Synthesis and bioactivity of readily hydrolysable novel cationic lipids for potential lung delivery application of mRNAs

• Published in: Chemistry and physics of lipids Vol. 243; p. 105178
• Main Authors: Pei, Yihua, Bao, Yanjie, Sacchetti, Cristiano, Brady, Juthamart, Gillard, Kyra, Yu, Hailong, Roberts, Scott, Rajappan, Kumar, Tanis, Steven P., Perez-Garcia, Carlos G., Chivukula, Padmanabh, Karmali, Priya P.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2022
• Subjects: Cationic lipids; DOTAP; Humans; Lipid nanoparticles; Liposomes - chemistry; LNP; Lung; mRNA; Nanoparticles - chemistry; Nebulization; Research Paper; RNA, Messenger - administration & dosage; Lung; Cationic lipids; mRNA; Nebulization; DOTAP; Lipid nanoparticles; LNP
• ISSN: 0009-3084; 1873-2941
• DOI: 10.1016/j.chemphyslip.2022.105178

Lipid nanoparticles (LNPs) mediated mRNA delivery has gained prominence due to the success of mRNA vaccines against Covid-19, without which it would not have been possible. However, there is little clinical validation of this technology for other mRNA-based therapeutic approaches. Systemic administration of LNPs predominantly targets the liver, but delivery to other organs remains a challenge. Local approaches remain a viable option for some disease indications, such as Cystic Fibrosis, where aerosolized delivery to airway epithelium is the preferred route of administration. With this in mind, novel cationic lipids (L1-L4) have been designed, synthesized and co-formulated with a proprietary ionizable lipid. These LNPs were further nebulized, along with baseline control DOTAP-based LNP (DOTAP+), and tested in vitro for mRNA integrity and encapsulation efficiency, as well as transfection efficiency and cytotoxicity in cell cultures. Improved biodegradability and potentially superior elimination profiles of L1-L4, in part due to physicochemical characteristics of putative metabolites, are thought to be advantageous for prospective therapeutic lung delivery applications using these lipids. [Display omitted] •Readily hydrolysable cationic lipids are synthesized and formulated into LNPs.•Integrity of encapsulated mRNA is retained post freeze thaw and nebulization.•Cationic lipids 1–4 were found to be more biodegradable than DOTAP.•Co-formulation with ionizable lipids helps transfection and translation of mRNA.•Cell viability is retained with pre and post nebulized cationic LNPs.