An Acid Sensitive Ketal-Based Polyethylene Glycol-Oligoethylenimine Copolymer Mediates Improved Transfection Efficiency at Reduced Toxicity

Knorr, Veronika; Ogris, Manfred; Wagner, Ernst

doi:10.1007/s11095-008-9700-6

Cited by 65 publications

(40 citation statements)

References 43 publications

(66 reference statements)

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“…21 However, our results show that PEGylation, although reducing the size and surface charge density of liposomes, can significantly reduce the pDNA transfection efficiency of complexes of DC-Chol/ DOPE liposomes/pDNA and pH-sensitive PEGylated liposomes, which is consistent with a previous report. 22 PEGylation also reduces the cytotoxicity and pH sensitivity of complexes of DC-Chol/DOPE liposomes/pDNA and pH-sensitive PEGylated liposomes. Our f inding that PEGylation had a negative effect on the pH-sensitivity of pH-sensitive liposomes is again consistent with previous studies.…”

Section: Resultsmentioning

confidence: 99%

Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors

Chen

Ji²,

Lü³

et al. 2013

IJN

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pH-sensitive liposomes represent an effective gene vector in cancer therapy. However, their use is greatly hampered by their relatively low transfection efficiency. To improve the transfection efficiency of pH-sensitive liposomes, we prepared complexes containing 3β-[N-(N′,N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and dioleoylphosphatidyl ethanolamine (DOPE) liposomes and pH-sensitive liposomes composed of cholesteryl hemisuccinate (CHEMS) and DOPE, and evaluated the influence of various factors on plasmid DNA (pDNA) transfection efficiency. All DC-Chol/DOPE liposome/pDNA and pH-sensitive liposome complexes showed similarly potent pH sensitivity. In the presence of serum-containing medium, two optimized complexes of DC-Chol/DOPE liposomes/pDNA and pH-sensitive PEGylated liposomes showed high transfection efficiency of 22.94% and 20.07%, respectively. Notably, DC-Chol/DOPE (2:3) liposomes/pH-sensitive PEGylated (1%) liposome complexes with a charge ratio of 1:1 (m/m [+/−]) showed enhanced accumulation in tumors in vivo. Our results show the influence of various factors on pDNA transfection efficiency in complexes of DC-Chol/DOPE liposomes and pH-sensitive PEGylated liposomes. Understanding of such mechanisms will lead to better design of complexes of DC-Chol/DOPE liposomes and pH-sensitive liposomes for gene therapy.

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Section: Resultsmentioning

confidence: 99%

Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors

Chen

Ji²,

Lü³

et al. 2013

IJN

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“…To achieve a better carrier profile with stability on demand, strategies using biodegradable polymers have been explored. The concept often included bioreversible cross-linkage of nontoxic LMW oligomers into HMW carriers via hydrolysable ester, acetal bonds, or reducible disulfide bonds (4,26,31,34,49,51,79,109). Thus, extracellular polyplex stability and transfection efficiency is partnered with intracellular disassembly and polymer degradation into nontoxic fragments.…”

Section: Introductionmentioning

confidence: 99%

Bioreducible Polycations as Shuttles for Therapeutic Nucleic Acid and Protein Transfection

Klein

Wagner

2014

Antioxidants & Redox Signaling

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Significance: Nucleic acids such as gene-encoding DNAs, gene-silencing small interfering RNAs, or recombinant proteins addressing intracellular molecular targets present a major new therapeutic modality, provided efficient solutions for intracellular delivery can be found. The different physiological redox environments inside and outside the cell can be utilized for optimizing the involved transport processes. Recent Advances: Intracellular delivery of nucleic acids or proteins requires dynamic carriers that discriminate between different cellular locations. Bioreducible cationic polymers can package their therapeutic cargo stably in the extracellular environment, but sense the reducing intracellular cytosolic environment. Based on disulfide cleavage, carriers are degraded into biocompatible fragments and release the cargo in functional form. Disulfide linkages between oligocations, between the carrier and the cargo, or spatial caging of complexed cargo by disulfides have been pursued, with polymers or precise sequence-defined peptides and oligomers. Critical Issues: A quantitative knowledge of the bioreductive capacities within different biological compartments and the involved cellular reduction processes would be greatly helpful for improved carriers with disulfides cleaved within the right compartment at the right time. Future Directions: Novel designs of multifunctional nanocarriers will incorporate macromolecular disulfide entry mechanisms previously optimized by natural evolution of toxins and viruses. In addition to extracellular stabilization and intracellular disassembly, tuned disulfides will contribute to deshielding at the cell surface, or translocation from intracellular compartments to the cytosol. Antioxid. Redox Signal. 21, 804-817.

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“…Polymers were synthesized incorporating chemistries known to be labile within the physiological milieu. These include disulfide (16,17), diacrylate (18), and acid-labile poly-orthoester (19) and ketal (20,21) bonds. Another commonly used strategy has been to attach different types of ligands to branched or linear PEI, including attaching various hydrophobic moieties (11,22,23), the hydrophilic polymer poly(ethyleneglycol) (24,25), carbohydrates such as dextran (26), and ligands which bind to cell surfaces with a greater degree of specificity than polycations do (27,28).…”

Section: Introductionmentioning

confidence: 99%

Dendrimeric Alkylated Polyethylenimine Nano-carriers with Acid-Cleavable Outer Cationic Shells Mediate Improved Transfection Efficiency Without Increasing Toxicity

Steele

Shier

2010

Pharm Res

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An Acid Sensitive Ketal-Based Polyethylene Glycol-Oligoethylenimine Copolymer Mediates Improved Transfection Efficiency at Reduced Toxicity

Abstract: PEG-OEI-MK mediated the highest gene transfer at lowest cytotoxicity levels and also best in vivo biocompatibility.

Cited by 65 publications

References 43 publications

Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors

Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors

Bioreducible Polycations as Shuttles for Therapeutic Nucleic Acid and Protein Transfection

Dendrimeric Alkylated Polyethylenimine Nano-carriers with Acid-Cleavable Outer Cationic Shells Mediate Improved Transfection Efficiency Without Increasing Toxicity

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