Small Interfering RNA Imaging Probes for Neurological Applications

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Small Interfering RNA Imaging Probes for Neurological Applications

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Title: Small Interfering RNA Imaging Probes for Neurological Applications
Author: Ifediba, Marytheresa Akuigwe
Citation: Ifediba, Marytheresa Akuigwe. 2012. Small Interfering RNA Imaging Probes for Neurological Applications. Doctoral dissertation, Harvard University.
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Abstract: Small interfering RNAs (siRNAs) have emerged as a potent new class of therapeutics that regulate gene expression through sequence-specific inhibition of mRNA translation. Clinical trials of siRNAs have highlighted the need for robust delivery and detection techniques that would enable the application of these therapeutics to increasingly complex diseases and organ systems. Here we detail the generation and evaluation of siRNA-based optical and magnetic resonance imaging (MRI) contrast agents for the treatment of neurological diseases, including ischemic stroke and glioblastoma multiforme brain cancer. First, we designed and tested a fluorescent probe for neuroprotection in the setting of stroke that consists of siRNA complexed with myristoylated poly-arginine peptide (MPAP). MPAP, a peptide shown to cross cell membranes and the blood brain barrier, promoted robust internalization of siRNA by neurons in vitro and in mouse brain after intracerebral injection. Cellular uptake of MPAP-siRNA probes directed against a protein implicated in stroke pathology, c-Src, led to statistically-significant reductions of endogenous mRNA expression. The neuroprotective potential of probes was tested in a mouse model of ischemic stroke. Second, superparamagnetic iron oxide nanoparticles were investigated as vectors for siRNA delivery to glioblastoma multiforme brain tumors. Nanoparticles were designed to enhance chemotherapeutic treatment of tumors through siRNA-mediated knockdown of O6-methylguanine–DNA methyltransferase (MGMT), a protein implicated in glioblastoma chemotherapy resistance. The iron oxide core of nanoparticles rendered them detectable by MRI while fluorescent labeling was used for optical imaging. Functionalizing nanoparticles with the peptide chlorotoxin enabled tumor targeting and cellular accumulation of probe. Probe uptake was accompanied by reductions in MGMT activity and enhanced cellular responses to the chemotherapeutic temozolomide. Nanoparticles were tested in an orthotopic glioblastoma mouse model, where intratumoral administration proved effective in suppressing MGMT expression and tumor volume. These studies serve as proof-of-principle that siRNA-based imaging agents can be used as therapeutic tools for diseases of the central nervous system.
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