The development of tertiary amine cationic lipids for safe and efficient siRNA delivery

2019 ◽  
Vol 7 (7) ◽  
pp. 2777-2792 ◽  
Author(s):  
Ziming Lin ◽  
Moxyel Bao ◽  
Zexuan Yu ◽  
Lingjing Xue ◽  
Caoyun Ju ◽  
...  
Keyword(s):  
Tertiary Amine ◽  
Sirna Delivery ◽  
Cationic Lipid ◽  
Cationic Liposomes ◽  
Cationic Lipids

Tertiary amine-derived cationic lipid serves as the primary lipid of cationic liposomes, which can balance the effectiveness and safety of siRNA vectors.

Niosomes Containing Spermine-Based Cationic Lipid with Different Linkers for siRNA Delivery

2019 ◽  
Vol 819 ◽  
pp. 169-174
Author(s):  
Supusson Pengnam ◽  
Praneet Opanasopit ◽  
Theerasak Rojanarata ◽  
Nattisa Ni-yomtham ◽  
Boon Ek Yingyongnarongkul ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Cellular Uptake ◽  
Sirna Delivery ◽  
Weight Ratio ◽  
Cationic Lipid ◽  
Cationic Lipids ◽  
Molar Ratio ◽  
Ionic Surfactant ◽  
Low Toxicity ◽  
Cationic Niosomes

Niosomes are a lipid nanoparticle which have been widely used as non-viral carrier for therapeutic DNA or siRNA. They are formulated from non-ionic surfactant and other helper lipids. The aim of this study were to formulate niosome containing spermine-based cationic lipid with different linkers and to evaluate the efficiency of siRNA delivery in cervical cancer cell (HeLa cell). The niosomes were formulated from cholesterol (Chol), Span 20 and different cationic lipid (Ay, By, Cy and Dy) at various molar ratios. The properties of niosomes and ability of niosome to complex with siRNA were characterized. The cellular uptake, gene silencing efficiency and cytotoxicity were also determined. From the results, niosomes formulated at Chol:Span20:lipid molar ratio of 2.5:2.5:2 showed positive zeta potential and they were in nanosize (<200 nm). The binding ability of cationic niosomes to siRNA depended on types of cationic lipid. Among niosome/siRNA complexes, the niosome By/siRNA complex provided the highest gene silencing efficiency at weight ratio of 20. The highest cellular uptake also obtained by using niosome By as a carrier. The cytotoxicity revealed that cationic niosomes had low toxicity (cell viability > 80%). In conclusion, the cationic niosomes prepared from Chol, Span 20 and spermine-based cationic lipids are able to complex with siRNA and suitable for siRNA delivery with low toxicity.

Effect of cationic lipid in cationic liposomes on siRNA delivery into the lung by intravenous injection of cationic lipoplex

2018 ◽  
Vol 27 (2) ◽  
pp. 217-227 ◽  
Author(s):  
Yoshiyuki Hattori ◽  
Mari Nakamura ◽  
Nozomi Takeuchi ◽  
Kyoko Tamaki ◽  
Satono Shimizu ◽  
...  
Keyword(s):  
Intravenous Injection ◽  
Sirna Delivery ◽  
Cationic Lipid ◽  
Cationic Liposomes

scholarly journals Transdermal Delivery of Small Interfering RNA with Elastic Cationic Liposomes in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiyuki Hattori ◽  
Masataka Date ◽  
Shohei Arai ◽  
Kumi Kawano ◽  
Etsuo Yonemochi ◽  
...  
Keyword(s):  
Sirna Delivery ◽  
Cationic Lipid ◽  
Tween 80 ◽  
Sodium Cholate ◽  
Cationic Liposomes ◽  
Gene Suppression ◽  
Liposomal Formulations ◽  
Siha Cells ◽  
Interfering Rna ◽  
Edge Activator

We developed elastic cationic liposomal vectors for transdermal siRNA delivery. These liposomes were prepared with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as a cationic lipid and sodium cholate (NaChol) or Tween 80 as an edge activator. When NaChol or Tween 80 was included at 5, 10, and 15% (w/w) into DOTAP liposomal formulations (C5-, C10-, and C15-liposomes and T5-, T10-, and T15-liposomes), C15- and T10-liposomes showed 2.4- and 2.7-fold-higher elasticities than DOTAP liposome, respectively. Although the sizes of all elastic liposomes prepared in this study were about 80–90 nm, the sizes of C5-, C10- and C15-liposome/siRNA complexes (lipoplexes) were about 1,700–1,800 nm, and those of T5-, T10-, and T15-lipoplexes were about 550–780 nm. Their elastic lipoplexes showed strong gene suppression by siRNA without cytotoxicity when transfected into human cervical carcinoma SiHa cells. Following skin application of the fluorescence-labeled lipoplexes in mice, among the elastic lipoplexes, C15- and T5-lipoplexes showed effective penetration of siRNA into skin, compared with DOTAP lipoplex and free siRNA solution. These data suggest that elastic cationic liposomes containing an appropriate amount of NaChol or Tween 80 as an edge activator could deliver siRNA transdermally.

scholarly journals Cellular Pathway of Plasmids Vectorized by Cholesterol-based Cationic Liposomes

2002 ◽  
Vol 50 (7) ◽  
pp. 983-991 ◽  
Author(s):  
Dominique Briane ◽  
Denis Lesage ◽  
An Cao ◽  
Robert Coudert ◽  
Nicole Lievre ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Transfection Efficiency ◽  
Cationic Lipid ◽  
Cationic Liposome ◽  
Cationic Liposomes ◽  
Cationic Lipids ◽  
Mcf7 Cells ◽  
Gold Particles ◽  
Transmission Electron ◽  
Perinuclear Area

We investigated by transmission electron microscopy the cellular route in tumor MCF7 cells of DNA labeled with digoxigenin, carried by cationic liposomes (Lip+) prepared from TMAEC-Chol [3β( N-( N',N',N'-trimethylaminoethane)-carbamoyl)cholesterol iodide] and TEAPC-Chol [3β( N-( N',N',N'-triethylaminopropane)-carbamoyl)cholesterol iodide], two cholesterol-based cationic lipids containing a quaternary ammonium. In a previous work we showed the pathway of cationic lipid/plasmid complexes from the beginning of endocytosis until their entry into the perinuclear area. Beyond this limit, unlabeled exogenous plasmids cannot be distinguished with nuclear DNA. This work dealt with the cellular fate of cationic liposome-vectorized plasmids labeled with digoxigenin using an immunogold procedure. Early after the beginning of transfection (30 min, 1 hr, 5 hr), gold particles were observed only in the cytoplasm and in endosome-like vesicles, whereas after 24 hr gold particles were densely present in the nucleus. These results demonstrate the nuclear localization of plasmids vectorized by the cationic liposomes used. The results are discussed in comparison with transfection efficiency measurements.

scholarly journals Сationic liposomes as delivery systems for nucleic acids

2020 ◽  
Vol 15 (1) ◽  
pp. 7-27
Author(s):  
A. A. Mikheev ◽  
E. V. Shmendel ◽  
E. S. Zhestovskaya ◽  
G. V. Nazarov ◽  
M. A. Maslov
Keyword(s):  
Gene Therapy ◽  
Nucleic Acids ◽  
Serum Proteins ◽  
Transfection Efficiency ◽  
Biological Fluids ◽  
Genetic Material ◽  
Cationic Liposomes ◽  
Delivery Systems ◽  
Cationic Lipids

Objectives. Gene therapy is based on the introduction of genetic material into cells, tissues, or organs for the treatment of hereditary or acquired diseases. A key factor in the success of gene therapy is the development of delivery systems that can efficiently transfer genetic material to the place of their therapeutic action without causing any associated side effects. Over the past 10 years, significant effort has been directed toward creating more efficient and biocompatible vectors capable of transferring nucleic acids (NAs) into cells without inducing an immune response. Cationic liposomes are among the most versatile tools for delivering NAs into cells; however, the use of liposomes for gene therapy is limited by their low specificity. This is due to the presence of various biological barriers to the complex of liposomes with NA, including instability in biological fluids, interaction with serum proteins, plasma and nuclear membranes, and endosomal degradation. This review summarizes the results of research in recent years on the development of cationic liposomes that are effective in vitro and in vivo. Particular attention is paid to the individual structural elements of cationic liposomes that determine the transfection efficiency and cytotoxicity. The purpose of this review was to provide a theoretical justification of the most promising choice of cationic liposomes for the delivery of NAs into eukaryotic cells and study the effect of the composition of cationic lipids (CLs) on the transfection efficiency in vitro.Results. As a result of the analysis of the related literature, it can be argued that one of the most promising delivery systems of NAs is CL based on cholesterol and spermine with the addition of a helper lipid DOPE. In addition, it was found that varying the composition of cationic liposomes, the ratio of CL to NA, or the size and zeta potential of liposomes has a significant effect on the transfection efficiency.Conclusions. Further studies in this direction should include optimization of the conditions for obtaining cationic liposomes, taking into account the physicochemical properties and established laws. It is necessary to identify mechanisms that increase the efficiency of NA delivery in vitro by searching for optimal structures of cationic liposomes, determining the ratio of lipoplex components, and studying the delivery efficiency and properties of multicomponent liposomes.

scholarly journals Aliphatic Quaternary Ammonium Functionalized Nanogels for Gene Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1964
Author(s):  
Huaiying Zhang ◽  
Damla Keskin ◽  
Willy H. de Haan-Visser ◽  
Guangyue Zu ◽  
Patrick van Rijn ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Tertiary Amine ◽  
Quaternary Ammonium ◽  
Gene Transfection ◽  
Genetic Material ◽  
Cationic Lipid ◽  
Endosomal Escape ◽  
Hereditary Diseases ◽  
Viral Gene

Gene therapy is a promising treatment for hereditary diseases, as well as acquired genetic diseases, including cancer. Facing the complicated physiological and pathological environment in vivo, developing efficient non-viral gene vectors is needed for their clinical application. Here, poly(N-isopropylacrylamide) (p(NIPAM)) nanogels are presented with either protonatable tertiary amine groups or permanently charged quaternized ammonium groups to achieve DNA complexation ability. In addition, a quaternary ammonium-functionalized nanogel was further provided with an aliphatic moiety using 1-bromododecane to add a membrane-interacting structure to ultimately facilitate intracellular release of the genetic material. The ability of the tertiary amine-, quaternized ammonium-, and aliphatic quaternized ammonium-functionalized p(NIPAM) nanogels (i.e., NGs, NGs-MI, and NGs-BDD, respectively) to mediate gene transfection was evaluated by fluorescence microscopy and flow cytometry. It is observed that NGs-BDD/pDNA complexes exhibit efficient gene loading, gene protection ability, and intracellular uptake similar to that of NGs-MI/pDNA complexes. However, only the NGs-BDD/pDNA complexes show a notable gene transfer efficiency, which can be ascribed to their ability to mediate DNA escape from endosomes. We conclude that NGs-BDD displays a cationic lipid-like behavior that facilitates endosomal escape by perturbing the endosomal/lysosomal membrane. These findings demonstrate that the presence of aliphatic chains within the nanogel is instrumental in accomplishing gene delivery, which provides a rationale for the further development of nanogel-based gene delivery systems.

scholarly journals Influence of Environmental Conditions on the Fusion of Cationic Liposomes with Living Mammalian Cells

Nanomaterials ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 1025 ◽  
Author(s):  
Rejhana Kolašinac ◽  
Sebastian Jaksch ◽  
Georg Dreissen ◽  
Andrea Braeutigam ◽  
Rudolf Merkel ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Mammalian Cells ◽  
High Efficiency ◽  
Phase State ◽  
Chinese Hamster ◽  
Cationic Lipid ◽  
Cationic Liposomes ◽  
Biological Macromolecules ◽  
Lipid Mixture ◽  
Fusion Efficiency

Lipid-based nanoparticles, also called vesicles or liposomes, can be used as carriers for drugs or many types of biological macromolecules, including DNA and proteins. Efficiency and speed of cargo delivery are especially high for carrier vesicles that fuse with the cellular plasma membrane. This occurs for lipid mixture containing equal amounts of the cationic lipid DOTAP and a neutral lipid with an additional few percents of an aromatic substance. The fusion ability of such particles depends on lipid composition with phosphoethanolamine (PE) lipids favoring fusion and phosphatidyl-choline (PC) lipids endocytosis. Here, we examined the effects of temperature, ionic strength, osmolality, and pH on fusion efficiency of cationic liposomes with Chinese hamster ovary (CHO) cells. The phase state of liposomes was analyzed by small angle neutron scattering (SANS). Our results showed that PC containing lipid membranes were organized in the lamellar phase. Here, fusion efficiency depended on buffer conditions and remained vanishingly small at physiological conditions. In contrast, SANS indicated the coexistence of very small (~50 nm) objects with larger, most likely lamellar structures for PE containing lipid particles. The fusion of such particles to cell membranes occurred with very high efficiency at all buffer conditions. We hypothesize that the altered phase state resulted in a highly reduced energetic barrier against fusion.

scholarly journals Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment

2015 ◽  
Vol 112 (25) ◽  
pp. 7779-7784 ◽  
Author(s):  
Xi Zhu ◽  
Yingjie Xu ◽  
Luisa M. Solis ◽  
Wei Tao ◽  
Liangzhe Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Sirna Delivery ◽  
Cationic Lipid ◽  
Small Cell ◽  
Solid Polymer ◽  
Small Cell Lung ◽  
Formidable Challenge

RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid–polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 ∼8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.

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