Polyoxometalate Supramolecular Complexes For Biomedical Applications

Polyoxometalates?POMs?,as a class of inorganic metal-oxide nanosized clusters,exhibit precise chemical structure,controllable charge number and topological architectures through a precisely modulated synthesis.The abundant chemical compositions and rich physical and chemical properties of POMs,such as magnetism,medicine,antiviral,antibacterial,catalysis,photo and electrochemistry have been used for attracting building blocks for various materials.In the field of biomedicine area,the application of polyoxometalates in the emerging molecular imaging technology and tumor photothermal therapy based on the magnetism and redox property has become a new research hotspot and needs to be developed urgently.The main drawbacks,however,are possible toxicity and structural instability in the physiological environment of a living organism.Therefore,protection of the polyanionic clusters has become the dominant requirement while the surface properties and biocompatibility can be modified greatly.It has been proven that encapsulation of POMs by cationic surfactants with suitable hydrophilic terminals through electrostatic interaction improved the POM's performance in biomimic systems,and at the same time increased their stability and reduced their toxicity.Based on the guidance of supramolecular self-assembly,we can obtain structurally stable polyoxometalate supramolecular complexes by choosing organic soft materials and functional polyoxymetalate clusters as building blocks.The combination of the two building blocks gives more excellent properties and the synergistic effect may also bring new functionality for supramolecular materials.In this dissertation,through choosing functional polyoxometalate clusters and rationally designing cationic molecules,we could construct a series of biocompatible polyoxometalate supramolecular complexes with the supramolecular self-assembly and synergistic effect as the central idea,further use it to load small molecules,such as probes or drug,realizing functional bioapplication:molecular imaging,photothermal-chemotherapy,even the clinical integration.First,we prepared two water-soluble supramolecular dendrimers for application as MRI contrast agents by using two cationic dendrons bearing terminal groups of triethylene glycol monomethyl ether in different generations to encapsulate a paramagnetic polyoxometalate cluster through electrostatic interaction.We use NMR,IR,TGA spectra and elemental analysis to character the structure of the complex.The stability and safety of contrast agent in aqueous solution and physiological condition are evaluated by means of NMR,dynamic light scattering and cytotoxicity test.We use transmission electron microscopy and dynamic light scattering method to study the aggregation behavior in aqueous solution and physiological condition.The measured relaxavity of the contrast agents are about four times than the commercial contrast agent Gd-DTPA.We further study the influence of surfactant covering and the state of aggregation on the relaxation rate.The in-vitro and in-vivo magnetic resonace imaging tests in mice showed excellent imaging capability,especially in liver,which reveal the complex dendrimers are a suitable model for liver-specific MRI contrast agents.In this section,we developed a general and simple method for the preparation water soluble polyoxometalate supramolecular contrast agent.The results obtained realized the dendritic polyoxometalate supramolecular hybrid complexes for potential MRI contrast agents.Second,we further synthesis highly generation dendritic surfactant to encapsulate paramagnetic polyoxometalate,the formed electrostatic complex are characterized accurately by ¹H?NMR,IR,TGA spectra and the elemental analysis results.We found the formed electrostatic complex are monodispersed in aqueous solution and the diameter is less than 10 nm through dynamic light scattering and transmission electron microscopy methods,which are more suitable for bioapplication.The complex display an ambivalent micellar structure,is then demonstrated to act as a suitable carrier for the uptake of cationic fluorescent dyes,forming a loaded complex for fluorescence and MRI multifunctional contrast agent.We evaluated its structural stability and physiological safety by ¹H?NMR,DLS spectra and the cell cytotoxicity text.The dye-loaded complex is thus proven to display high relaxivity as a contrast agent.Confocal laser scanning microscopic observation also demonstrates the fluorescence imaging property of the prepared complex upon consumption under physiological conditions.Both in vivo fluorescence imaging and MRI further confirm that the complex may be a suitable liver-specific contrast agent for clinical diagnosis.In this section,we have synthesized a discrete and monodisperse dendrimer complex as a new dual functional contrast agent through a simply electrostatic self-assembly approach,which provide a new method biological application of polyoxometalate.Third,we chose an organic dendron bearing a cationic head and triethylene glycol?TEG?chain tails to encapsulate a highly negatively charged giant wheel-like POM Mo₁₅₄54 through a simple ionic replacement reaction.We use NMR,IR,TGA spectra and elemental analysis to character the structure of the complex.We use TEM and DLS method to study the aggregation behavior in aqueous solution and physiological condition,Arising from their assembly,the formed core–shell supramolecular composite has uniform size,exhibit mono-dispersion and diameter is about 7.5 nm.Due to the giant polyoxometalate cluster possesses strong absorption characteristics in the near infrared region,the obtained complexe can effectively convert light energy into heat,and the photothermal conversion efficiency can reach 30.9%.We further use this complex to load anti-cancer drug doxorubicin hydrochloride.As the TEG surfactant covering,the complex exhibits a lower critical solution temperature?LCST?behavior,when the temperature increased,the monodispersed complex start to aggregate rapidly,thus leading to NIR-controlled drug release.When irradiated with an 808 nm NIR laser,the formed complex had significant in vitro and in vivo photothermal-chemotherapeutic effects on tumor tissue.In this section,we introduced heteropolyblue clusters which have strong absorbance in the near infrared region into the temperature-sensitive supramolecular complex system,and further use it to load anti-cancer drugs.It's the first time to directly use giant polyoxometalate cluster for photothermal therapy.Therefore,we successfully fabricated an ultra-small thermosensitive nanocomposite as a comprehensive platform and realized NIR-triggered photothermal-chemotherapy,which lays the foundation of supermolecular synergistic effect.Fourth,we synthesis cationic surfactant with reactive terminal groups to encapsulate functional polyoxometalate with both magnetic and photothermal properties,then grafting tumor targeted molecules.We use NMR,IR,TGA spectra and elemental analysis to character the structure of the complex.We use TEM and DLS method to study the aggregation behavior in aqueous solution and physiological condition.The stability and safety of the complex in aqueous solution and physiological con dition are evaluated by means of NMR,dynamic light scattering and cytotoxicity test.The prepared complexe exhibit obvious magnetic contrast imaging and outstanding photothermal conversion capability.When irradiated with an 808 nm NIR laser,the prepared complex had significant in vitro and in vivo photothermal effects on tumor cells and tumor tissue.In this section,we firstly realized polyoxometalate supramolecular complexes as a agent combines diagnosis and treatment,which provide new material primitives for cancer diagnosis and treatment.In conclusion,we constructed a series of biocompatible polyoxometalate supramolecular complexe by choosing functional polyoxometalate and rationally designed organic surfactants as building blocks through electrostatic self-assembly method.We realize the functionalization of paramagnetic supermolecule complex as magnetic contrast agent by using the magnetic properties of polyoxometalate.We realize the functionalization of reductive heteropolyblue supermolecular complex as therapeutic agent by using the photothermal properties of polyoxometalate.On the basic of multiple supramolecular forces,we used the unimicellar supramolecular complexes to load small organic molecule such as fluorescence probe and drug effectively and realized multimodal imaging and photothermal-chemotherapy.We believe that these reaserach findings provide a universal method for biological application of polyoxometalate and fill blank spaces in the region of polyoxometalate biomedicine,and provide new material primitives for cancer diagnosis and treatment.