Development of Nanoparticle Conjugates for Diagnostic and Therapeutic ApplicationsPublic Deposited
Spherical Nucleic Acids (SNAs) are nanoparticle bioconjugates that have found use in a wide-range of diagnostic and therapeutic applications. These nanomaterials are composed from inorganic or organic core nanoparticle scaffolds that are functionalized with a dense surface layer of nucleic acids (typically DNA or RNA) that are oriented in a three-dimensional structure. This dense surface loading of highly oriented oligonucleotides gives rise to the important biochemical properties of SNAs, which include cooperative binding behavior with complementary nucleic acid sequences, efficient cellular uptake without the need for auxiliary transfection agents, and minimal off-target immune response effects. These attributes enable the realization of highly sensitive and potent tools for diagnosis and treatment of disease, respectively. This work exploits these attributes along with the chemical tailorability of SNAs to synthesize nanoparticle conjugates with enhanced biomolecule detection capabilities and unique, stimuli responsive surface chemistries. I begin by making an important step forward by applying SNAs as diagnostic probes in a clinically relevant high-throughput bioassay for identification of high-risk, aggressive prostate cancer. In addition, I widen the scope of gold-based nanoscale biomolecule probes by designing PEG-biotin-gold nanoparticle probes that enable the simultaneous detection of both nucleic acid and protein targets from a single sample. Additionally, I engineer new SNAs with thermally responsive surface ligands for step-wise conjugation and controlled-release of oligonucleotides. The nanoparticle constructs developed in this work expand the nanotechnology toolkit and may enable advances in disease diagnosis, management, and treatment.