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Engineering Multifunctional Mesoporous Silica Nanoparticles for Stimuli-Responsive Drug Delivery and Bioimaging

  • Author(s): Cheng, Chi-An
  • Advisor(s): Zink, Jeffrey I
  • et al.
Creative Commons 'BY-NC-ND' version 4.0 license
Abstract

This dissertation makes contributions to the fields of formulation and delivery of anticancer drugs, antibiotics, and imaging agents, primarily focused on engineering mesoporous silica nanoparticles (MSNs) for stimuli-responsive drug delivery. The strategies and techniques developed in this dissertation will be especially useful for achieving precision medicine or personalized medicine, which is defined as the “right drug, right dosage at right timing to right patient”. Although various emerging approaches for personalized disease treatment that take individual variability into account have been developed, the necessity of delivering the desired therapeutics at the desired time to the specific site of the disease and with accurate dosage remains a challenge. Here we first review the previously reported stimuli-responsive MSNs controlled by supramolecular nanomachines for antibiotic and drug delivery. In the second part of the dissertation, we report novel MSNs-based nanoparticles engineered to be responsive to noninvasive stimuli, such as alternating magnetic field (AMF) or high-intensity focused ultrasound (HIFU). AMF-responsive drug delivery demonstrates the controlled therapeutic efficacy for pancreatic cancer cells in vitro by adjusting different lengths of AMF exposure time. The HIFUresponsive MSNs provide a promising platform for magnetic resonance imaging (MRI)-guided HIFU (MRgHIFU)-stimulated cargo delivery. The change of T1 reports on the amount of released cargo which is imageable by MRI ex vivo. Both AMF-and MRgHIFU-stimulation strategies offer the potential for the spatial, temporal, and dosage control of drug delivery. In the last part, we develop an approach to achieve both high loading and high release amount of a water-insoluble antibiotic clofazimine (CFZ) carried by MSNs by using acetophenone (AP) as a chaperone molecule, solving the water insolubility problem faced when treating multidrug-resistant tuberculosis. The treatment of Mycobacterium tuberculosis infected macrophages with optimized CFZ-loaded MSNs shows good therapeutic efficacy in vitro. Finally, we develop a hollow mesoporous silica nanoparticle (HMSN) formulated near infrared (NIR) fluorophore IR-140, to realize a novel biocompatible shortwave infrared (SWIR) optical imaging contrast agent for bioimaging with a higher tissue penetration depth. The J-aggregates of IR-140 stabilized inside HMSNs showed the potential to overcome the stability, toxicity, and brightness challenges faced by common SWIR contrast agents.

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