The objective of this proposal is to synthesize polycationic nanoscale hydrogels capable of delivery of small interfering RNA (siRNA) to disease targets, specifically those along the gastrointestinal tract. The research plan describes the characterization and optimization of a number of variables that will ultimately affect the suitability of the hydrogel Oral delivery of siRNA using pH-responsive nanogel carriers promises to improve the treatment of various gastrointestinal diseases because oral delivery is more efficient and less painful than intravenous and intraperitonealI injections. The applicant manages a lab that has 40 % women and 20 % minority students. As part of the outreach to K-12 students, the applicant is offering 10 high school students summer internships.
The landmark discovery of RNA mediated interference (RNAi) in 1998 sparked a massive research effort in all fields of biological science and redefined our understanding of gene regulation mechanisms. RNAi pathways are guided by the presence of small interfering RNA (siRNA), short strands of duplex RNA capable of selective, potent, and reversible silencing of target genes. Theoretically, siRNA could be used as a powerful and versatile therapeutic to treat nearly any disease resulting from aberrant gene expression. Furthermore, recent advances in genomics, bioinformatics, and increased understanding of the molecular and genetic nature of disease enable siRNA technology to be rapidly adapted for disease treatment. Owing to its remarkable potency and low therapeutic dosage, siRNA holds extraordinary promise as a new biological therapeutic. However, efficient delivery has been implicated as the major hurdle to its widespread clinical application. The overall goal of this NSF grant was to develop a novel platform technology for siRNA delivery, a synthetic polymer carrier capable of providing siRNA to disease targets, specifically those along the gastrointestinal tract. We developed novel polycationic nanoscale hydrogels for oral siRNA delivery. These carriers are advantageous over their self-assembled counterparts because of their inherent mechanical integrity and stability in the GI tract. Optimization of molecular architecture was completed via a thorough study of several key parameters, including polymer composition, core hydrophobicity, cross linking ratio, and incorporation of functional groups for targeting. We arrived at a system able to efficiently encapsulate siRNA, protect it from the environment of the small intestine, and facilitate endosomal release following cellular uptake. The final result of this research was a platform technology for drug delivery; a safe, efficient polymer carrier capable of delivering manifold siRNA cargoes to the epithelial cells in the small intestine. Successful development of this system paves the way for improved treatment of gastrointestinal diseases where current treatment is sub-optimal, such as Crohnâ€™s disease, ulcerative colitis, celiac disease, and gastrointestinal carcinomas. This proposal emphasizes a unique and innovative approach to develop new carrier systems for siRNA. The oral delivery of siRNA for disease treatment was largely unexplored. Innovation in this area represents a departure from current thrusts in siRNA delivery, which relied on painful intravenous or impractical intraperitoneal injections. The central aim of this work was of great medical significance, as advances in this area could significantly improve the ease and availability of siRNA therapy to patients. As siRNA is capable of potent and specific gene silencing, it represents an improved treatment option for many diseases. However, the challenges of advancing this promising therapeutic to the clinical stage are significant and need to be met with innovative solutions. This project presented a great opportunity to develop the next generation of pharmaceuticals by enabling the efficient delivery of a potent, highly specific therapeutic via a non-invasive, patient friendly route. As most biotherapeutics are administered via intravenous, intraperitoneal, or local injection, an ingestible drug formulation capable of providing therapeutically-relevant concentrations in the local environment and/or transport of the drug from the intestinal lumen to the bloodstream would be of significant scientific and medical importance.