Abstract 4995: Lung specific target gene inhibition following intravenous delivery of siRNA nanocomplexes
| Autor: | Elaine Brunhoeber, Richard Congo, Gregory Slobodkin, Jennifer Rice, Angela Rea-Ramsey, Khursheed Anwer, Jason G. Fewell, Jeff Sparks, Kevin Polach, Casey Pence, Majed Matar, Diane McClure, Leslie Wilkinson |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:4995-4995 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | RNA interference offers the promise of a new class of therapeutics that can specifically target many diseases that have aberrant gene expression as the root cause. This is potentially true even for diseases that are currently considered non-druggable by small molecules or other conventional therapies. The means to efficiently deliver RNAi based therapeutics into target cells still poses arguably the most significant barrier to overcome for this platform technology. Cationic systems (lipids and polymers) have been extensively used for siRNA delivery and a wide range of experimental approaches have indicated that siRNA specific knockdown in vivo can be achieved using these systems. However, there is considerable concern that the dose levels required to achieve therapeutically relevant knockdown will result in unacceptable toxicity. This is particularly relevant when applied to systemic delivery. To address this issue we have developed a novel core cationic lipopolyamine structure that is chemically flexible allowing for incorporation of active moieties that improve safety, stability, and efficiency, creating a family of functionalized RNAi delivery systems. Here we show that systemic (intravenous) administration of siRNA nanocomplexes formulated with one of these functionalized systems produces significant target gene knockdown specifically in the lung with duration of at least 7 days following a single injection. Administration was well tolerated with no indications of acute or long term toxicities. Detailed biodistribution analysis reveals that siRNA is initially distributed primarily to lungs, liver and spleen, with the majority of the siRNA accumulating in the liver. Lung specific knockdown is explained through the observed rates of siRNA clearance, which are considerably faster for the liver and spleen than those observed in the lung. This results in higher lung siRNA concentrations on the timescale of RNAi mediated transcript knockdown. In a model of metastatic lung cancer administration of siRNA targeting STAT3 resulted in significant transcript depletion in the lungs and a significant reduction in tumor burden. These results support the continued evaluation of this delivery system as a potential siRNA based therapeutic approach for a variety of diseases of the lung. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4995. doi:10.1158/1538-7445.AM2011-4995 |
| Databáze: | OpenAIRE |
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