Although many types of cationic lipids have been developed as efficient gene vectors, the construction of lipid molecules with simple procedures remains challenging. Passerini reaction, as a classic multicomponent reaction, could directly give the α-acyloxycarboxamide products with biodegradable ester and amide bonds. Herein, two series of novel cationic lipids with heterocyclic pyrrolidine and piperidine as headgroups were synthesized through Passerini reaction (P-series) and amide condensation (A-series), and relevant structure-activity relationships on their gene delivery capability was studied. It was found that although both of the two series of lipids could form lipid nanoparticles (LNPs) which could effectively condense DNA, the LNP derived from P-series lipids showed higher transfection efficiency, serum tolerance, cellular uptake, and lower cytotoxicity. Unlike the A-series LNPs, the P-series LNPs showed quite different structure-activity relationship, in which the relative site of the secondary amine had significant effect on the transfection performance. The othro-isomers of the P-series lipids had lower cytotoxicity, but poor transfection efficiency, which was probably due to their unstable nature. Taken together, this study not only validated the feasibility of Passerini reaction for the construction of cationic lipids for gene delivery, but also afforded some clues for the rational design of effective non-viral lipidic gene vectors.
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http://dx.doi.org/10.1016/j.bmc.2024.117635 | DOI Listing |
Front Cell Infect Microbiol
December 2024
Servicio de Microbiología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Introduction: Murepavadin is an antimicrobial peptide (AMP) in clinical development that selectively targets LptD and whose resistance profile remains unknown. We aimed to explore genomic modifications and consequences underlying murepavadin and/or colistin susceptibility.
Methods: To define genomic mechanisms underlying resistance, we performed two approaches: 1) a genome-wide association study (GWAS) in a clinical collection (n=496), considering >0.
J Nanobiotechnology
December 2024
Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
In the post-COVID-19 era, drug-resistant bacterial infections emerge as one of major death causes, where multidrug-resistant Acinetobacter baumannii (MRAB) and drug-resistant Pseudomonas aeruginosa (DRPA) represent primary pathogens. However, the classical antibiotic strategy currently faces the bottleneck of drug resistance. We develop an antimicrobial strategy that applies the selective delivery of CRISPR/Cas9 plasmids to pathogens with biomimetic cationic hybrid vesicles (BCVs), irrelevant to bacterial drug resistance.
View Article and Find Full Text PDFEur J Pharm Sci
December 2024
Department of Infectious Diseases, LUCID, Leiden University Medical Center (LUMC), The Netherlands.
Tuberculosis (TB) remains a significant global health challenge, latently affecting around a quarter of the global population. The sole licensed TB vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), shows variable efficacy, particularly among adolescents and adults, underscoring the pressing need for more effective vaccination strategies. The administration route is crucial for vaccine efficacy, and administration via the skin, being rich in immune cells, may offer advantages over conventional subcutaneous routes, which lack direct access to abundant antigen-presenting cells.
View Article and Find Full Text PDFInt J Pharm
December 2024
Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork T12 YN60, Ireland; Department of Haematology and Cancer Research@UCC, Cork University Hospital, University College Cork, Cork T12 XF62, Ireland. Electronic address:
The presence of multiple hydroxyl groups, at positions C2, C3 and C6 on the cyclodextrin (CD) ring structure allows for extensive functionalisation, enabling the development of biomaterials with significant potential for therapeutic siRNA delivery. To identify structural modifications that enhance activity, a range of cationic amphiphilic CDs, including both β- and γ-CDs, were synthesised, compared and evaluated. Each CDs incorporated a C lipid chain on the primary face of the CD.
View Article and Find Full Text PDFInt J Pharm
December 2024
Department of Medical BioSciences, Radboud University Medical Center, The Netherlands; Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Bahrain. Electronic address:
Messenger RNA is a highly promising biotherapeutic modality with great potential in preventive and therapeutic vaccination, and in the modulation of cellular function through transient expression of therapeutic proteins. However, for cellular delivery, mRNA requires packaging into delivery vehicles that mediate uptake and also shield the mRNA against degradation. Lipid-coated calcium phosphate (LCP) nanoparticles encapsulate the mRNA in a calcium phosphate core, which is coated by a bilayer of structural lipids, positively charged lipids and pegylated lipid to mediate cellular uptake and achieve colloidal stabilization.
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