Design and Synthesis of Multifunctional Mesoporous Silica Nanoparticles for Drug Delivery and Bioimaging Applications

Author(s): Chen, Wei | Advisor(s): Zink, Jeffrey I | Abstract: Multifunctional mesoporous silica nanoparticles (MSNs) have aroused much attention during the past decades for drug delivery and bioimaging applications because of their intrinsic properties including extremely high surface area, large pore volume, tunable pore diameter, easy surface modification, and high biocompatibility. Even though MSNs have these preeminent properties, rendering this unique nanostructure a promising nanocarrier for biomedical applications, several hurdles still challenge the fields of drug delivery and bioimaging when using MSNs as the nanocarries: (i) high loading and high release amounts of water-insoluble drugs delivered to the site of diseases; (ii) precise control of the dosage of drugs delivered to the site of diseases using non-invasive external stimuli; and (iii) construction of MSNs-based shortwave infrared optical imaging contrast agents as an innovative tool for bioimaging and cancer diagnostics. Therefore, this dissertation primarily focuses on the development of innovative strategies that solve these unmet needs and that advance the research in the field of biomedical applications using MSNs as the nanocarriers.In this dissertation, first of all, we review the research work, which mainly focuses on the design and synthesis of multifunctional MSNs and nanomachines for biomedical applications in Accounts of Chemical Research. A wide variety of nanomachines responsive to the different stimuli (pH, redox, enzyme, heat, light, and/or magnetic field) are discussed in this Account. Additionally, we develop a facile strategy for MSNs delivery and release of the water-insoluble drug clofazimine (CFZ), which is used to treat multidrug-resistant tuberculosis. The strategy employs a companion molecule as a chaperone to improve both the loading of CFZ into the pores of MSNs and its subsequent release, thus enabling both high loading and high release of this water-insoluble drug by MSNs. In vitro treatment of macrophages infected with Mycobacterium tuberculosis with the optimized CFZ-loaded MSNs killed the bacteria in the cells in a dose-dependent manner. These studies demonstrate a highly efficient method for loading nanoparticles with water-insoluble drug molecules and the efficacy of the nanoparticles in delivering drugs into eukaryotic cells in aqueous media. Additionally, we used a noninvasive alternating magnetic field (AMF) to stimulate and control the dosage of drug release from MSNs. Noninvasive stimuli-responsive drug delivery using AMF in conjunction with superparamagnetic nanoparticles also offers the potential for the spatial and temporal control of drug release. In vitro studies showed that the death of pancreatic cancer cells treated by drug-loaded nanoparticles was controlled by different lengths of AMF exposure time due to different amounts of drug released from the carriers. Finally, to develop a new shortwave infrared (SWIR) optical imaging contrast agent which has a higher tissue penetration depth, we demonstrate that J-aggregates of near infrared (NIR) fluorophore IR-140 can be prepared inside hollow mesoporous silica nanoparticles (HMSNs) to result in nanomaterials that absorb and emit SWIR light. The use of J-aggregates stabilized in HMSNs as SWIR imaging agents has the potential to overcome the stability, toxicity, and brightness challenges of contrast agents for this compelling region of the electromagnetic spectrum. Collectively, in this dissertation, we explore and develop innovative strategies to load and deliver high amounts of water-insoluble drugs; control the dosage of anticancer drugs released from MSNs triggered by an AMF; and establish a new SWIR optical imaging contrast agent based on the superior carriers – MSNs.