All-in-One Theranostic Platform Based On Hollow Microcapsules For Intragastric Targeting Anti-Ulcer Drug Delivery,CT Imaging,and Synergistically Healing Gastric Ulcer

Bismuth-containing therapy has been suggested as the first-line and alternative therapy to treat gastric ulcer（GU）and eradicate Helicobacter pylori（HP）.At present,the treatment strategy is called quadruple therapy,which includes proton pump inhibitor,bismuth and two broad-spectrum antibiotics.Its bioavailability is low and it may affect the medication compliance of patients.Metal-phenolic network（MPN）has attracted extensive attention because of its applications in synthetic biology,drug delivery and biomedical imaging.In this study,from the point of view of natural products,the active polyphenol components of gallic tannin with anti-GU activity were screened,and the related molecular mechanism of active components with anti-GU activity was clarified.An integrated therapeutic platform for gastric targeting was established:drug delivery carrier（Bi G@MCs）composed of several synergistic anti-gastric ulcer drugs including bismuth,gallotannin（GA）and tetracycline was obtained;Furthermore,the therapeutic effect of Bi G@MCs on indomethacin-induced rat gastric ulcer model was evaluated.It is expected to solve the problems of low compliance and low bioavailability of GU’s current clinical combination.In previous studies,the incorporation of different types of metals into MPN made microcapsules easy to be functionalized for various applications,such as magnetic resonance imaging（Gd II）,quinoline catalytic hydrogenation（Rh III）and positron emission tomography（Cu II）.Bismuth is considered as a stable element with the largest atomic number in the periodic table,with low toxicity.It is widely used in chemical industries such as medicine and cosmetics.As a main component of drug development,it has a wide application prospect.But so far,bismuth atoms have not been successfully combined with phenolic networks.In this study,because of its CT imaging ability and unique pharmacological activity against GU（under the condition of p H value of gastric juice,bismuth can form a firm colloidal precipitate of bismuth oxide on the ulcer surface or granulation tissue of ulcer base,and become a protective film,thus isolating the erosion of gastric acid,enzymes and food on ulcer mucosa.It can reduce the activity of pepsin,increase the secretion of mucin,and promote the release of prostaglandins from mucosa,thus promoting the repair and healing of ulcer tissue）,which was used as the central atom of chelate for the first time.At room temperature,when GA and Bi III are mixed in water,thin film deposition will occur.The method has the advantages of easily available raw materials,low price,convenience and strong operability.The hydrophilicity of natural GA can be used as an insoluble drug carrier,thus reducing the use of organic solvents in the preparation process.The results showed that Bi G@MCs was spherical with uniform particle size（3 0.5μm）,which could be released in the acidic environment of stomach（p H 2.0-3.0）to prevent the premature drug leakage of Bi G@MCs under physiological conditions.It is worth noting that bismuth components can be easily identified by computer tomography（CT）and other detection instruments,which provides the possibility for drug tracing.In a word,these results indicate that Bi G@MCs provides a multifunctional gastric targeted drug delivery platform for GU treatment.The main research contents and conclusions of this thesis are as follows:（1）Summarizes the different interaction modes of polyphenols and the research and application of metal phenolic network in biomaterials,especially medicine.Polyphenol is a ubiquitous secondary metabolite of plants,an important component of human diet,and vital to plant functions.Because of their important biological activities and fascinating chemical and physical properties,they have aroused great interest of researchers.Polyphenols can establish the whole chemical and physical interaction with interesting molecules and surfaces.Therefore,polyphenols can be used as general components for preparing various functional materials,such as microcapsules,antibacterial and antioxidant films,micro/nano particles,films,electronic and energy storage materials,hydrogels and cell encapsulation agents,and their structures and characteristics are fascinating.In addition to their important role in functional materials engineering,they also play an important role in the construction of multifunctional surfaces,including antifouling,antibacterial,antioxidant,cell adhesion and proliferation,enzyme immobilization,patternable and peptide-embedded surfaces.（2）Study on the mechanism and properties of polymer hollow microcapsules formed by layer-by-layer self-assembly with sacrificial template method.And characterized that gallotannin,the active ingredient of gallotannin,was used as the ligand,bismuth atom in bismuth nitrate pentahydrate Bi（NO₃）₃·5H₂O was used as the central atom,poly（sodium4-styrenesulfonate）was used as the surfactant,and tetracycline,a broad-spectrum antibiotic,was used as the model for drug loading.The drug loading platform（Bi G@MCs）was constructed by coprecipitation method.Its composition and structure were confirmed by UV,LC-MS and energy dispersive X-ray spectroscopy.The morphology of Bi G@MCs was confirmed by atomic force microscope,transmission electron microscope,scanning electron microscope and inverted fluorescence microscope.The obtained Bi G@MCs was spherical with uniform particle size（3±0.5μm）.In vitro release studies showed that at p H 7.4,59.5 3.1%of Bi G@MCs remained intact after 22 hours,indicating that Bi G@MCs decomposed slowly in physiological environment.On the contrary,at p H 1.5,about 93.5%of Bi G@MCs completely degraded after 4-8 hours,indicating that the drug release behavior of the drug carrier was triggered under acidic conditions.（3）The diagnostic and therapeutic effects of multi-drug polymer self-assembled microcapsules in gastric ulcer diseases.Then,the visualization imaging of drug tracing in vivo and the biological effect of multi-drug combination therapy on gastric ulcer were studied.It is worth noting that bismuth components can be easily identified by computer tomography（CT）and other detection instruments,which provides the possibility for drug tracing.The therapeutic effect of the carrier platform in rodent model was further evaluated,and the possible mechanism of promoting ulcer healing through polyphenol-mediated molecular interaction was discussed at the gene level.In a word,these results indicate that Bi G@MCs provides a multifunctional gastric targeted drug delivery platform for GU treatment.