Breathing Life into Polycations:  Functionalization with pH-Responsive Endosomolytic Peptides and Polyethylene Glycol Enables siRNA Delivery

Meyer, Martin; Philipp, Alexander; Oskuee, Reza Kazemi; Schmidt, Claudia; Wagner, Ernst

doi:10.1021/ja710344v

Cited by 253 publications

(205 citation statements)

References 14 publications

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“…This can be attributed to the enhanced lytic activity at acidic pH, which triggered the destabilization of endosomal membranes. 109,110) The pH-sensitive fusogenic membrane peptide GALA (WEAALAEALAEALAEHLAEALAEALEALAA) was developed based on the endosomal escape mechanism of the influenza virus, an envelope-type RNA virus.…”

Section: Acceleration Of Endosomal Escape Via Membrane Fusionmentioning

confidence: 99%

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Hatakeyama

Akita

Harashima

2013

Biological & Pharmaceutical Bulletin

425

276

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Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.

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Section: Acceleration Of Endosomal Escape Via Membrane Fusionmentioning

confidence: 99%

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Hatakeyama

Akita

Harashima

2013

Biological & Pharmaceutical Bulletin

425

276

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“…Behr and colleagues 37 showed that Gene therapy progress and prospects D Schaffert and E Wagner making siRNAs 'gene-like,' by incorporating short complementary sticky overhangs, increased PEI polyplex stability and gene silencing up to 10-fold. Alternatively, novel polymers, 25,38 or modifications of existing polymers, 3,39,40 have been generated with improved siRNA transfer potential. Building on and extending previous related studies, Wang et al 27 have reported a small solid-phase synthesis derived library of reversibly polymerizable surfactants for siRNA delivery, which consist of a lipophilic anchor, a cationic siRNA complexing region and free thiols, encaging the payload into nanoparticles by thiol-mediated template polymerization.…”

Section: Combinatorial Chemistry Allows Rapid Polymer Development Formentioning

confidence: 99%

“…57 pH-responsive polyplexes were also developed for siRNA delivery. 3,36 An elegant strategy was developed for hepatocyte-targeted in vivo siRNA delivery by Rozema et al 36 A membrane-destabilizing poly(vinyl ether) polymer was covalently conjugated with siRNA through a disulfide bond and reversibly masked by pH-labile ligation of PEG as shielding domain and N-acetylgalactosamine as targeting ligand. The applied linkers are either cleaved at acidic pH in endosomes or the reductive intracellular environment.…”

Section: Combinatorial Chemistry Allows Rapid Polymer Development Formentioning

confidence: 99%

Gene therapy progress and prospects: synthetic polymer-based systems

2008

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Low efficiency, significant toxicity, polymer polydispersity and poorly understood delivery mechanisms have initially plagued the field of polymer-based gene therapy. Numerous strategies have helped to improve polyplexes, including the development of biodegradable polymers with reduced toxicity, incorporation of cell targeting, surface shielding and additional transport domains for effective and specific delivery, or improved chemistry for syntheses of polymers with uniform size and topology. Combined biooptical imaging and bioinformatics, providing insights into transfer bottlenecks, have helped to design improved polyplexes. Bioresponsive multifunctional polymers adapt in a dynamic manner to delivery barriers for efficient transfer of pDNA or siRNA to the target site.

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“…In the past report, the use of a MEND composed of a pH-sensitive cationic lipid, YSK05 (YSK-MEND) caused a significant gene reduction in tumor tissue when intratumorally and intravenously injected into tumor-bearing mice [10,11]. A number of pH sensitive siRNA carriers, such as liposomes [12,13], polyplexes [14] and micelles [15], have been evaluated for use in tumor targeting. pH-sensitive carriers are generally thought to be more suitable for tumor targeting than conventional cationic carriers because of their highly specific fusiogenicity in acidic endosomes [16].…”

Section: Introductionmentioning

confidence: 99%

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

Sakurai

Hatakeyama

Sato

et al. 2014

Journal of Controlled Release

107

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Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to α V β 3 integrin, which is selectively expressed at high levels in TECs.We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0 mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy.

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Breathing Life into Polycations: Functionalization with pH-Responsive Endosomolytic Peptides and Polyethylene Glycol Enables siRNA Delivery

Cited by 253 publications

References 14 publications

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Gene therapy progress and prospects: synthetic polymer-based systems

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

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