Novel Gated Mesoporous Silica Drug Delivery Systems With Dual Drug Loading And Stimuli-Responsive Controlled Release

Nanomedicine requires the intersection of many disciplines including nanoscience,life science,chemistry,medicine,and other disciplines,which results in the development of new functional materials,diagnostic techniques and therapeutic tools and dedicates to improving human health and medical conditions.Drug delivery systems currently dominate nanomedicine studies,including research and application of drug delivery,targeting and therapy.The application of nanotechnology to drug delivery can improve the uptake efficiency in the target cells or tissues,protect the drug from premature degradation,enhance the therapeutic efficacy of drugs,reduce toxic side effects and improve safety and biocompatibility of delivery system.Mesoporous silica nanoparticles(MSN)can serve as an ideal drug delivery vehicle.The controllable preparation,ordered mesoporous structure,silanol groups on the surface make MSN such a versatile material.It has so many useful properties,such as high specific surface area,large pore volume,uniform and tunable pore size,low mass density,low toxicity,ease of surface modification and biocompatibility.Combination therapy by co-delivering two or more drugs to the patient,has become one of the dominant strategies in the clinical treatment of cancer,HIV/AIDS and diabetes.It aims at developing the optimal treatment program for each patient.In this thesis,the integration of combination therapy and controlled release into a single delivery system can maximize the synergistic therapeutic effects and provide an effective solution for individualized treatment.The system is capable of delivering a variety of drugs simultaneously or combining multiple therapy strategies(chemotherapy and photothermal therapy).Any drug/gene delivery system must meet the requirements of clinical applications,that is to achieve the target positioning controlled release of drug/gene within the appropriate concentration and time.MSN-based stimuli-responsive systems have designed many different gatekeepers to regulate the encapsulation and release behaviors of drugs.Cyclodextrin(CD)is well-known and readily available macrocyclic host.Moreover,CD with two hydrophilic rims and a hydrophobic cavity can accommodate hydrophobic drugs with the ability to enhance solubility,stability,and bioavailability of drugs.It is a smart strategy to take advantage of the specific structure and properties of CD for use in the MSN-based drug delivery systems not only as gatekeepers but also as drug carriers.Native duplex DNA is the target of some of drugs for achievement of therapeutic efficacy.The intercalation of drugs within double-stranded DNA structures is the main binding mechanism for antibacterial and antitumoral drugs to interact with duplex DNA.The unique recognition capability and structural features make DNA very important in the gatekeeper design.9-Acridinamine is a highly fluorescent dye used clinically as an antibacterial drug and is capable to interact with DNA as an intercalative agent.Doxorubicin(DOX)is a broad-spectrum and potent anthracycline anticancer drugs.It has a good effect in the treatment of acute leukemia,malignant lymphoma,and a variety of solid tumors.Due to the importance of this drug,many DOX derivatives have been synthesized to improve effectiveness and to reduce toxicity.DOX is also known to intercalate itself into the DNA,with the inhibition of both DNA and RNA polymerase,ultimately inhibition of macromolecule production leading to cell toxicityBased on the above strategies,the thesis have designed and developed CD or native DNA gated MSN vehicles with dual drug loading for multi-stimuli-responsive release.CD and duplex DNA not only act as gatekeepers but also as drug carriers.The major research work is divided into the following four parts:1.Construction of cyclodextrin-gated phenylboronic acid-functionalized mesoporous silica drug delivery system with dual drug loading and multi-stimuli-responsive controlled releaseCombination drug therapy can maximize therapeutic efficacy and overcome drug resistance.The stimuli-responsive y-CD-gated MSN drug delivery system was constructed through dual dynamic covalent bonds of disulfide-linked boronate esters.MSN was co-modified with disulfide-linked carbamoylphenylboronic acid moieties and amines on the surfaces,which facilitated the development of the intermolecular N-B coordination interactions for ?-CD binding under physiological conditions.?-CD acted on not only as a gatekeeper to encapsulate one drug within MSN pores but also as a drug carrier to accommodate the other drug in its cavity.Simultaneous release of the two drugs was realized via the hydrolysis of the boronate ester bonds and the weakening of the binding affinity of the drugs included in the ?-CD cavities at acidic pH.Cascade release of two drugs could be realized upon first cleavage of disulfide bonds or competitive binding of saccharides(fructose or galactose)and subsequent trigger of acidic pH.The smart?-CD-gated MSN delivery system could resist susceptibility of serum and normal blood glucose levels and have promising practical biological applications in targeted combination drug therapy.2.Construction of DNA-gated acridinamine-functionalized mesoporous silica drug delivery system with dual drug loading and multi-stimuli-responsive controlled releaseMultidrug delivery systems need to be developed to improve the delivering efficiency and to achieve the synergistic therapeutic effects.The MSN functionalized with disulfide-linked acridinamine intercalators could tether DNA through intercalative binding for encapsulation of drugs in MSN pores.The novel native DNA-gated MSN released cargo under different stimuli,including disulfide reducing agents,elevated temperature,and deoxyribonuclease ?(DNase ?),for codelivery of drugs and DNA/gene in different forms.Furthermore,the cascade release of encapsulated and intercalative drugs was controlled by AND logic gates in combination of dual stimuli.The ingeniously designed DNA-gated MSN vehicles integrated multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/gene but also for cascade release of two drugs and had promising biological applications to meet diverse requirements of controlled release.3.Construction of DNA-gated metal-chelating phosphonate-functionalized mesoporous silica drug delivery system with dual drug loading and multi-stimuli-responsive controlled releaseNovel and multi-stimuli-responsive controlled release systems need to be invented for clinical combination therapy by controlled release behaviors of each drug individually.Gold nanorods(GNR)were first prepared and then encapsulated with mesoporous silica(GNR@MSN).GNR@MSN was functionalized with titanium(?)-chelating phosphonates and then was capped with duplex DNA through the phosphonate-Ti?-DNA phosphate coordination.The combination drug delivery system was built for simultaneous and cascade release of two drugs.The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating.Coordination chemistry was the first strategy for DNA capping through multivalent chelating interactions in drug delivery systems not only as a gatekeeper but also as a drug carrier.The ingenious native DNA-gated MSN delivery system integrated a simultaneous and cascade release of two drugs into smart single nanovehicles for promising practical applications in targeted combination drug therapy.The combination of NIR light-based thermotherapy and triggered chemotherapy(thermo-chemotherapy)could maximize the therapeutic efficacy.4.Construction of DNA-gated DOX prodrug-functionalized mesoporous silica drug delivery system with dual drug loading and multi-stimuli-responsive controlled releaseMany prodrugs can be synthesized to increase the bioavailability,enhance targeting and reduce side effects.The DOX prodrugs was modified on MSN surface using two methods.The first approach,MSN surface was firstly modified with amino group,and then was conducted amidation reaction with disulfide-linked DOX derivative terminated with N-hydroxysuccinimide ester.The second approach,acylhydrazone-linked DOX derivative terminated with thiol group and allyltriethoxysilane were firstly reacted to synthesis silane reagent,and then was linked on MSN surface.Native DNA was tethered to the DOX prodrug functionalized MSN surface through the intercalative binding for encapsulation of drugs.The DNA-gated MSN system released drug encapsulated in the pores under three kinds of stimuli,glutathione(GSH)or acidic pH,elevated temperature,and DNase I.Furthermore,the cascade release of the encapsulated and intercalative drugs ware achieved in combination of dual stimuli(elevated temperature/GSH,DNase I/GSH or elevated temperature/pH 5.0,DNase I/pH 5.0).The smart system which intergrated DNA nanogate and DOX prodrug into a single MSN nanodevice for combination release of two anticancer drugs,could achieve the synergistic therapeutic effects and develop the optimal dosage regimen.