Most current chemotherapeutics have non-specific mechanisms of action and poor biodistribution profiles which result in dose-limiting toxicities tha prevent optimal efficacy from being obtained. Ribonucleic acid interference (RNAi) has the potential to be a safe, selective and personalized treatment approached for a variety of genetic-based diseases, including cancer. In particular, the design of small interfering RNA (siRNA) sequences to prevent the expression of cancer-fueling mutations provides an alternative to current therapeutic approaches. However, an effective delivery vehicle is required for systemic RNAi therapy to protect siRNA during circulation, concentrate siRNA at tumor sites and mediate cellular uptake as well as endosomal escape. This project is designed to optimize a novel, combinatorial RNAi treatment for advanced breast cancer based on delivery by calcium phosphate nanoparticles, called NanoJackets. Building on the demonstrated in vivo efficacy of an untargeted siRNA NanoJacket prototype, an active targeting ligand will be added and evaluated for improved biodistribution, cellular uptake and in vivo efficacy of siRNA NanoJackets for breast cancer therapy. If successful, the development of this targeted, combinatorial RNAi nano-therapeutic will provide a novel option for the personalized treatment of breast cancers that fail to respond to current therapies.
The convergence of biology, medicine, and material sciences has led to the engineering of Nanoscale materials that have the potential to radically improve cancer therapies and dramatically increase the number of highly effective therapeutic agents. The therapeutic use of small interfering ribonucleic acids (siRNAs) to mediate RNA interference (RNAi) holds great potential to target the disease mechanisms of cancer, however systemic delivery has proven challenging. Calcium phosphate NanoJackets have been developed as customizable, targeted, drug delivery vehicles capable of ferrying large doses of anti-neoplastic agents or siRNAs into malignant cells while sparing healthy cells. This type of drug delivery has the potential to greatly increase efficacy while reducing or eliminating the undesirable side effects that accompany many current cancer therapies. This project details the further optimization of combinatorial siRNA NanoJackets by conjugating an active targeting moiety to the particle surface for improved tumor accumulation and efficacy against drug-resistant breast cancers.