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Data from Intravesical Delivery of Small Activating RNA Formulated into Lipid Nanoparticles Inhibits Orthotopic Bladder Tumor Growth
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<div>Abstract<p>Practical methods for enhancing protein production <i>in vivo</i> remain a challenge. RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21<sup>WAF1/CIP1</sup> (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2′-fluoro-modified derivative (dsP21-322-2′F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis <i>in vitro</i> following treatment with LNP-formulated dsP21-322-2′F (LNP-dsP21-322-2′F) or one of its nonformulated variants. Both 2′-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2′F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2′F treatment also facilitates p21 activation <i>in vivo</i> leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes. <i>Cancer Res; 72(19); 5069–79. ©2012 AACR</i>.</p></div>
American Association for Cancer Research (AACR)
Title: Data from Intravesical Delivery of Small Activating RNA Formulated into Lipid Nanoparticles Inhibits Orthotopic Bladder Tumor Growth
Description:
<div>Abstract<p>Practical methods for enhancing protein production <i>in vivo</i> remain a challenge.
RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression.
This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing.
Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21<sup>WAF1/CIP1</sup> (p21).
In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2′-fluoro-modified derivative (dsP21-322-2′F) into lipid nanoparticles (LNP) for intravesical delivery.
LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA.
We confirm p21 induction, cell-cycle arrest, and apoptosis <i>in vitro</i> following treatment with LNP-formulated dsP21-322-2′F (LNP-dsP21-322-2′F) or one of its nonformulated variants.
Both 2′-fluoro modification and LNP formulation also improve duplex stability in urine.
Intravesical delivery of LNP-dsP21-322-2′F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer.
LNP-dsP21-322-2′F treatment also facilitates p21 activation <i>in vivo</i> leading to regression/disappearance of tumors in 40% of the treated mice.
Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes.
<i>Cancer Res; 72(19); 5069–79.
©2012 AACR</i>.
</p></div>.
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