期刊论文详细信息
JOURNAL OF CONTROLLED RELEASE 卷:325
Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: The impact of cationic lipid selection
Article
Lou, Gustavo1,2  Anderluzzi, Giulia1,2  Schmidt, Signe Tandrup1,4  Woods, Stuart1  Gallorini, Simona2  Brazzoli, Michela2  Giusti, Fabiola2  Ferlenghi, Ilaria2  Johnson, Russell N.3  Roberts, Craig W.1  O'Hagan, Derek T.3  Baudner, Barbara C.2  Perrie, Yvonne1 
[1] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, 161 Cathedral St, Glasgow G4 0RE, Lanark, Scotland
[2] GSK, Siena, Italy
[3] GSK, Rockville, MD USA
[4] Statens Serum Inst, Ctr Vaccine Res, Dept Infect Dis Immunol, Artillerivej 5, DK-2300 Copenhagen S, Denmark
关键词: Self-amplifying RNA;    Lipid nanoparticles;    Microfluidics;    Cellular uptake;    In vitro potency;    Pharmacokinetics;    Immunogenicity;   
DOI  :  10.1016/j.jconrel.2020.06.027
来源: Elsevier
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【 摘 要 】

Self-amplifying RNA (SAM) represents a versatile tool that can be used to develop potent vaccines, potentially able to elicit strong antigen-specific humoral and cellular-mediated immune responses to virtually any infectious disease. To protect the SAM from degradation and achieve efficient delivery, lipid nanoparticles (LNPs), particularly those based on ionizable amino-lipids, are commonly adopted. Herein, we compared commonly available cationic lipids, which have been broadly used in clinical investigations, as an alternative to ionizable lipids. To this end, a SAM vaccine encoding the rabies virus glycoprotein (RVG) was used. The cationic lipids investigated included 3 beta-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol), dimethyldioctadecylammonium (DDA), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), 1,2-stearoyl-3-trimethylammonium-propane (DSTAP) and N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis (oleoyloxy)propan-1-aminium (DOBAQ). Whilst all cationic LNP (cLNP) formulations promoted high association with cells in vitro, those formulations containing the fusogenic lipid 1,2-dioleoyl-sn-3-phosphoethanolamine (DOPE) in combination with DOTAP or DDA were the most efficient at inducing antigen expression. Therefore, DOTAP and DDA formulations were selected for further in vivo studies and were compared to benchmark ionizable LNPs (iLNPs). Biodistribution studies revealed that DDA-cLNPs remained longer at the injection site compared to DOTAP-cLNPs and iLNPs when administered intramuscularly in mice. Both the cLNP formulations and the iLNPs induced strong humoral and cellular-mediated immune responses in mice that were not significantly different at a 1.5 mu g SAM dose. In summary, cLNPs based on DOTAP and DDA are an efficient alternative to iLNPs to deliver SAM vaccines.

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