Rare Earth Upconversion Nanoparticles For The Theranostic Studies Of Cancer And Alzheimer Diseases

In recent years,with the continuous development of science and technology,people's living standards have being remarkably improved.However,various diseases are still threatening the health of people and lowering the life quality of patients.Among them are malignancy and Alzheimer's diseases,which causes direct death or indirect dementia of human beings.These diseases were deeply associated with human microenvironmental factors such as reactive oxygen species?ROS?,pH,metal ions and oxygen,which could be understood with great difficultlies.The new multifunctional nano-diagnostic agent based on rare earth upconversion luminescent nanopartiles?UCNPs?is a hotspot of researches in materials science and clinical medicine,which is a kind of multifunctional biomedicals material with great potential for clinical application.In this research,several kinds of smart multifunctional UCNPs-based nanotheranotics have been successfully constructed as agents and/or carriers to realize the accurate detections and efficient treatments of tumors and Alzheimer's diseases.The main research results include:1.Rare earth upconversion nanotheranotics for Alzheimer's disease.We synthesized NaYF₄:Yb/Er/Tm upconversion luminescent nanoparticles by high-temperature pyrolysis method.And then UCNPs were linked with a chelating agent 8-hydroxyquinoline-2-carboxylic acid?HQC?.The HQC have a significant inhibitory effect on metal-induced amyloid protein?A??aggregation,which can target A?precipitation,seize and displace Cu²⁺in A?,inhibit A?aggregation,and decompose the toxic intermediate Cu²⁺-A?.Meanwhile,it will change the luminescence intensity of UCNPs after Cu²⁺bonding to the surface of UCNPs,and this change can be used to sensitively detect the concentration of Cu²⁺,thereby marking the location of A?in situ,and diagnosing the severity of Alzheimer's disease.Nerve cell experiments and biopsy imaging have effectively demonstrated that our designed nanoparticles can accurately target A?,and effectively inhibit cell apoptosis,and may play a highly effective role in AD therapeutics.2.Co-release of carbon monoxide?CO?and tirapazamine?TPZ?induced by near-infrared light?NIR?for gas therapy/chemotherapy of hypoxic tumours.We synthesized NaYF₄:Yb/Tm upconversion luminescent nanoparticles by high-temperature pyrolysis method with uniform size and excellent dispersion.This functional core can generate ultraviolet and visible light for upconversion fluorescence imaging through an upconversion mechanism under near-infrared light irradiation at 980 nm.And then,a layer of NaYF₄ was coated around the core surface to greatly enhances the luminecent intensity of the core.Next,the inverse microemulsion method and hot water etching method were further adopted.Finally,the UCNPs core/mesoporous silica shell structure containing a cavity in between?UCMSN?was obtained.This structure not only show excellent biocompatibility,but also has a large inner space,which is used to carry a large number of bioreductive anti-cancer drugs TPZ,and meanwhile,metal carbonyl compounds is loaded in the pore channels of the mesoporous silica shell to release CO.The chemotherapeutic drug TPZ can produce large amounts of ROS in hypoxic tumor cells,causing a strong killing effect on hypoxic tumor cells.The metal carbonyl compounds can stop the free release of TPZ in non-target areas,comparatively,it can decompose under ultraviolet light to generate CO in tumor,which will not only inhibit the activity of tumor cells,also elevates the"hypoxic"levels of the tumors and,thus enhance the cell-killing effect of TPZ,resulting in the synergetic therapeutic effect on tumor.The in vivo experimental results shows that the synergetic treatment strategies combining gas therapy and chemotherapy by this new type of inorganic nanoplatform can effectively inhibit tumor growth,and the invasion,and metastasis of cancer cells.3.UCL/MR dual-modality imaging and targeted therapy for breast cancer bone metastasis.We successfully synthesized NaYF₄:Yb/Tm@NaGdF₄@mSiO₂upconversion luminescent nanoparticles by mentioned methods above,which shows good upconversion luminescence properties and T₁ weighted magnetic resonance imaging?MRI?capabilities.The experimental results show that the nanotheranostic agent has good biocompatibility through the modification of the targeting ligand ZA and the pH-responsive group PAA,which can efficiently target the bone cell region of breast cancer,and responsively release the therapeutic drug PL,resultanly killing metastatic tumor cells.Moreover,the agent can also reduce the secretion of RANKL and sclerostins of bone cells,reduce osteoclast activation,inhibit the development of breast cancer bone metastasis.This novel multifunctional UCNPs-based nanotheranotics will enable the imaging-guided precise,anti-metastasis and anti-recurrence targeted therapy for early breast cancer bone metastasis.In this reaserch,we focus on the application in the field of Alzheimer's disease and malignant tumors of UCNPs based on nano-synthesis chemistry.The reasarches on designs of synthestic,medical application and related biological effects of UCNP have been carried out in order to make it a significant role in the diagnosis and treatmen of clinically human diseases in the future.