Global Gene Expression Profiling in Cultured Cells Is Strongly Influenced by Treatment with siRNA–Cationic Liposome Complexes

Tagami, Tatsuaki; Hirose, K; Barichello, José Mário; Ishida, Tatsuhiro; Kojima, Hiroshi

doi:10.1007/s11095-008-9663-7

Cited by 21 publications

(14 citation statements)

References 34 publications

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“…However, examining the production of certain types of cytokines is not sufficient to guarantee the safety of a systemic siRNA delivery system. To address this issue, gene expression profiling represents a promising approache to understanding the underlying mechanism of host responses by delivery systems, in the form of toxicogenomics studies [46][47][48][49]. However, the response of a host to a systemically administrated non-viral gene vector has not been examined using this approach.…”

Section: Discussionmentioning

confidence: 99%

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

et al. 2011

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Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment.In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen.

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Section: Discussionmentioning

confidence: 99%

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

et al. 2011

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“…The sequence of siRNA against Argonaute2 (siAgo2) was sense: 5′-UGA GGC ACU UAC CAU CCA UTT-3′ and antisense sequence, 5′-AUG GAU GGU AAG UGC CUC ATT-3′ [21]. The sequence of the non-silencing control siRNA (siNS), which was targeting against GFP, was sense: 5′-GGC UAC GUC CAG GAG CGC ATT-3′ and antisense: 5′-UGC GCU CCU GGA CGU AGC CTT-3′ [22].…”

Section: Animals and Tumor Cell Linementioning

confidence: 99%

Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model

Tagami

Lila

Matsunaga

et al. 2012

Drug Deliv. and Transl. Res.

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Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. Recently, we showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated siBcl-2-lipoplex in DLD-1 solid tumor mouse model. In this study, to extend our work, we investigated the effect of metronomic S-1 dosing on the intratumoral accumulation and, thereby, therapeutic efficacy of PEG-coated siAgo2-lipoplex in Lewis lung carcinoma cells (LLCC) solid tumor mouse model. Also, we tried to elucidate the probable mechanism of the enhanced intratumoral accumulation of PEG-coated siRNA-lipoplexes induced by S-1 combination therapy. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siAgo2-lipoplexes into a LLCC solid tumor. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes resulted in potent tumor growth suppression. These findings offer proof-of-concept for the improved systemic delivery of PEG-coated siRNA-lipoplexes by metronomic S-1 dosing in whatever tumor model used, and this may pose a promising therapeutic strategy to conquer cancer progression.

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“…Therefore, non-viral vector systems should overcome these adverse side effects and represent safer and more efficient alternatives with improved bioavailability and reduced cellular toxicity in the clinics (Akhtar et al, 2000;Somia and Verma, 2000;Panyam and Labhasetwar, 2003). It has been shown that cationic polymers and lipid-based transfection reagents could elicit cellular gene expression changes and complexation with siRNA increased these changes (Omidi et al, 2003;Omidi et al, 2005;Fedorov et al, 2006;Hollins et al, 2007;Tagami et al, 2007;Tagami et al, 2008). Beyerle et al analyzed the expression changes of genes related to cytotoxicity, inflammation and oxidative stress in a pathway focused qRT-PCR array system upon treatment with different PEI-PEG copolymers in murine lung epithelial cells (LA-4 cell line) and could show that PEGylated PEI copolymers altered the gene expression profile on cost of upregulation of genes involved in inflammatory and oxidative stress processes while PEI 25 kDa mainly induced genes related to cytotoxicity and apoptosis (Beyerle et al, 2010a).…”

Section: Toxicogenomics Of Pei-based Non-viral Vector Systemsmentioning

confidence: 99%

Toxicity of Polymeric-Based Non-Viral Vector Systems for Pulmonary siRNA Application

Beyerle¹,

Kissel²,

Stoeger³

2011

Non-Viral Gene Therapy

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Global Gene Expression Profiling in Cultured Cells Is Strongly Influenced by Treatment with siRNA–Cationic Liposome Complexes

Abstract: Non-specific effects of siRNA-lipoplexes may either enhance, attenuate or even fully mask the desired outcomes of siRNA-based biochemical studies and therapies.

Cited by 21 publications

References 34 publications

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model

Toxicity of Polymeric-Based Non-Viral Vector Systems for Pulmonary siRNA Application

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