Application Of Multifunctional Stimulus-response Intelligent Nanoprobe In Tumor Diagnosis And Treatment

In recent years,with the extensive interdisciplinary of nanotechnology and biomedical field,nanomaterials have been widely used in the development of novel composite nanoparticles for the treatment of tumors due to their versatility,easy preparation and high stability.Therefore,developing imaging-guided multifunctional theranostic nanoplatform offers great promising potential in the early diagnosis and effective cancer therapy.Based on the difference between tumor microenvironment and normal tissues,this thesis focuses on synthesizing stimulus-responsive nanoplatforms for early diagnosis and treatment of tumor,combining chemotherapy with gene therapy,photothermal therapy or sonodynamic therapy to precisely control drug release.The main findings are summarized as follows:Firstly,a novel nanoprobe was fabricated for targeted imaging-guided treatment of tumor in vivo that tactfully integrated chemotherapy,photothermal therapy?PTT?and gene therapy.Briefly,folic acid-modified silver sulfide@mesoporous silica core-shell nanoparticle was first modified with desthiobiotin?db?on the surface,then doxorubicin?DOX?was loaded into pore.Avidin was employed to prevent leakage of DOX via desthiobiotin-avidin interaction.At the same time,db-modified survivin antisense oligonucleotide?db-DNA?which could inhibit survivin expression was also grafted on avidin at the outer layer of nanoparticle.DOX release and db-DNA dissociation were simultaneously triggered by overexpressing biotin in cancer cells,then combining PTT from Ag₂S QD to inhibit tumor growth.Collectively,this robust nanoplatform for targeted imaging and combinational therapy of tumor might provide an insight for cancer theranostics.Secondly,developing targeting delivery and on-demand controlled drug release nanocarrier offers great promising potential for effective cancer therapy.Here,a near-infrared?NIR?light-triggered smart nanocarrier was designed for targeted imaging-guided treatment of cancer that tactfully integrated photothermal therapy?PTT?with chemotherapy to accurately control drug release time and dosage.This delivery system was composed of Ag₂S QD coating with dendritic mesoporous silica?DMSN?,which acted as nanocarrier of doxorubicin localized inside pores.To provide the nanocarrier with controlled release capability,the polypeptide-engineered that structure was reversible to photothermal effect of Ag₂S QD,was covalently grafted to the external surface of Dox-loaded DMSNs as“gatekeeper”.Due to acidity-triggered charge reversal of polypeptide,which significantly extended circulation time and improved targeting ability,fluorescence and photoacoustic signals were still obvious at tumor site post-12 h by tail intravenous injection of probe.The drug release amount could be accurately controlled to realize multiple small amount local release by adjusting irradiation time and on/off cycle.Furthermore,mild PTT with multiple short-term exposures not only reduced the side effect of overdose drug but also avoided skin damage caused by long-term irradiation.Mice skin showed smaller wound area and faster healing speed after treatment.Therefore,this novel approach provided an ideal NIR light-triggered nanocarrier with accurate control of area,time,and especially dosage.In addition,non-invasive sonodynamic therapy?SDT?has been developed rapidly due to its advantages of high penetration depth and low side effects,but tumor hypoxia greatly restricts its therapeutic effect.Here,based on the natural enzyme system of red blood cell?RBC?,biomimetic nanoparticle?QD@P?R was fabricated by encapsulating Ag₂S QD in vesicles of RBC membrane.After the oral administration of anti-tumor drug PEITC in mice assisted to increase the intracellular H₂O₂ concentration,the enzyme in the nanoprobe catalyzed endogenous H₂O₂ of tumor cells to increase the O₂ content and effectively alleviate tumor hypoxia.Ag₂S QD,as a sonosensitizer for the first time,was triggered by ultrasound under the guidance of fluorescence imaging to generate reactive oxide species?ROS?to induce tumor cell death,and the increase content of O₂significantly enhanced the effect of SDT.This work tactfully integrated the advantages of natural system and SDT,providing an insight for effective treatment of deep-seated tumors.To sum up,based on the versatility of silver sulfide quantum dots and the special microenvironment of tumor tissues,we developed a variety of stimulus-responsive multifunctional nanoplatforms.And the endogenous overexpressed molecules of tumor cells were fully utilized as stimulation sources or raw material sources in the treatment,which was safely and efficiently used for early diagnosis and treatment of cancer.At present,the research was mainly in the initial stage of animal experiments.In order to realize further clinical application,the safety,simplicity of preparation and reasonable configuration of probe functions need to be considered.Therefore,in the future,we will select complementary functions in the probe design,develop simple preparation methods,and improve the yield to provide a basis for clinical transformation.It is believed that with the continuous development of nanomedicine technology,the transformation from basic research to clinical application can be realized as soon as possible,and it can be better used for the diagnosis and treatment of malignant tumors.