multifunctional theranostic micromaterials and nanomaterials that combine PA/US imaging and inflammation inhibiting ability.The utility of the theranostic materials were validated through material characterization,in vitro cell experiment,and in vivo animal experiment.(1)Multimodal PA/US imaging was performed on seven small joints of 118 RA patients to measure the oxygen saturation(SO2)values of the synovium.The SO2 values were divided into three categories,including hyperoxia,intermediate status,and hypoxia.And we assessed the association between oxygenation status,ultrasound scores and clinical scores.(2)FAM-TNF-a-siRNA-cMBs were prepared by binding fluorescein amide(FAM)-labeled tumour necrosis factor-a(TNF-α)small interfering RNA(siRNA)to cationic microbubbles(cMBs).The anti-inflammatory therapeutic effect of FAM-TNF-α-siRNA-cMBs was verified by cellular and animal experiments.And the whole treatment process was monitored by PAI and contrast-enhanced ultrasound(CEUS).(3)MPDA@CeO2 nanoparticles were prepared using mesoporous polydopamine(MPDA)and cerium dioxide(CeO2)nanoparticles.The morphology,photothermal properties,and catalytic activity of the nanoparticles were examined.We verified the efficacy of PA-guiding light-controlled synergistic photothermal/oxygen-release/reactive oxygen species(ROS)scavenging therapy of MPDA@CeO2 by cellular and animal experiments.Conclusions and results(1)Among 118 patients,34 had hypoxic wrist synovium,which was significantly lower than that of healthy volunteers.The synovial oxygenation state is typically low in RA patients when their local Doppler blood flow is low.And PA-synovial hypoxia state is associated with high disease activity.Compared with the ultrasound score alone,the new PA-US score has a better correlation with clinical disease activity.Multimodal PA/US imaging could be applied as a useful imaging method to assess disease activity for RA patients.(2)FAM-TNF-α-siRNA-cMBs successfully mediated gene silencing treatment and suppress inflammation in both cellular and animal experiments.The process was visualized by PAI and CEUS.The theranostic MBs can be utilized as an important supplementary to systemic RA treatment.(3)MPDA@CeO2 nanoparticles have a synergistic photothermal/oxygen-release/ROS scavenging anti-inflammatory effect.According to the animal experiments,PAI can be used to visualize the nanoparticles’ distribution and tissue oxygenation changes for guiding treatment.MPDA@CeO2 nanoparticles are also promising theranostic materials in assisting RA treatment.In summary,the study initially identified the relationship between PA-oxygen saturation and RA disease activity,and suggested the possible value of multimodal PA/US imaging for RA assessment.On the other hand,this study successfully developed theranostic microbubbles and nanoparticles for PA/US guided synergistic inflammatory inhibition therapy.