Nanomaterials for regulating cancer and stem cell fate
Creators: name: Shah, Birju P.
Publisher: name: No Publisher Supplied
Year: 2014

description: The realm of nanomedicine, defined as the applications of nanotechnology for medical purposes such as diagnosis, monitoring and treatment of diseases, has grown exponentially over the past few decades; with several research efforts translating into commercial success stories. Such applications requires the amalgamation of research efforts from different disciplines such as chemistry, biology, physics, engineering and clinical medicine. While the earlier efforts in nanomedicine were focused mainly on improving the properties of the available therapeutics, current research efforts are more geared towards developing novel therapeutics or imaging modalities based on the supramolecular assembly of nanoscale building blocks. There is a plethora of nanoscale platforms that are being developed for clinical uses, including, polymeric nanoparticles, liposomes and micelles, metallic nanostructures,  semiconductor quantum dots and silicon oxide nanoparticles.  However, there are several obstacles that need to be overcome, prior to the wide-spread clinical applications of these nanoparticles, such as (i) developing well-defined nanoparticles of varying size, morphology and composition to enable various clinical applications; (ii) optimization of the biopharmaceutical properties such as physiological stability, solubility and systemic circulation of the nanoparticle-based therapeutics; (iii) delivery of different kinds of therapeutics without altering their pharmacological effects; (iv) overcome various physiological barriers encountered in order to deliver the therapeutics to the target location; and (v) real-time monitoring of the nano-therapeutics within the human body for tracking their uptake, localization and effect. Hence, this dissertation focuses on developing multimodal nanotechnology-based approaches to overcome the above-mentioned challenges by combining either different nanoparticle compositions or different therapeutic moieties, towards a singular purpose of regulating cancer and stem cell fate, such as proliferation, differentiation and cell death.     The initial part of this dissertation describes the synthesis and characterization of well-defined and monodisperse multimodal magnetic core-shell nanoparticles (MCNPs), comprised of a highly magnetic core surrounded by a thin gold shell. As a result of combining two different elements (Fe and Au) within a single nanoplatform, these multimodal core-shell nanoparticles possessed both magnetic and plasmonic properties, which allowed for enhanced therapy and imaging. These nanoparticles were utilized for mainly two applications: (i) Magnetically-facilitated delivery of siRNA and plasmid DNA to neural stem cells for inducing neuronal differentiation and non-invasive imaging and (ii) Combined hyperthermia and targeted delivery of a mitochondria-targeting peptide for enhancing apoptosis in brain and breast cancer cells.     The following part of this dissertation presents the synthesis and applications of a multi-functional polymeric delivery platform (known as DexAMs), composed of a dendritic cationic polyamine conjugated to a single beta-cyclodextrin moiety. The DexAM molecule was utilized as a single vehicle to simultaneously deliver two orthogonal therapeutics - anticancer drugs and siRNAs against oncogenes, in a target-specific manner to brain tumor cells. This combined delivery of chemotherapeutics and siRNA targeted the multiple dysregulated pathways in cancer cells and this resulted in a synergistic effect on the apoptosis of brain tumor cells, as compared to the individual treatments.      The final part of this thesis presents synthesis of stimuli-responsive fluorescence resonance energy transfer (FRET)-based mesoporous silica nanoparticles for real-time monitoring of drug release in cells. These MSNs were composed of a porous silica support which allowed for drug loading, a stimuli-responsive valve composed of disulfide bonds, and a FRET donor-acceptor pair of coumarin and fluorescein integrated within the disulfide bond. The stimuli-responsive valve was cleaved only in the presence of increased glutathione concentrations found within cancer cells, resulting in change in the FRET signal, thus allowing for real time monitoring of drug release.     Taken together, these nanomaterial-based approaches combine therapeutic and imaging modalities within a single nanoplatform and as a result have the potential for regulating cancer and stem cell fate such as proliferation, differentiation and apoptosis as well as allowing for real-time monitoring of these events in a non-invasive manner.