Design And Construction Of Ultrasound/Light-Responsive Metal-Organic Coordination Nanomaterials For Tumor Theranostic

Cancer is a serious threat to human life safety and health.Traditional cancer theranostic techniques can also bring huge side effects while treating patients.To further improve the simultaneous diagnosis and treatment of cancer,in recent years,researchers have developed a series of new multifunctional nanomaterials for cancer theranostic.Among them,metal-organic coordination nanomaterials have received tremendous attention due to their unique and excellent properties:(a)can be degraded/metabolized in vivo;(b)easy to control ingredients;(c)have a large specific surface area;(d)easy to surface modification etc.Therefore,metal-organic coordination nanomaterials have been widely used in multifunctional imaging guided sonodynamic therapy(SDT),photodynamic therapy(PDT),chemodynamic therapy(CDT),photothermal therapy(PTT),chemotherapy,etc.Although the current metal-organic coordination nanomaterials have great application prospects in the field of cancer theranostic,there are still some problems to be solved:(a)Nanoscale metal-organic coordination materials are composed of noncovalent bonds and can be slowly metabolized in vivo.However,the size of nanoscale metal-organic coordination materials is usually tens to hundreds of nanometers,which are easy to accumulate in the reticuloendothelial system organs,which is a potential threat to biosafety.(b)The tumor microenvironment(TME)is a complex and variable system(for example:lack of glucose,low p H,hypoxia,and high intracellular H₂O₂ and glutathione(GSH)content).Among them,endogenous GSH is reductive,and can seriously affect the effect of reactive oxygen species(ROS)based cancer treatment.(c)SDT/PDT is an efficient technology that uses ultrasound/light to excite a sonosensitizer/photosensitizer to generate ROS to kill cancer cells.However,when the ultrasound/light is removed,the therapeutic effect of PDT/SDT also stops immediately,which often results in low tumor suppression rates and high recurrence rates.(d)Single metal-organic coordination nanomaterials sometimes cannot achieve diversification of their functions,and additional functional nanoparticles(NPs)need to be introduced to form multifunctional composite materials to further enhance the theranostic effect of metal-organic coordination nanomaterials.Focusing on the above-mentioned key scientific issues,this paper designs and constructs four new multifunctional metal-organic coordination nanomaterials from the directions of material structure optimization,TME adjustment,drug delivery system(NDDSs)design,and multi-modal combined theranostic.It is expected to further promote the application of metal-organic coordination nanomaterials in cancer theranostic:(1)Ultra-small Gd³⁺-hemoporphyrin coordination nanomaterials for tumor sonodynamic theranostics and rapid metabolismNanoscale metal-organic coordination materials are usually tens to hundreds of nanometers in size,which are easy to accumulate in the reticuloendothelial system organs,and there is still a potential threat to biosafety.To solve this problem,ultra-small Gd³⁺-hemoporphyrin coordination nanodots(Gd HF-NDs)were synthesized by a two-step ultrasonic method.In the first step,the mixed solution containing Gd³⁺ions and hematoporphyrin monomethyl ether(HMME)molecules were treated by a typical mild bath sonication process,where Gd³⁺-hematoporphyrin framework aggregate(Gd HF-A)was self-assembled through covalent coordination.In the second step,the Gd HF-A were exfoliated with an intense probe sonication to prepare nanodots(Gd HF-NDs).Due to the small size effect of Gd HF-NDs(?5 nm),the sonosensitizer can not only be rapidly metabolized from the body,but the effective amount of ROS generated under the same conditions is 2.3 times that of Gd HF-A.When Gd HF-NDs/PEG dispersions were injected into tumor-bearing mice through the tail vein,they displayed high MRI in the tumor area.Under ultrasound conditions,compared with Gd HF-A/PEG,Gd HF-NDs/PEG has a better SDT effect on tumors.More importantly,due to the ultra-small size of Gd HF-NDs,most Gd HF-NDs/PEG can be eliminated quickly through the kidneys,ensuring high biological safety.Therefore,Gd HF-NDs/PEG can be used as a high-performance,biosafety,sonodynamic theranostics nanoplatform.(2)Mn³⁺-hemoporphyrin coordination nanomaterials with tumor microenvironment enhanced sonodynamic theranostics and metabolismThe tumor microenvironment(TME)is a complex and variable system(for example:lack of glucose,low p H,hypoxia and high levels of H₂O₂/GSH).The over-expressed reduced GSH usually affects the effect of ultrasound-driven SDT.To solve this problem,an Mn³⁺sealed Mn³⁺-hemoporphyrin framework(Mn(III)-HFs)is designed and constructed,which is composed of amorphous nanoparticles with a size of?100 nm.Under GSH conditions,Mn(III)-HFs shows three unique excellent properties:(a)GSH can collapse the nanostructure of Mn(III)-HFs/PEG and promote the degradation/metabolism of nanomaterials;(b)Under ultrasound conditions,both the consumption of endogenous glutathione and the release of free HMME can promote the production of reactive oxygen species(ROS)and improve the effect of SDT;(c)Mn²⁺ions have better magnetic resonance imaging(MRI)capabilities compared to Mn³⁺ions.As a result,when the Mn(III)-HFs/PEG dispersion is injected into tumor-bearing mice through the tail vein,it exhibits high-contrast T₁/T₂ dual-modal MRI imaging while significantly inhibiting the growth rate of deep tumors.(3)DOX@Mn³⁺-hemoporphyrin coordination nanomaterials for tumor drug delivery and photodynamic-chemo therapyUnder light/ultrasound excitation,the photosensitizer/sonosensitizer in the tumor can effectively kill the cancer cells.However,when the light/ultrasound is turned off,the therapeutic effect of PDT/SDT will also stop immediately,often resulting in a low tumor suppression rate and high recurrence rate.To make up for the limitations of PDT,an activatable nanoscale drug delivery system(NDDSs)was prepared for the combined treatment of PDT and chemotherapy.In addition,the average size of Mn CPs is 100 nm and has a large specific surface area(52.6 m~2 g^-1).After loading DOX,DOX@Mn CPs/PEG shows a high drug loading rate(27.2%).DOX@Mn CPs/PEG can react with GSH in the TME to collapse the structure of NDDSs,leading to the production of Mn²⁺ions for enhanced MRI,free HMME for enhanced photodynamic effect,and free DOX for enhanced chemotherapy.When DOX@Mn CPs/PEG NDDSs is injected into tumor-bearing mice through the tail vein,it exhibits an efficient tumor homing,and then exerts an obvious suppression for tumor growth rate by synergistic photodynamic-chemo therapy in vivo.In addition,this strategy can also be used to design other NDDSs with multifunctional combination therapy.(4)DOX/Cu S@Cu-MOF composite nanomaterials for tumor multimodal theranosticsCu-based metal-organic coordination nanomaterials(Cu-MOF)have been widely used in the combined treatment of CDT and chemotherapy due to their large specific surface area.However,its therapeutic effect is limited.It is necessary to further introduce photothermal therapy to enhance the CDT effects to maximize the anti-cancer effect of Cu-MOF.To further expand the anti-cancer efficacy of Cu-MOF for CDT,a simple in-situ growth strategy was used to construct a Cu S@Cu-MOF multifunctional composite nanomaterial.The Cu S@Cu-MOF nanocomposite is composed of a fusiform Cu-MOF with an average size of about 200 nm in length and 40 nm in width.Ultra-small Cu S nanodots(?4 nm)are uniformly distributed on the surface or the pore structure of Cu-MOF.Due to the local surface plasmon resonance(LSPR)effect of Cu S,the composite nanomaterial exhibits strong NIR light absorption and high light-to-heat conversion efficiency(39.6%).In particular,Cu S@Cu-MOF/PEG exhibits a photothermally enhanced Fenton effect under NIR light conditions,realizing efficient CDT.In addition,Cu S@Cu-MOF/PEG has good DOX loading capacity(25.5%)and p H response drug release ability.When the DOX/Cu S@Cu-MOF/PEG dispersion is injected into the tumor,the tumor-bearing mice can be monitored by photoacoustic(PA)imaging and thermal imaging.At the same time,due to the multi-modal combination therapy of photothermal-chemodynamic-chemo therapy,the tumor growth of mice was significantly inhibited.Therefore,synthesizing NPs@MOF multifunctional composite nanomaterials through a simple in-situ growth strategy can further expand the anti-cancer efficacy of MOF-based nanomaterials and realize multi-modal combined theranostics.