| Cancer has become a leading cause of death in the last few decades.Conventional chemotherapeutic agents are inclined to be eliminated by renal clearance and distributed nonspecifically in vivo, leading to distressing effects and limitation to therapeutic effectiveness. Therefore, drug delivery vehicles based on nanomaterials have emerged as ground-breaking candidates to overcome the disadvantages of direct injection owing to their unique physical and chemical properties. In the recent several years, various drug delivery vehicles based on the difference between normal and tumor tissues, including metabolic states, vascular pathophysiology, pH and oxygenation have been designed. In order to realize controllable drug release, different stimuli including physical or chemical signals such as temperature, magnetic field, pH and enzymatic activities have been employed. Among these, pH-sensitivity is an important pathway for controllable release owing to the acidic pH inendosomal/lysosomal compartments of cells (pH 4.0-6.5). Nanocarriers with the desired size range and surface properties preferably accumulate at tumor sites due to enhanced permeability and retention (EPR) effect.Therefore, drug-loaded nanocarriers could be accumulated at tumor tissues by EPR effect and then release drug in acidic endosomal/lysosomal compartments, generating comparatively higher local concentration and enhanced drug efficiency.To date, great efforts have been made to develop various pH-responsive drug carriers such as mesoporous nanoparticles, liposomes, micelles and polymersomes.Thereare some reports about the multifunctional nanomaterials as drug delivery vehicles for diagnostic and therapeutic applications.MOFs have drawn considerable attention due to their high specific surface areas, crystallized structures, wide range of pore sizes and facilely tailorable functionalities compared with conventional nanocarriers. In particular, zeoliticimidazolate framework-8 has exhibited the desired characteristics of high drug loading content and pH-sensitive as a drug delivery system in terms of the tumor microenvironment. However, there are few reports of metal-organic frameworks (MOFs) based drug delivery vehicles for intracellular bifunctional imaging and pH-triggered drug release with enhanced antitumor efficacy in vivo.This thesis is focused on the conjugation of fluorescence characteristics with pH responsive and magnetic properties into a single material of Fe3O4@C@ZIF-8 nanoparticles. To evaluate the drug loading and release behavior as well as therapeutic effect in vivo of the delivery system, the hydrophilic antitumor drug doxorubicin, was loaded into the Fe3O4@C@ZIF-8 nanoparticles. The main details are as follows:1. The superparamagnetic Fe3O4@C nanospheres were prepared via a facile solvothermal method. Subsequently, the microspheres first interacted with Zn2+ions and induced the ZIF-8 growth on the surfaces to form the Fe3O4@C@ZIF-8 nanoparticles. The nanoparticles were uniform with an average size of-220 nm. The DOX loading content reached approximately 73 mg DOX/100 mg Fe3O4@C@ZIF-8 nanoparticles. The release profiles showed that the cumulative release amount of DOX was considerably larger at acidic pH than that at physiological pH. In addition, the nanoparticles showed superparamagnetic property and the specific relaxivity (r2*) value was calculated to be 331.79 mM-1s-1, suggesting that Fe3O4@C@ZIF-8 nanoparticles have enough sensitivity as T2*-weighted MR imaging for cancer diagnosis.2. The MTT assay demonstrated the good biocompatibility of Fe3O4@C@ZIF-8 nanoparticles.T2*-weighted magnetic resonance imaging (MRI) and fluorescence imaging showed efficient cellular internalization and delivery DOX into cell nuclei. Moreover, it was also demonstrated that DOX-loaded Fe3O4@C@ZIF-8 nanoparticles could inhibit tumor growth effectively without side effects on A549 lung cancer mice model. These results provide convincing evidence for the pH-responsive and bifunctional imaging Fe3O4@C@ZIF-8 nanoparticles as a promising candidate for tumor therapy. |
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