Preparation And Antitumor Application Of Rare Earth Upconversion/Mesoporous Silica Nanomaterials

Based on the interdisciplinary research of chemistry,material,biology and medicine,smart cancer therapy system with multifunctional structure design,enabling the realization of targeted drug delivery,imaging diagnosis and stimulus responsive on-demand treatment,may become the inevitable trend for nanomedicine development in the future.Because of the ability of upconversion nanoparticles(UCNP)that can absorb near-infrared(NIR)light with deep tissue penetration and convert them into ultraviolet(UV)or visible light with poor tissue penetration,smart cancer therapy system consists of UCNP and traditional mesoporous silica(MS)not only are able to meet the light demand for light-responsive drug release,photodynamic therapy(PDT),synergistic therapy and bioimaging,but also can solve the low therapy efficiency problems induced by the poor tissue penetration ability of traditional excitation light source(UV or visible light).However,these MS-coated UCNP assisted system are still severely restricted by the following challenges,such as tedious synthesis process and poor sensitivity of nanovalves,uncontrolled loading dosage,aggregation and leakage problems of photosensitizer(PS),integration challenges of multiple functional unit,and so on.In view of the above problems,novel nanovalves design and PS loading technique are explored first,and then dual-mode and diagnosis/three-mode treatment are further integrated into a single system respectively in this work through integration and regulation of MS coated UCNP core-shell structure,design and modification of surface functionalization,and selection and assembly of functional units.First,to overcome the disadvantages of tedious synthesis process,poor sensitivity,and high power activation of the current NIR light-triggered nanovalves,novel NIR light-triggered hydrophobic-to-hydrophilic nanovalve has been designed and fabricated.In vitro studies demonstrated the hydrophobic-to-hydrophilic nanovalve could be sensitively controlled by NIR light to release the drug for killing cancer cells effectively.Compared with NIR light-triggered nanovales based on the photoisomerization,photothermal and photolysis mechanism,hydrophobic-to-hydrophilic nanovalves can sensitively and precisely control drug release upon moderate NIR light intensity,indicating hydrophobic-to-hydrophilic nanovalves have promising advantages in cancer chemotherapy(Chemo).Second,to avoid the concerns of long loading process,uncontrollable loading dosage,and PS aggregation or leakage,a novel electrostatic-driven ultrafast PS loading technique has been developed.The electrostatic-driven loading technique not only guarantees the PS quantitative loading and excellent distribution,but also prevents the PS agglomeration and realizes the PS zero-leakage.The in vitro cell lethality experiments demonstrate that cancer cells can be effectively killed by the PDT nanocomposite on the basis of the electrostatic-driven PS loading technique.Therefore,this work is of great significance for the design and preparation of high-efficiency PDT system.Third,on the basis of optimizing Chemo and PDT,two types of PDT and Chemo synergistic therapy(PDT/Chemo)nanocomposite that is progressive in efficacy have been prepared through the integration and regulation of core-shell structure and design of surface functionalization,realizing remarkable superadditive(namely ‘1 + 1 > 2')effects.First,it is proved that an improved anticancer effect was obtain in single-PS PDT/Chemo through structure design and integration.On this basis,Dual-PS PDT/Chemo was prepared,whose cancer killing rate reaches at 96% due to the synergistic effects.The death rate of cancer cell treated with Dual-PS PDT/Chemo was 2.7 times,2.1 times and 1.4 times higher than that of single Chemo,PDT and single-PS PDT/Chemo treated cancer cell respectively,which can be ascribed to enhanced synergistic effects induced by the improved PDT efficiency because of the fully absorbing upconverted fluorescence by dual PS.This work provides a novel strategy to design Chemo/PDT system,which can be utilized in co-loading of most anticancer drugs and photosensitizers.Last,an imaging guided multimodal synergistic therapy nanocomposite integrating cell imaging,Chemo,photothermal therapy(PTT)and PDT(Chemo/PTT/PDT)has been designed and fabricated through core-shell design on the basis above.The imaging guided multimodal synergistic therapy nanocomposite exhibits good cellular imaging capability,which can be utilized to visually monitor the accumulation of nanoparticles in cancer cells and determine the optimal time for the implementation of treatment.The in vitro studies demonstrated that the death rate of cancer cell treated with Chemo/PTT/PDT at low doses was 2.9 times and 5.7 times higher than that of PTT/PDT and Chemo respectively.The in vivo studies demonstrated that tumor ablation was achieved successfully after Chemo/PTT/PDT treatment once.No recurrence of tumor within 14 days was found.These results above indicate the imaging guided multimodal synergistic therapy nanocomposite has significant potential clinical applications.In conclusion,on the basis of exploring novel mechanism nanovalves and optimizing PS loading technique,Chemo/PDT,Chemo/Dual-PS PDT,and diagnosis and Chemo/PTT/PDT were respectively integrated into a single nanocomposite through integration and regulation of the MS coated UCNP core-shell structure,and the progressive design and construction of nanocomposite has been realized for cancer treatment.