Studies On Design,Synthesis And Applications Of Stimuli-Responsive MOFs-Based Microneedles

Pharmacotherapy has been wildly used to effectively treat diseases,maintain health and prolong individual life.However,some drugs are affected by their own properties such as solubility,molecular weight and stability,and could hardly be delivered into human body directly,which limits their clinical applications.Using nanotechnology and polymeric technology to construct drug delivery systems could effectively improve the therapeutic efficacy.Among them,nanoscale metal-organic frameworks（MOFs）have extensive applications in the construction of drug delivery systems due to their unique pore structure,high surface area and tunable composition and structure.Besides,polymeric microneedles（MNs）have also been widely used in the construction of drug delivery systems due to its characteristic of painless transdermal drug delivery.However,traditional drug delivery systems have the disadvantage of non-specific distribution or uncontrolled release of drugs.Therefore,stimuli-responsive drug delivery systems,which can respond to external stimuli and achieve controlled drug release or intelligent drug delivery,are considered to be ideal next-generation drug delivery systems.It will help people maintain health from the aspects of enhancing efficiency of drugs,reducing side effects,and so on.In this thesis,starting from the design and synthesis of MOFs-based stimuli-responsive materials by regulating the composition and pore size distribution of MOFs,we prepared different MOFs-based stimuli-responsive microneedles from the aspect of combining the respective advantages of MOFs and microneedles for the applications in different biotherapeutic fields,and based on the design and fabrication experience of MOFs-based microneedles,we further constructed stimuli-responsive microneedles based on fluorescent rare earth complex nanoparticles and photothermal carbon quantum dots as drug delivery platforms.The thesis is divided into the following six chapters.Chapter 1:We briefly expound the research backgrounds of stimuli-responsive drug delivery systems,and emphatically introduced the design strategies and research progresses of stimuli-responsive drug delivery systems based on MOFs and microneedles.Chapter 2:Based on the engineering of MOF composition,we synthesized glucose oxidase（GOx）and insulin（Ins）-loaded cobalt（Co）-doped mimic multi-enzyme MOF（Ins/GOx@Co-ZIF-8）,and then combined it with microneedles for painless glucose-mediated transdermal insulin delivery.When microneedles were inserted into the skin and exposed to high concentration of glucose,glucose oxidase loaded in the MOF would consume glucose and generate gluconic acid and hydrogen peroxide（H₂O₂）.The gluconic acid would result in the degradation of MOF and thus preloaded insulin would be released.Meanwhile,catalyzed by cobalt ions(Co²⁺)in the MOF framework,the byproduct H₂O₂ was decomposed to avoid the inflammation caused by its excess.Possible free Co²⁺would also be chelated by ethylene diamine tetraacetic acid modified silicon dioxide nanoparticles（EDTA-SiO₂）in MNs to avoid its entering into human body.The results showed that our composition-engineered MOF-based MNs showed good responsiveness to glucose concentration and could release insulin without divulging H₂O₂ and Co²⁺,which makes it a good candidate for the treatment of diabetic patients.Our MOF-based microneedles offer a new strategy for designing stimuli-responsive transdermal drug delivery systems.Chapter 3:Based on the research on engineering the composition of MOF,we prepared a hierarchically porous GOx-loaded iron（Fe）-doped MOF（GOx@Fe-ZIF-TA）by using tannic acid（TA）as the etching agent to etch the MOF,and further fabricated hierarchically porous MOF-based glucose-responsive microneedles for the treatment of diabetic wound infections.The hierarchically porous MOF could consume glucose to generate antibacterial hydroxyl radicals（·OH）.When microneedles were inserted into the wound site,GOx@Fe-ZIF-TA would be released,and sequentially the GOx loaded in the MOF would consume glucose to generate gluconic acid and H₂O₂.The latter could be catalyzed by ferrous ions(Fe²⁺)to generate antibacterial·OH,which would not result in antimicrobial resistance.The results showed that GOx@Fe-ZIF-TA revealed satisfactory glucose-responsive antibacterial activity due to the engineered composition and pore distribution,and the hierarchically porous MOF-based MNs showed enough stiffness for penetration,which makes it a good candidate for the treatment of infected diabetic wounds.This study on hierarchically porous MOF-based microneedles offers a new strategy for designing stimuli-responsive transdermal systems for the treatment of infected diabetic wounds and other diseases.Chapter 4:We utilize the self-assembly of the amphiphilic polymer Pluronic（F127）to prepare fluorescent rare earth terbium complex nanoparticles（Tb-complex@F127）through one-pot reaction,and based on the design and fabrication experience of MOFs-based microneedles,we sequentially fabricated stimuli-responsive fluorescent nanoparticles-based microneedles which were arranged in specific orders to record medication.We loaded fluorescent Tb-complex@F127together with different model drugs into microneedles arranged in different way,and thus constructed corresponding relationships between the fluorescence patterns（‘L’,‘Z’,‘U’）and the types of drugs.The experimental results showed that the prepared Tb-complex@F127 could not only emit characteristic green fluorescence of rare earth under the irradiation of UV light,but also showed good biocompatibility due to the encapsulation of rare earth complex in polymers.The fluorescent nanoparticles-based microneedles showed enough stiffness for penetration.The Tb-complex@F127-based microneedles could be used to record medication while delivering the drugs,realizing the combination of transdermal drug delivery and fluorescent encoding.Chapter 5:Based on the concept of functional modularity of microneedles,combining the previous design and fabrication experience of stimuli-responsive microneedles,we fabricated carbon quantum dots（CDs）-based photothermal responsive microneedles which could promote drug delivery under irradiation by loading photothermal CDs into the base of the microneedles and loading model drugs or drug-loaded nanoparticles into the needle body of the microneedles.Other than loading photothermal materials together with drugs into the needle body of microneedles,we load photothermal CDs only in the base of microneedles and load drugs in the needle body of the microneedles,thus making different parts of the microneedles have different functions.When the microneedles were inserted into the skin,the needle body would dissolve and release the drugs,and under the irradiation of 660 nm light,the photothermal CDs in the base of the microneedles would convert the energy of light into heat,leading to the elevation of local temperature and further promoting the drug delivery.The results showed that the as-prepared CDs-based microneedles can effectively increase the local temperature under irradiation and promote the delivery of drugs.This functionally modular photothermal responsive microneedle could be used as a drug delivery platform to deliver various types of drugs or drug-loaded nanoparticles,which enriches the strategies of construction and also expands the application scope of stimuli-responsive microneedles.Chapter 6:Summary and outlook.