Design And Performance Study Of Tumor Microenvironment Responsive Self-assembly Croconaine Theranostic Probe

Hepatocellular carcinoma is one of the deadliest cancers and it is a serious threat to human health and life for many years.At present,surgical resection is the most effective treatment for HCC.In order to precisely remove all tumors during surgery,reducing the recurrence caused by tumor remnants,and protecting the remaining liver to the maximum extent,it has great clinical value to develop a targeted probe for accurate imaging of HCC.Near infrared fluorescence imaging is the most appropriate intraoperative imaging method because of its low background signal,high detection sensitivity,cheap price and convenient operation.However,HCC is prone to potential tumor metastasis,so it is often combined with non-interventional therapy to kill tumor in clinical practice.Ultrasound used in sonodynamic therapy has stronger tissue penetration ability.So that it is expected to exert its unique advantages of sonodynamic therapy in the treatment of deep HCC.Nanoparticle-based multi-drug delivery platforms can effectively retain theranostic probes in the tumor through EPR effect,providing more possibilities for the integration of cancer diagnosis and treatment.But normal liver tissue often has unexpected uptake of large nanoparticles.Therefore,the design of size-environment-responsive nano-drugs has great significance in enhanced the stability at in vivo circulation of nanoparticles and drug retention in liver tumor.Based on the above considerations,we modified a near infrared fluorescence croconaine dye by chemical process,designed and synthesized a water-dispersived theranostics near-infrared fluorescent probe,CR-PEG-GBP,which can target the Glyphican-3(phosphatidylinositol protein,GPC3),a tumor marker highly expressed in HCC,and slef-assemble into nanoparticles under slightly acidic conditions so that it can remain in the tumor microenvironment.And it was used for the targeted imaging of HCC.And we further developed the sonodynamic treatment function of the croconaine probe,and the enhanced sonodynamic therapy for HCC was realized by photothermal heating.We validated the potential of croconaine probe in imaging and targeted therapy at the molecule level,cellular level and in vivo experiments,confirmed that this croconaine probe can be precise targeting of HCC,can be used to NIRF imaging and optical imaging.And the probe showed a good effect of tumor suppression in the murine tumor model after enhanced SDT by heating with PTT.Our study has great scientific significance and potential clinical value for the development of fluorescence imaging and biological application of croconaine fluorescence probe.Different from previous tumor environmental response nanoparticle to drug release,the in situ self-assembled probe designed by us can reduce the uptake by normal liver,providing a new design idea for the targeting of HCC.On the other hand,for the first time,croconaine was used as a sound sensitizer for the treatment of HCC,which not only explored the new function of croconaine,but also provided more possible options for the effective treatment of HCC.