Fabrication And Low Intensity Light Controlled Anticancer Research Of Rare Earth Upconversion/Silica Nanoparticles

Cancer is one of the major diseases that endanger human health.Until now,traditional chemotherapy(Chemo),radiotherapy and surgery are still the most commonly used cancer treatment in the clinical,but there are some disadvantages or deficiencies,such as poor treatment effects and large side effects.In recent years,due to the controllability of light both spatially and temporally,light-triggered cancer treatment,named as photo-controlled therapy,can effectively improve the treatment effect,which has attracted widespread attention and research.In particular,the near-infrared(NIR)light(700 ? 1100 nm),which has a deep tissue penetration,has become a research focus in the field of light-controlled therapy.At present,NIR light-controlled treatment mainly include photo-controlled Chemo,photodynamic therapy(PDT)and photothermal therapy(PTT).Among them,NIR light-controlled Chemo and PDT usually require the upconvertion nanoparticles to convert NIR light into ultraviolet/visible light.Although these NIR light-controlled therapies can effectively improve the treatment effect,there is a general problem as the laser intensity used is generally too high(1 ? 4 W/cm~2),which is much higher than the safe intensity(0.33 ? 0.35W/cm~2)according to the American National Standard for Safe Use of Lasers and can cause severe light damage side effects on normal tissues.In addition,there are many special defects in various light-controlled therapies,such as: the release of drug is slowly in photo-controlled Chemo.The therapitic effect of PDT will be decreased by the intracellular overexpressed glutathione and tumor hypoxic environment.Therefore,these factors have deeply limited the therapeutic effect of light-controlled treatment,hindered its further development,and urgently needed a reasonable solution.In order to further improve the light-controlled treatment system,this paper has carried out three researches on the challenges raised above.The specific research contents are as follows:Firstly,in order to solve the problem of high laser intensity in NIR light-controlled Chemo,this study synthesized light-controlled nanovalves by synthesizing upconversion nanoparticles with high luminous efficiency and selecting thioether light-breaking molecules with smaller bond dissociation energy.The low-intensity NIR light-controlled drug-releasing nanoparticles were successfully prepared to achieve drug release at a safe intensity(0.30 W/cm~2).In vitro cell experiments,under low-intensity NIR light irradiation,the cell survivalrate was significantly reduced(16.3%),showing good light-controlled drug release performance.Secondly,in view of the problem of high laser intensity and intracellular over-expressed glutathione limitation in PDT,the low-intensity(0.30 W/cm~2)NIR light triggered PDT/Chemo endogenous/exogenous dual-synergistic nanoparticles were prepared by synthesizing high-luminescence upconversion nanoparticles,quantitatively loading photosensitizers and modifying an anticancer drug camptothecin using the disulfide bonds.When the nanoparticles are endocytosed by He La cells,high concentrations of glutathione in the cells can trigger disulfide bond cleavage,consuming glutathione and releasing the anticancer drug camptothecin.The depletion of glutathione reduces its elimination effect on singlet oxygen to endogenously enhance the anticancer effect of PDT,while the released anticancer drug camptothecin can increase the sensitivity of cells to singlet oxygen to exogenously enhance the PDT efficacy.In the in vitro cell experiments,the therapeutic effects of the endogenous/exogenous dual-synergistic nanoparticles were 2.4 times,2.3 times,and 1.8 times that of single chemotherapy,photodynamic therapy,and endogenous enhanced photodynamic therapy,respectively.In vivo anti-tumor experiments,this dual-synergistic nanoparticles showed good tumor inhibition effects in tumor growth.Finally,when the synergistic therapy has gradually become an effective cancer treatment method,the low-intensity NIR light triggered PDT/PTT/Dual-Chemo tri-synergistic nanoparticles were prepared to overcame the problems of slow drug release in photo-controlled Chemo and the tumor hypoxia environment limitation the PDT efficacy,through introducing the photothermal reagent into the research of the above work.Photothermal reagent were introduced Through the photothermal effect of photothermal agents,three purposes can be achieved: one is to accelerate the release of chemotherapeutic drugs,the release rate of which is increased by 31 times;the second is to increase the tissue oxygen supply of tumor tissues and enhance PDT efficacy;the third is to achieve PTT,and the synergistic effect with PDT and Chemo which will further enhance the therapeutic efficacy.In the in vivo anti-tumor experiment,the tumor disappeared and there was no recurrence within 14 days in the tri-synergistic anticancer nanoparticle treatment group,showing an excellent anti-tumor efficacy.This paper has successfully solved the common problem of high laser intesnty in photo-controlled treatment.In all mouse experiments,low-intensity near-infrared illumination of all established photo-controlled treatment did not cause black scar and photodamage to the skin of mice,demonstrating that low-intensity photo-controlled treatment with little side effect has been successfully achieved and reduced the side effects.At the same time,the spectialproblems of light-controlled Chemo and PDT had been solved through the endo-/exogenous and multiple synergistic enhancement effect,improving the therapeutic effect of various low-intensity NIR light-controlled treatments.In a word,this paper has improved the low-intesntiy light-controlled treatment system,opening up a new therapeutic prospects for low-intensity light-controlled treatment.