Development of Novel Amphiphilic N-substituted 1.4-dihydropyridine Derivatives as Gene Delivery Agents

  • Plotniece, A. (Co-author)
  • Anna Krapivina (Co-author)
  • Martins Rucins (Co-author)
  • Davis Lacis (Co-author)
  • Anastasija Metlova (Co-author)
  • Arkadij Sobolev (Co-author)
  • Antons Sizovs (Co-author)
  • Karlis Pajuste (Speaker)

Activity: Talk or presentation types › Poster presentation

Description

Liposomes have been extensively studied as delivery systems due to their efficiency and biocompatibility. Cationic 1,4-dihydropyridines (1,4-DHP)  were studied earlier as membranotropic compounds and have been proposed as delivery systems. The properties of liposomes primarily depend on the characteristics of their constituent lipids.  Design, evaluation and optimization of the structure of lipids have provided delivery systems with improved performance. The objective of this study was to synthesize a series of novel N-substituted cationic 1,4-DHP derivatives and evaluate their monolayer and self-assembling properties and transfection activity.. Five cationic N-benzyl 1,4-DHP derivatives with varying pyridinium substituents at positions 2 and 6 were synthesized. The monolayer properties were characterized using surface pressure–molecular area isotherms, obtained by KSV NIMA Langmuir trough. The self-assembling properties were studied using dynamic light scattering, samples were prepared by the ethanol injection method. Green fluorescent protein-expressing plasmid was loaded into liposomes and transfection efficiency was assessed in vitro using fluorimetry. Lipofectamine served as a positive control, while untreated cells were used as a negative control. Cytotoxicity was determined using the MTT assay.. The target compounds were obtained in 35-75% yields. The structures were confirmed by NMR. The mean molecular area varied from 131-191Å2. The compounds displayed self-assembling properties and formed nanoparticles with an average diameter of 660-1973 nm for the freshly prepared samples. Polydispersity indexes were in the 0.01-2.65 range. Zeta-potential varied from 35.7-90.9 mV. The critical micelle concentration of 1,4-DHPs ranged from 0.006-2.646 µM. All data obtained for the novel N-benzyl 1,4-DHPs was compared with N-unsubstituted 1,4-DHP as a control.. The lipid monolayer, self-assembling properties, and transfection activity of cationic 1,4-DHPs strongly depend on their structure. The introduction of N-substituent to 1,4-DHP cycle and substituents at the cationic head-groups will be discussed from the perspective of structure-activity relationships. Funded by the EuroNanoMed3 Project NANO4GLIO; the PostDoc project No1.1.1.2/VIAA/3/19/587(K.P.).
Period29 Mar 2023
Event titleRSU International Research Conference 2023: Knowledge for Use in Practice
Event typeConference
OrganiserRīga Stradiņš University
LocationRiga, LatviaShow on map
Degree of RecognitionInternational

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