Construction Of Multimodal Tumor Theranostic Probe Based On Hydrophobic Hydration-shell Coated Upconversion Nanoparticles And Initial Application

Cancer remains one of the key public health concerns in the world.Owing to the extraordinary death rate as well as treatment expanses,prodigious exertions were dedicated toward the development of effective cancer treatment methodologies.In the past decades,combined nanotherapeutic platforms have demonstrated promising for efficient cancer treatment.The photodynamic therapy（PDT）,chemodynamic therapy（CDT）and photothermal therapy（PTT）attract wide interests,which show the integrated merits of minimal invasiveness and synergistic therapeutic effects.Near-infrared light（NIR）driven lanthanide-doped upconversion nanoparticles（UCNP）based PDT holds great prospects for deep tumor therapy.However,also has been highly hindered by the low upconversion luminescence（UCL）efficiency,hypoxia of solid tumor environment,and low therapeutic efficiency by using single PDT modality.On the other hand,the disintegration of UCNP in bio-media also lead to the rare-earth leakage involved bio-risks.When combining PDT and PTT for tumor treatment,the need to use two individual excitation sources leads to difficulty in ensuring the dual laser’s spatial-temporal distribution homogeneity in tissues.In this paper,photosensitizer Chlorin e6（Ce6）and oxygen carrying perfluorocarbon（PFC）co-doped hydrophobic hydration-shell（HHS）and photothermal/CDT responsive metal-phenolic network（Fe-TA）were tandemly decorated to an optimized Nd³⁺cascade sensitized UCNP,which triggered simultaneous PDT/PTT by single NIR irradiation.The PTT also leads to enhanced CDT.Based on the above results,MnO₂,which can consume tumor overexpressed GSH and supply self-sufficiency O₂ in tumor microenvironment,was in situ grown on the surfaces of UCFS@Fe-TA using KMnO₄ reduction.Although Fe-TA is destroyed due to oxidation by KMnO₄ and significantly lost its PTT function during MnO₂growth,it has achieved effective protection to photosensitizer and PDT.The O₂carrying/self-generation multifunctional tumor targeting intelligent probe with GSH-responsiveness was successfully constructed for synergistic tumor PDT/CDT.The research contents are as follows:（1）Engineered cascade-sensitized red-emitting upconversion nanoplatform with tandem hydrophobic hydration-shell and metal-phenolic network decoration for single 808 nm triggered simultaneous tumor multimodal therapy.Firstly,a binary sodium solvothermal method was used to prepare multi-shell structured Nd³⁺cascade-sensitized UCNP（Na Er F₄:Yb/Tm（69/1%）@Na Lu F₄:Yb（15%）@Na Lu F₄:Nd/Yb（30/10%）@Na Lu F₄）,the thickness of sensitized shell(Na Lu F₄:Nd/Yb（30/10%）and inert shell（Na Lu F₄）based on UCNP was further optimized for enhanced strong red emission.Then,the HHS coating is achieved by co-doping O₂-carrying PFC and photosensitizing Ce6 into mesoporous silica（m Si O₂）on the UCNP surface（UCFS）,which can not only realize PDT by fluorescence resonance energy transfer（FRET）from UCL to Ce6,but also strengthen PDT of the UCFS via O₂-carrying/UCL protection capacity of the HHS.Finally,Fe-TA coating can supply 808nm triggered PTT,and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster·OH production rate of CDT to match with the real-timely released ¹O₂ in PDT,leading to a PTT assisted reactive oxygen species（ROS）storm for efficient tumor suppression.The UCFS@Fe-TA with multimodal synergistic therapeutic function shows good biocompatibility in dark toxicity and could be efficiently simultaneous PDT/CDT/CDT under 808 nm irradiation.The study provides a highly effective nanoplatform with high biocompatibility that can collaborate with multi-mode tumor therapy.The UCFS@Fe-TA supply a safe and effective multimodal synergistic tumor therapy probe.（2）O₂ carrying/self-generation multifunctional tumor targeting intelligent probe with GSH-responsiveness for synergistic tumor PDT/CDT.In consideration of the tumor overexpressed GSH can consume ROS and seriously inhibit the therapy effect,MnO₂ was in situ grown onto the surface of UCFS@Fe-TA by using KMnO₄ reduction.Then,HA,as a natural ligand of the CD44 molecule,was decorated onto the MnO₂ modified nanoprobe,which is supposed to endow the as-designed UCFS@Fe-TA@MnO₂ better tumor targeting ability.Although Fe-TA is destroyed due to oxidation by KMnO₄ and significantly lost its PTT function during MnO₂ growth,it has achieved effective protection to photosensitizer and PDT.The MnO₂layer could react with H₂O₂ to generate O₂,thus relieving tumor hypoxia.Meanwhile,the MnO₂ could react with GSH and then release Mn²⁺to reduce consumes the ROS and improve the therapeutic efficiency.The Mn²⁺can achieve CDT by generating·OH via a Fenton-like reaction with endogenous H₂O₂in bicarbonate buffers.And UCL based PDT can produce¹O₂ to enhance ROS in tumor.The intelligent PDT/CDT probe demonstrates high tumor killing ability.In addition,the degradation of MnO₂ can also lead to fluorescence recovery of Ce6,which can be used to detect GSH content in tumor.