Aptamer-siRNA Chimera/Nanoparticle Conjugates for MRI Guided Cancer Therapy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): One of the major challenges of modern medicine is the development of novel approaches for the efficient delivery of therapeutics and molecular specific treatment of pathology that can be carried out under imaging guidance and monitoring. Recent advances in nanotechnology, biochemistry and molecular biology give an opportunity to combine all these capabilities in a single entity. In this research program we will use recent achievements in nanotechnology and biochemistry to engineer a nanomaterial with both therapeutic and MRI contrast enhancing capabilities. This material will provide the optimized combination of: efficient delivery of a deactivated therapeutic compound, selective activation of the prodrug using external stimuli, molecular specific therapeutic effect upon activation and MRI monitoring and guidance. The nanomaterial will consist of a gold-coated iron oxide nanoparticle carrier with attached oligonucleotide handles that interact with fluorinated aptamer-siRNA chimera molecules through complementary nucleotides. The aptamer portion of the chimera will be specific for a cancer biomarker and the siRNA portion will be used to down-regulate expression of genes that are essential for cancer cell survival. The oligonucleotide handle will be designed to interact with and reversibly deactivate the aptamer portion of the chimera; this will ensure that the particles do not spontaneously bind to their target especially in normal tissue. These bioconjugated nanoparticles will be delivered in cancerous tissue under T2 weighted MRI monitoring of their accumulation and biodistribution. Then, near infrared (NIR) irradiation will be delivered to the treatment site that will lead to the local heating of the gold layer, melting of the double stranded helix between oligonucleotide handles and the aptamer portion of chimera molecules, and release of the chimeras which will then diffuse deep into the cancerous tissue. We hypothesize that release and diffusion of chimera molecules can be imaged by 19F MRI. The aptamer portion will refold and regain molecular specificity, delivering the therapeutic siRNA inside cancer cells thereby inducing cell death. The nanoparticle carrier will improve delivery, reduce non-specific toxicity, and enable monitoring of accumulation and activation of molecular specific cancer therapy. Initial tests with cell cultures and mouse xenograft models will demonstrate its efficacy. The main objective of this program is to develop and initially test a new, nontoxic nanomaterial that can be activated via NIR light irradiation to release a targeted molecular compound that can be selectively internalized by cancer cells and induce a therapeutic gene-silencing response. The nanoparticle carrier will improve delivery, reduce non-specific toxicity, and enable monitoring of accumulation and activation of molecular specific cancer therapy. Initial tests with mouse xenograft models will demonstrate its efficacy. Successful completion of this project will make an important advance toward realization of one of the ultimate goals of cancer medicine, a material that can be used to simultaneously detect and treat cancer.