Fabrication Of Photothermal Ultrasound Contrast Agents For Theranostics Of Tumor

Tumor is a fatal disease which has great effect on patients’ quality of life. Although many kinds of therapeutic methods including surgery, chemotherapy, radiotherapy and photodynamic therapy have been applied to treat tumor, the therapeutic effectiveness is still unsatisfactory. Preparation of multifunctional contrast agents has gained great attentions. More and more researches focusing on photothermal therapy for tumor and to improve the efficiency of gene delivery were published. Therefore, choosing the medical materials with the function of photothermal effect to prepare multimodal imaging contrast agents to realize photothermal therapy and gene delivery has become a new direction in the field of tumor treatment.This research aims to prepare multimodal imaging contrast agent through the application of photothermal heating materials with better biological safety, to realize multimodal imaging guided photothermal therapy and ultrasonic imaging guided gene delivery.To make use of photothermal effect to improve gene transfection efficiency, we firstly combined chitosan, a widely used and safe biomedical material, with prussian blue approved by FDA to prepare chitosan stabilized prussian blue nanoparticles(CS/PB NPs). Evaluation of the photothermal effect on gene transfection efficiency in vitro has proved that CS/PB NPs were successfully prepared and it could enhance gene delivery by photothermal effect.To improve gene transfection efficiency with ultrasound image guide targeted delivery by ultrasound-targeted microbubble destruction and photothermal effect, CS/PB NPs were combined with DNA, and were integrated with microbubbles to prepare chitosan stabilized prussian blue nanoparticles microcapsules. Evaluation of the photothermal effect and the ultrasound-targeted microbubble destruction on gene transfection efficiency in vitro, the imaging effect in vitro and in vivo and the biocompatibility for four cell lines in vitro and histological changes in vivo has proved that it was successfully prepared, while it could realize the function of gene delivery guided by ultrasonic imaging and enhanced with ultrasound wave irradiation and near infrared light irradiation. Due to the good biological safety and the ablity of photocontrollable gene delivery, these two materials would be applied in clinic in future.Photothermal heating materials could absorb the energy of the light an d elevate the temperature, improve the permeability of the cell membranes to enhace gene transfection efficiency, and kill tumor cells directly with higher temperature to realize the function of photothermal therapy.Poly(lactic acid) with good biocompatibility were choosen and prepared polymeric microcapsules through water-in-oil-in-water double emulsion method to realize the function of ultrasound contrast imaging agent. At the early phase of preparing polymeric microcapsules, superparamagnetic iron oxide nanoparticles were added, and graphene oxide were deposited on the surface of polymeric microcapsules to form iron oxide loaded poly(lactic acid) microcapsules coated with graphene oxide. Evaluation of the photothermal effect in vitro and the imaging and biocompatibility in vitro and in vivo had proved the capabilities of it to serve as a novel theranostic agent with the combination of multimodal US/MRI/PAT contrast imaging and NIR photothermal therapy.To perpare the multifunctional ultrasound contrast agents with the function of up-conversion luminescence imaging, upconversion nanoparticles were added to form the primary microcapsules, and copper sulfide were deposited on the surface of polymeric microcapsules to form upconversion nanoparticle loade d poly(lactic acid) microcapsules coated with copper sulfide. The data of the imaging and biocompatibility in vitro and in vivo and the photothermal effect in vitro had proved that it could be served as a novel theranostic agent with the combination of multimodal US/UC/PAT contrast imaging and photothermal therapy.The development of multifunctional ultrasonic contrast agents with the function of photothermal effect would help to improve the cancer treatment, and provide the references of the new generation contrast agents and more therapeutic methods for tumor.