Versatile cationic lipids for siRNA delivery

Sparks, Jeff; Slobodkin, Gregory; Matar, Majed; Congo, Richard; Ulkoski, David; Rea-Ramsey, Angela; Pence, Casey; Rice, Jennifer; McClure, Diane; Polach, Kevin J.; Brunhoeber, Elaine; Wilkinson, Leslie; Wallace, Kirby; Anwer, Khursheed; Fewell, Jason G.

doi:10.1016/j.jconrel.2011.11.006

Cited by 36 publications

(37 citation statements)

References 29 publications

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“…To achieve a therapeutic effect we administered 3 doses at 2-week intervals. We assumed that knockdown of target proteins would have a 2–4 day time to 50% inhibition and sustained inhibition for at least 10 days as previously reported using Star:Star-mPEG delivery of siRNA to mouse lung[17, 18]. We also assumed the tissue half-life of antimiR-145 would be similar to tiny locked nucleic acids (LNA) in vivo , which is 4–6 days[37].…”

Section: Resultsmentioning

confidence: 99%

“…However, a recently described liposomal system (Star:Star-mPEG) has been shown to direct the biological activity of systemically administered small interfering RNA (siRNA) to the lung. Specifically, intravenous delivery of siRNA formulated with these liposomal nanoparticles resulted in RNAi-mediated knockdown of several transcripts and proteins including caveolin-1, CD-31, and Tie-2[17, 18]. Although the precise mechanism of lung specific activity of the Star:Star-mPEG system has not been elucidated, it has been suggested that it is not the result of increased lung uptake of siRNAs from the blood, but rather a decreased clearance from lungs relative to other organs.…”

Section: Introductionmentioning

confidence: 99%

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Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension

McLendon

Joshi

Sparks

et al. 2015

Journal of Controlled Release

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Therapies that exploit RNA interference (RNAi) hold great potential for improving disease outcomes. However, there are several challenges that limit the application of RNAi therapeutics. One of the most important challenges is effective delivery of oligonucleotides to target cells and reduced delivery to non-target cells. We have previously developed a functionalized cationic lipopolyamine (Star:Star-mPEG-550) for in vivo delivery of siRNA to pulmonary vascular cells. This optimized lipid formulation enhances the retention of siRNA in mouse lungs and achieves significant knockdown of target gene expression for at least 10 days following a single intravenous injection. Although this suggests great potential for developing lung-directed RNAi-based therapies, the application of Star:Star-mPEG mediated delivery of RNAi based therapies for pulmonary vascular diseases such as pulmonary arterial hypertension (PAH) remains unknown. We identified differential expression of several microRNAs known to regulate cell proliferation, cell survival and cell fate that are associated with development of PAH, including increased expression of microRNA-145 (miR-145). Here we test the hypothesis that Star:Star-mPEG mediated delivery of an antisense oligonucleotide against miR-145 (antimiR-145) will improve established PAH in rats. We performed a series of experiments testing the in vivo distribution, toxicity, and efficacy of Star:Star-mPEG mediated delivery of antimiR-145 in rats with Sugen-5416/Hypoxia induced PAH. We showed that after subchronic therapy of three intravenous injections over 5 weeks at 2 mg/kg, antimiR-145 accumulated in rat lung tissue and reduced expression of endogenous miR-145. Using a novel in situ hybridization approach, we demonstrated substantial distribution of antimiR-145 in lungs as well as liver, kidney, and spleen. We assessed toxic effects of Star:Star-mPEG/antimiR-145 with serial complete blood counts of leukocytes and serum metabolic panels, gross pathology, and histopathology and did not detect significant off-target effects. AntimiR-145 reduced the degree of pulmonary arteriopathy, reduced the severity of pulmonary hypertension, and reduced the degree of cardiac dysfunction. The results establish effective and low toxicity of lung delivery of a miRNA-145 inhibitor using functionalized cationic lipopolyamine nanoparticles to repair pulmonary arteriopathy and improve cardiac function in rats with severe PAH.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension

McLendon

Joshi

Sparks

et al. 2015

Journal of Controlled Release

Self Cite

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show abstract

“…The therapeutic potential of cationic lipid carriers is also significantly enhanced by PEGylation, which improves lung uptake and retention of siRNAs (Polach et al, 2012; Sparks et al, 2012). A cationic lipopolyamine formulation (Staramine-mPEG) delivered relatively high levels of caveolin-1 silencing siRNA to the lung in mice with a longer long half-life in the lung compared to the liver and other tissues sufficient to reduce caveolin-1 expression by ~60% after a single dose.…”

Section: Delivery and Therapeutic Potential Of Noncoding Rna Mimicmentioning

confidence: 99%

Epigenetic targets for novel therapies of lung diseases

Comer

Singer

et al. 2015

Pharmacology & Therapeutics

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In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is compelling need for new therapeutic approaches to address severe persistent asthma that is insensitive to inhaled corticosteroids. Although the prevalence of steroid-resistant asthma is 5–10%, severe asthmatics require a disproportionate level of health care spending and constitute a majority of fatal asthma episodes. None of the established drug therapies including long-acting beta agonists or inhaled corticosteroids reverse established airway remodeling. Obstructive airways remodeling in patients with chronic obstructive pulmonary disease (COPD), restrictive remodeling in idiopathic pulmonary fibrosis (IPF) and occlusive vascular remodeling in pulmonary hypertension are similarly unresponsive to current drug therapy. Therefore, drugs are needed to achieve long-acting suppression and reversal of pathological airway and vascular remodeling. Novel drug classes are emerging from advances in epigenetics. Novel mechanisms are emerging by which cells adapt to environmental cues, which include changes in DNA methylation, histone modifications and regulation of transcription and translation by noncoding RNAs. In this review we will summarize current epigenetic approaches being applied to preclinical drug development addressing important therapeutic challenges in lung diseases. These challenges are being addressed by advances in lung delivery of oligonucleotides and small molecules that modify the histone code, DNA methylation patterns and miRNA function.

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“…siRNA can be delivered with a therapeutic intent using lipid-based delivery platforms such as stable nucleic acid lipid particles (SNALP) with a lipid bilayer containing cationic as well as fusogenic lipids and a diffusible PEG-lipid coat, polymers, cationic complexes, recombinant fusion proteins, conjugates, or polyconjugates [1][2][3], [7][8][9], [19][20], [25][26][27][28][29][30][31][32][33][34]. Several investigators have reported preclinical and early clinical proof of concept studies demonstrating that systemic delivery of an siRNA nanoparticle targeting a specific gene transcript can elicit biologic responses in vivo [11], [35][36][37][38][39][40][41][42]. Davis et al reported siRNA-loaded multifunctional nanoparticles that consist of a cyclodextrin-based synthetic polymer, a transferring receptor ligand for active targeting, and polyethylene glycol as a hydrophilic polymer for nanoparticle stability [11].…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, several recombinant fusion proteins that consist of a cell surface targeting moiety (e.g an antibody fragment or ligand) and an oligonucleotide complexation moiety (e.g truncated protamine) have been designed for targeted delivery of siRNA [27][28][29], [42]. The oligonucleotide complexing cationic moieties condense and mask the negative charge of the oligonucleotides and thereby assist their uptake through the cell membrane.…”

Section: Introductionmentioning

confidence: 99%