Annealing novel nucleobase-lipids with oligonucleotides or plasmid DNA based on H-bonding or π-π interaction: Assemblies and transfections

Abstract

Lipid derivatives of nucleoside analogs have been highlighted for their potential for effective gene delivery. A novel class of nucleobase-lipids are rationally designed and readily synthesized, comprising thymine/cytosine, an ester/amide linker and an oleyl lipid. The diversity of four nucleobase-lipids termed DXBAs (DOTA, DNTA, DOCA and DNCA) is investigated. Besides, DNCA is demonstrated to be an effective neutral transfection material for nucleic acid delivery, which enbles to bind to oligonucleotides via H-bonding and π-π stacking with reduced toxicity in vitro and in vivo. Several kinds of nucleic acid drugs including aptamer, ssRNA, antisense oligonucleotide, and plasmid DNAs can be delivered by DXBAs, especially DNCA. In particular, G4-aptamer AS1411 encapsulated by DNCA exhibits cellular uptake enhancement, lysosome degradation reduction, cell apoptosis promotion, cell cycle phase alteration in vitro and duration prolongation in vivo, resulting in significant anti-proliferative activity. Our results demonstrate that DNCA is a promising transfection agent for G4-aptamers and exhibites bright application prospects in the permeation improvement of single-stranded oligonucleotides or plasmid DNAs.

Feasibility of cRGD conjugation at 5′-antisense strand of siRNA by phosphodiester linkage extension

“…The gemini-like cationic lipids (CLD) and cytidinyl lipid (DNCA) were synthesized by our group ( Figure S1 ), 28 , 37 and the synthesis method for RNA samples was described in previous studies. 20 In brief, siMB3s were obtained by an ABI 394 DNA/RNA synthesizer and purified via Waters 1525 HPLC.…”

“… 24 In this study, cRGD-siRNA conjugates at the 5′-terminus antisense strand via phosphodiester linkage have been reported, which were encapsulated with neutral cytidinyl lipid DNCA and the gemini-like cationic lipid CLD, both developed by our group ( Figure S1 ). 25 , 26 , 27 , 28 , 29 , 30 DNCA could provide hydrogen bond and π-π stacking with siRNA. 31 Overall, with a relative longer flexible linker, the siRNA conjugates effectively silenced the target mRNA in vitro and inhibited tumor proliferation in vivo .…”

Intervention of Polydopamine Assembly and Adhesion on Nanoscale Interfaces: State‐of‐the‐Art Designs and Biomedical Applications

“…The cooperation of π – π stacking and π ‐cation interactions plays crucial roles in biological recognition, [ 31,32 ] protein folding, [ 33,34 ] nucleobase stacking within either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules, etc., [ 35,36 ] and is considered to be closely related to the formation and function of biological structures. It was also widely observed that the parallel displaced and T‐shaped conformations are the most stable ones for the stacking with energy minima.…”

“…At present, concerns regarding the limitations of popular nanocarriers, including mesoporous silica, [6][7][8][9][10] carbon-based nanomaterials, [11][12][13][14] metalorganic frameworks materials, [15][16][17][18] black phosphorus, [19][20][21][22] etc., have been raised from the viewpoint of photoelectric inactivity, [23,24] guest loading restriction, [25,26] as well as poor biodegradability and structural control. [27][28][29][30] The cooperation of -stacking and -cation interactions plays crucial roles in biological recognition, [31,32] protein folding, [33,34] nucleobase stacking within either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules, etc., [35,36] and is considered to be closely related to the formation and function of biological structures. It was also widely observed that the parallel displaced and T-shaped conformations are the most stable ones for the stacking with energy minima.…”

Selective Anti-melanoma Effect of Phosphothioated Aptamer Encapsulated by Neutral Cytidinyl/Cationic Lipids

“…We found that the core sequence of BC15, BC15-31 (31 nt), showed higher target affinity and further enhanced bioactivity and stability with isothymidine (isoT) modification at 5′- and 3′-terminal regions ( Li et al, 2018 ). Application of neutral cytidinyl lipid DNCA, through H-binding and π-π interaction, to reduce or avoid the use of cystine-based cationic lipid CLD ( Ma et al, 2016 ), gave a safe and effective delivery system for oligonucleotides ( Ma et al, 2018 , 2019 ). In this study, phosphorathiolation (PS), LNA (ribose locked by a O -2′-C4′-methylene linkage), and 2′-methoxyethoxy (2′- O -MOE) modification strategies were used to improve the stability and target affinity of the aptamer BC15-31.…”