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Xuexiang Han ; Junchao Xu ; Ying Xu , et al. Nat. Commun.,2024,15(1):1762. DOI: 10.1038/s41467-024-45537-z PubMed ID: 38409275
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Abstract: The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.
CAS No. : | 4004-05-1 | MDL No. : | MFCD00057986 |
Formula : | C41H78NO8P | Boiling Point : | - |
Linear Structure Formula : | (C18H33O)2OCH2CHOCH2OPO3CH2CH2NH3 | InChI Key : | MWRBNPKJOOWZPW-NYVOMTAGSA-N |
M.W : | 744.03 | Pubchem ID : | 9546757 |
Synonyms : |
dioleoylphosphatidylethanolamine;1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine;1,2-Dioleoyl-sn-glycero-3-Phosphoethanolamine 1,2-DOPE;1,2-DOPE;1,2-Dioleoyl-sn-glycero-3-PE
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Chemical Name : | (Z)-(2R)-3-(((2-Aminoethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In dichloromethane; | (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethyl succinimidyl carbonate (50 mg, 0.17 mmol) was dissolved in 6 ml dry CH2Cl2 which was then added to a solution of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (127 mg, 0.17 mmol) in 4 ml dry CH2Cl2. NEt3 (78 μl, 0.55 mmol) was added and the solution was left stirring overnight.The product was purified directly by column chromatography (95:5CH2Cl2/MeOH) to yield the product as a colorless oil (114 mg, 73%). Analytical data:1H NMR (400 MHz, CDCl3) δ 9.35 (bs, 2H), 5.82 (s, 1H), 5.31 (m, 3H), 5.18 (m, 1H), 4.36 (dd, 2H), 4.11 (m, 3H), 3.92 (m, 4H), 3.57 (m, 1H), 3.38 (d, 2H), 3.07 (q, 6H), 2.62 (s, 4H), 2.23 (m, 8H), 1.97 (q,6H), 1.26 (m, 38H, should be 40H), 0.84 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 173.57, 130.00, 129.62, 129.59, 98.74, 62.68, 34.19, 34.01, 31.89, 29.75, 29.53, 29.31, 29.24, 29.22, 29.18, 29.15, 27.22, 24.90, 24.83, 22.67, 21.41, 20.15, 14.11; HRMS (ESI) calcd for C52H89NO10P[M-H]- 918.6224 found 918.6198. |