scholarly journals Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: The impact of cationic lipid selection

2020 ◽  
Vol 325 ◽  
pp. 370-379 ◽  
Author(s):  
Gustavo Lou ◽  
Giulia Anderluzzi ◽  
Signe Tandrup Schmidt ◽  
Stuart Woods ◽  
Simona Gallorini ◽  
...  
Keyword(s):  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
The Impact

scholarly journals Tuning the Immunostimulation Properties of Cationic Lipid Nanocarriers for Nucleic Acid Delivery

2021 ◽  
Vol 12 ◽  
Author(s):  
Arindam K. Dey ◽  
Adrien Nougarède ◽  
Flora Clément ◽  
Carole Fournier ◽  
Evelyne Jouvin-Marche ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Messenger Rna ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
Cationic Lipids ◽  
Fine Tuning ◽  
Target Cells ◽  
Substantial Impact ◽  
Lipid Nanocarriers ◽  
The Impact

Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.

scholarly journals Tuning the immunostimulation properties of cationic lipid nanocarriers for nucleic acid delivery

2021 ◽  
Author(s):  
Arindam K Dey ◽  
Adrien Nougarede ◽  
Flora Clement ◽  
Carole Fournier ◽  
Evelyne Jouvin-Marche ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Messenger Rna ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
Cationic Lipids ◽  
Fine Tuning ◽  
Target Cells ◽  
Substantial Impact ◽  
Lipid Nanocarriers ◽  
The Impact

Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.

scholarly journals Cationic and Biocompatible Polymer/Lipid Nanoparticles as Immunoadjuvants

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1859
Author(s):  
Yunys Pérez-Betancourt ◽  
Péricles Marques Araujo ◽  
Bianca de Carvalho Lins Fernandes Távora ◽  
Daniele Rodrigues Pereira ◽  
Eliana Lima Faquim-Mauro ◽  
...  
Keyword(s):  
Immune Responses ◽  
Methyl Methacrylate ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
Hybrid Nanoparticles ◽  
Ammonium Bromide ◽  
The Novel ◽  
Biocompatible Polymer ◽  
Dimethyl Ammonium ◽  
Oppositely Charged

Nanostructures have been of paramount importance for developing immunoadjuvants. They must be cationic and non-cytotoxic, easily assembling with usually oppositely charged antigens such as proteins, haptens or nucleic acids for use in vaccines. We obtained optimal hybrid nanoparticles (NPs) from the biocompatible polymer poly(methyl methacrylate) (PMMA) and the cationic lipid dioctadecyl dimethyl ammonium bromide (DODAB) by emulsion polymerization of methyl methacrylate (MMA) in the presence of DODAB. NPs adsorbed ovalbumin (OVA) as a model antigen and we determined their adjuvant properties. Interestingly, they elicited high double immune responses of the cellular and humoral types overcoming the poor biocompatibility of DODAB-based adjuvants of the bilayer type. The results suggested that the novel adjuvant would be possibly of use in a variety of vaccines.

scholarly journals Two Modes of Toxicity of Lipid Nanoparticles Containing a pH-Sensitive Cationic Lipid on Human A375 and A375-SM Melanoma Cell Lines

BPB Reports ◽  
2019 ◽  
Vol 2 (4) ◽  
pp. 48-55
Author(s):  
Ahmed Y. AlBaloul ◽  
Yusuke Sato ◽  
Nako Maishi ◽  
Kyoko Hida ◽  
Hideyoshi Harashima
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
Ph Sensitive ◽  
Melanoma Cell Lines

R-DOTAP (Versamune): A novel enantiospecific cationic lipid nanoparticle that induces CD4 and CD8 cellular immune responses to whole protein and tumor-specific peptide antigens.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15211-e15211
Author(s):  
Lauren Virginia Wood ◽  
Siva K Gandhapudi ◽  
Karuna Sundarapandiyan ◽  
Frank K Bedu-Addo ◽  
Gregory Conn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cationic Lipid ◽  
Cd8 T Cell ◽  
Lipid Nanoparticles ◽  
Type I ◽  
T Cell Epitopes ◽  
Ifn Γ

e15211 Background: Immunotherapy approaches are limited in their ability to induce antigen-specific CD8+ T cells in vivo able to recognize and kill tumor cells. We developed a novel immunotherapy approach using enantiomerically pure, R-DOTAP cationic lipid nanoparticles and tumor-derived T cell antigens, and previously demonstrated that R-DOTAP formulations efficiently prime cytotoxic T cells through enhanced cross presentation and induction of type I interferons.[1] A phase I clinical trial of a R-DOTAP HPV16 peptide formulation confirmed induction of strong in vivo HPV-specific CD8+ cytolytic T-cells without associated systemic toxicities. In this study, we assessed R-DOTAP nanoparticle formulations containing whole protein (ovalbumin) or long multi-epitope peptides from the tumor antigen TARP (T-cell alternate reading frame protein): a 58-residue protein overexpressed in prostate and breast cancers, documented to be immunogenic in humans. Methods: R-DOTAP formulations were prepared containing ovalbumin (OVA) or TARP peptides. C57BL/6K mice were immunized with 10 μg/mouse of OVA plus R-DOTAP, CFA or sucrose on Days 0, 15 and 30. OVA-specific cellular and humoral responses following vaccination were assessed by measuring splenic CD4 and CD8 T cell IFN-γ production and circulating OVA-specific antibodies in serum. HLA-A2 transgenic mice (AAD mice) were vaccinated with long, multi-epitope TARP peptides delivered as an R-DOTAP admixture or with CFA or sucrose on Days 0 and 7. Antigen-specific T cell responses were measured by IFN-γ ELISpot assay. Results: OVA R-DOTAP formulations induced strong antigen-specific effector CD4 and CD8 immune and memory responses detected 7 and 30 days, respectively, following vaccination as well as OVA-specific antibody responses. In TARP peptide vaccinated mice, R-DOTAP formulations were able to present multiple CD8 T cell epitopes and stimulate responses that were superior to CFA. Conclusions: Our results suggest that R-DOTAP is a versatile immune activating therapy that can be formulated with long, multi-epitope tumor-derived peptides or whole proteins. R-DOTAP formulations induce quantitatively robust antigen-specific CD4 and CD8 T cells in vivo compared to well-established immune stimulants. Reference: 1.Gandhapudi SK, Ward M, Bush JP et al. Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response. J Immunol 2019;202:3524-3536

Role of vitronectin-rich protein corona on tumor-specific siRNA delivery and transfection with lipid nanoparticles

Nanomedicine ◽  
2021 ◽  
Author(s):  
Dongyu Chen ◽  
Shanthi Ganesh ◽  
Weimin Wang ◽  
Adrien Lupieri ◽  
Mansoor Amiji
Keyword(s):  
Sirna Delivery ◽  
Cationic Lipid ◽  
Protein Corona ◽  
Lipid Nanoparticles ◽  
Αvβ3 Integrin ◽  
Systemic Delivery ◽  
Endothelial Lining ◽  
Endogenous Proteins

Aim: To evaluate the role of vitronectin-enriched protein corona on systemic delivery of siRNA-encapsulated cationic lipid nanoparticles (LNPs) to αvβ3 integrin expressing solid tumors. Materials & methods: 1,2-Dioleoyl-3-trimethylammonium-propane LNPs were formulated, protein corona formed in nude mice serum and its impact on drug delivery were analyzed. Results: 1,2-Dioleoyl-3-trimethylammonium-propane-containing LNP led to enhanced recruitment of vitronectin and showed preferential transfection to αvβ3-expressed cells relative to controls. Upon systemic administration in mice, the LNPs accumulated in the αvβ3-expressing endothelial lining of the tumor blood vessels before reaching tumor cells. Conclusion: These results present an optimized LNP that selectively recruits endogenous proteins in situ to its corona which may lead to enhanced delivery and transfection in tissues of interest.

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