You are here

RNAi Cancer Therapeutics using Nanotechnology


In 2011, the SBIR Development Center hosted an industry roundtable to solicit inputs from life science industry professionals on emerging areas that are ripe for technology development by the small business community. Participants at this meeting expressed strong interest in using the SBIR mechanism to foster and encourage the development of novel RNA interference (RNAi) delivery platforms, particularly as a strategy for addressing therapeutic targets previously deemed “undruggable” by small molecules. Such therapeutics are gaining prominence due to their versatility and efficiency in treating cancer, as well as a variety of other genetic diseases; however, treating patients with RNAi has proven challenging, as it is difficult to achieve intracellular delivery to specific tissues and organs expressing the target gene. In particular, cellular uptake of naked RNAi is extremely inefficient owing to its polyanionic nature. The majority of intravenously administered RNAi is removed from circulation by hepatic and renal clearance, and the remaining RNAi is subject to degradation by nonspecific nucleases in the blood. Moreover, injecting large quantities of RNAi may elicit an immune response, and other “off-target” effects may result in toxicity. While RNAi delivery to tumor cells poses these and other challenges, the ability to overcome these challenges is expected to facilitate the development of new and highly efficacious anti-cancer agents. Nanoparticle-based delivery systems are especially attractive as such strategies afford the opportunity to target specific cell, tissue, and organ types, while also increasing circulation half-life and shielding RNAi from degradation. Importantly, ongoing clinical trials are successfully utilizing nanoparticle-based delivery systems for cancer-related RNAi therapeutics, indicating that nanotechnology-based approaches hold great promise. To accelerate such efforts, the National Cancer Institute (NCI) requests proposals for the development of novel, commercially viable nanotechnology-based platforms for the delivery of RNAi cancer therapeutics. Project Goals Proposals submitted under this contract topic should involve the design, fabrication, characterization, and preclinical evaluation of novel nanoparticle-based drug formulations capable of delivering candidate RNAi therapeutics for the treatment of cancer. Of particular interest are delivery systems that can achieve targeted delivery of RNAi to tumor cells, favorable pharmacokinetics and circulation times, and efficient uptake of RNAi by tumor cells. Nanotechnologies which minimize immune responses and/or off-target effects of RNAi are also desirable. Nanotechnology-based RNAi therapeutic agents acceptable under this contract topic include siRNA, shRNA, miRNA, other ncRNA(s) and combinations thereof. Antisense oligonucleotides are also acceptable. This contract topic is not intended to fund basic research to identify molecular targets for RNAi therapy, conduct exhaustive comparative studies of multiple nanoparticle delivery systems, or establish new animal models. Concepts delivering DNA, messenger RNA, and/or proteins are also not acceptable candidates for this topic, nor are viral delivery platforms for RNAi. The RNAi-nanoparticle constructs under development may incorporate additional functionalities to supplement or enhance the therapeutic RNAi. Such functionalities may include, but are not necessarily limited to, the following: • Novel nanoparticle delivery vehicles • Constructs involving novel tumor targeting • Novel RNAi loading and releasing schemes • Nanoparticle constructs capable of crossing the blood-brain barrier, penetrating pancreatic stroma, overcoming multi-drug resistance, or treating metastatic cancer • Combination therapies utilizing multiple RNAi payloads (e.g., RNAi-based Logic Circuits) • Other combination therapies utilizing at least one RNAi therapeutic and one conventional chemotherapeutic agent (i.e., non-nucleic acid agent) Phase I Activities and Expected Deliverables • Provide a detailed experimental strategy to develop and deliver the RNAi/nanotherapeutic, and identify an appropriate cancer indication(s) for the nanoconstruct containing the RNAi(s) • Encapsulate and/or attach the selected RNAi therapeutic agent(s) to the nanoparticle • Demonstrate nanoconstruct stability in vitro, and demonstrate controlled release of the RNAi therapeutic agent(s) from the nanoconstruct • Perform in vitro efficacy studies in the relevant cancer cell line(s): (a) quantitate knockdown of the target gene transcript(s) and demonstrate a ≥70% reduction in the corresponding protein product(s) (knockdown of multiple gene products is encouraged but not required); and (b) evaluate appropriate correlative endpoints / phenotypic effects (e.g., cell death, cell cycle arrest, cell differentiation) Establish specificity of the RNAi therapeutic and its phenotypic effects using appropriate controls (e.g., mutational substitution, cDNA rescue, scrambled RNAi sequences) • Perform a small in vivo efficacy study in a relevant animal model of cancer: (a) quantitate knockdown of the target gene transcript (i.e., at least one gene) and demonstrate a ≥70% reduction in the corresponding protein product; (b) evaluate appropriate correlative endpoints / phenotypic effects Phase II Activities and Expected Deliverables (include at least three of the following) • Provide a plan and timeline to complete preclinical development for the RNAi/nanotherapeutic, culminating in the filing of an IND with the FDA • Demonstrate in vivo preclinical efficacy (properly powered studies) • Demonstrate acceptable safety (i.e., toxicity in rodents and/or large animals) • Demonstrate acceptable pharmacokinetics and pharmacodynamics • Conduct process development to support clinical manufacturing (e.g., scale-up feasibility) • Conduct other R&D activities needed to complete an IND application, carried out in a suitable pre-clinical environment
US Flag An Official Website of the United States Government