Synthesis And Imaging Properties Of Tumor Microenvironment-Responsive Upconversion-Based Antitumor Nanosystems

Cancer is one of the leading causes of death,resulting in more than 8.2 million deaths annually worldwide.In recent years,the nanostructures based on rare-earth upconversion nanoparticles have been showing advantages in realizing the integration of multimodal imaging and multimodal therapy.Compared with normal tissues,tumor microenvironment featured with higher interstitial fluid pressure,abnormal blood vessels,hypoxic,slightly acidic,higher contents of glutathione and hydrogen peroxide,et al.Based on these characteristics,the main purpose of this paper is to design and synthesize tumor microenvironment-responsive nanomedicines based on upconversion nanoparticles,so as to achieve efficient tumor theranostic on the premise of reducing side effects.The main research contents of this paper are:A tumor(U14)acidity-responsive polymer was synthesized and then coated on upconversion nanoparticles loaded with Pt(IV)prodrug.In the acidic tumor microenvironment,the polymer decomposes and exposes positively-charged core.The polymer decomposition leads to a rapid reduction in the nanomedicine size,which allows for deep tumor penetration.Since the membrane surface is negatively-charged,the exposed core is beneficial for promoting cell uptake and achieving accurate Pt(IV)delivery to tumor cells.The influence of glutathione and upconverted ultraviolet light on the reduction rate of Pt(IV)was studied.The upconversion nanoparticles endow the nanosystem with upconversion luminescence and X-ray computed tomography imaging functions.Mn was doped into the shell by hydrothermally treating the mesoporous silica coated upconversion nanoparticles in the solution of manganese sulfate hydrate.The Mn doping process results in the formation of hollow and mesoporous structure,which means that the obtained nanocapsules have potential doxorubicin loading capacity.Since the Mn-O bond is sensitive to tumor acidity and reductivity,this paper studied the degradation properties of the shell in different simulated solutions,and evaluated the drug release properties of nanomedicine in different simulated solutions using doxorubicin as the model.The breakage of the Mn-O bond leads to the release of Mn2+,which is promising to unite with upconversion nanoparticles to achieve tumor-enhanced upconversion fluorescence,magnetic resonance and X-ray computed tomography imaging.In addition,this paper studied the influence of doxorubicin release on the luminescence red-green ratio of nanocarrier,and focused on comparing the tumor inhibition efficiency of pure doxorubicin,non-responsive nanomedicine and the tumor-responsive nanomedicine.Further,polyoxometalate nanoclusters were modified on mesoporous shells.The acidity together with reductivity in the tumor microenvironment activate the absorptivity and photothermal conversion ability of 808 nm photons of the nanoclusters,and the generated thermal effect holds promise in promoting shell degradation and achieving synergistic photothermal therapy.The research focused on the influence of the light on the shell degradation rate and the antitumor efficiency of the nanomedicine.A in situ growth method was used to modify the polyoxometalate nanoclusters onto mesoporous silica coated upconversion nanoparticles,and the prepared nanocarrier has a hydrophilic surface.Polyoxometalates have self-assembly nature in acidic tumor microenvironment,which means that nanomedicine can selectively accumulate at tumor sites.Taking doxorubicin as the drug model,the influence of acidity,reductivity and 808 nm laser on the drug release properties of nanomedicine were studied.When coating mesoporous silica on upconversion nanoparticles,the chlorin e6 was covalently conjugated on silica shell,and then a mesoporous manganese dioxide was coated on silica by a facile ultrasonic method.The two mesoporous shells imply that the prepared nanoplatform has good doxorubicin loading capacity.The influence of acidity,reducibility and hydrogen peroxide on the degradation rate of manganese dioxide were studied.At the same time,the influence of the degradation on the magnetic resonance imaging effect was studied.In addition,the drug release properties of the nanomedicine in different simulated solutions were investigated.Manganese dioxide degradation can induce the decomposition of intratumoral hydrogen peroxide into oxygen,which is beneficial for improving the efficiency of photodynamic therapy.Upconversion nanoparticles endow the nanomedicine with upconversion luminescence,magnetic resonance and X-ray computed tomography imaging functions.The mesoporous silica was coated on upconversion nanoparticles and loaded with the photosensitizer of zinc phthalocyanine and photothermal agent of carbon dots,then the silica was modified with acidity/thermal-sensitive polymer of poly(n-isopropylamide-methacrylate),and the prepared nanocarrier was used to load doxorubicin.Under 980 nm laser excitation,the upconversion nanoparticles activated by Ho3+ emit relatively pure red emission due to the cross-relaxation effect caused by Ce3+,which is beneficial for activating zinc phthalocyanine to generate singlet oxygen,thus realizing photodynamic therapy.In addition,the photothermal properties and the drug release properties under different degree of acidity,temperature,without or with light irradiation were systematically characterized.Under the stimulation of acidity and high temperature,the polymer collapses and induces faster doxorubicin release,which is beneficial for achieving precise drug delivery.In addition,in vitro and in vivo bioimaging and antitumor properties of nanomedicine were studied in detail.