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Purity: ≥98%
| Targets |
Excipient for vaccines and drug delivery of gene therapy
Lipid A9 does not act through binding to specific biological targets; rather, its “target” is the intracellular endosomal compartment. As an ionizable cationic lipid, its mechanism is physicochemical: its pKa value of 6.27 allows it to remain neutral in circulation (pH 7.4) to reduce non-specific interactions, while upon cellular uptake it becomes protonated and positively charged in the acidic endosome (pH ~5.0-6.0), where it interacts electrostatically with negatively charged endosomal membranes to facilitate nucleic acid escape into the cytoplasm. |
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| ln Vitro |
The advent of mRNA for nucleic acid (NA) therapeutics has unlocked many diverse areas of research and clinical investigation. However, the shorter intracellular half-life of mRNA compared with other NAs may necessitate more frequent dosing regimens. Because lipid nanoparticles (LNPs) are the principal delivery system used for mRNA, this could lead to tolerability challenges associated with an accumulated lipid burden. This can be addressed by introducing enzymatically cleaved carboxylic esters into the hydrophobic domains of lipid components, notably, the ionizable lipid. However, enzymatic activity can vary significantly with age, disease state, and species, potentially limiting the application in humans. Here we report an alternative approach to ionizable lipid degradability that relies on nonenzymatic hydrolysis, leading to a controlled and highly efficient lipid clearance profile. We identify highly potent examples and demonstrate their exceptional tolerability in multiple preclinical species, including multidosing in nonhuman primates (NHP) [2].
As a component of lipid nanoparticles, the in vitro function of Lipid A9 is primarily reflected in its physicochemical properties that facilitate nucleic acid encapsulation and delivery. Its pKa value of 6.27 determines its protonation capability under acidic pH and endosomal escape efficiency. This compound has been used in combination with other lipids to formulate LNPs for mRNA delivery research. Its high LogP value (20.4) reflects strong lipophilicity, contributing to LNP self-assembly and stability. Solubility in DMSO is approximately 100 mg/mL (110.44 mM), facilitating formulation applications. |
| ln Vivo |
In vivo studies demonstrate that lipid nanoparticles containing Lipid A9 and encapsulating non-stimulatory siRNA induce innate immune activation, as evidenced by increased plasma levels of chemokine CCL2 (C-C motif ligand 2). Furthermore, these LNPs cause body weight reduction in mice, suggesting potential metabolic or immune-mediated effects. Lipid A9 has been used in the preparation of LNPs for in vivo delivery of mRNA and siRNA. In vaccine research, LNP systems containing Lipid A9 can effectively deliver antigen-encoding mRNA to induce immune responses.
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| Enzyme Assay |
Lipid A9 is not involved in traditional enzyme or receptor binding assays; its cell-free evaluation focuses on physicochemical characterization. A standard protocol includes: 1) pKa determination by pH titration (reference value 6.27): disperse Lipid A9 in aqueous buffer containing 150 mM NaCl, adjust pH range 3.0-9.0 with HCl or NaOH, and monitor changes in lipid protonation; 2) Measure LNP particle size (target 80-120 nm) and polydispersity index by dynamic light scattering; 3) Determine nucleic acid encapsulation efficiency using fluorescent dye methods (e.g., RiboGreen); 4) Verify compound purity (≥95-98%) by HPLC or mass spectrometry.
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| Cell Assay |
The in vitro cell assay protocol for Lipid A9 is as follows: 1) Seed target cells (such as HEK293T, HeLa, or dendritic cells) in culture plates and culture to appropriate density at 37°C with 5% CO₂; 2) Prepare LNPs containing Lipid A9 via microfluidic or ethanol injection methods, encapsulating reporter mRNA (e.g., luciferase mRNA or GFP mRNA); 3) Add LNPs at various concentrations (mRNA dose typically 0.1-5 μg/well) to cell culture medium and incubate for 24-48 hours; 4) Detect GFP expression by fluorescence microscopy or flow cytometry, or quantify by luciferase activity assay; 5) Assess cell viability by CCK-8 assay to evaluate formulation toxicity.
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| Animal Protocol |
An in vivo animal assay protocol for Lipid A9 is as follows: 1) Use 6-8 week old female or male mice (such as C57BL/6 strain); 2) Prepare LNPs containing Lipid A9 encapsulating target nucleic acids (such as mRNA or siRNA) via microfluidic technology; 3) Administer via tail vein intravenous injection at a nucleic acid dose of typically 0.2-1 mg/kg; 4) Collect blood samples at various time points post-administration (e.g., 6, 24, 48 hours) and measure plasma chemokine CCL2 levels by ELISA to assess innate immune activation; 5) Record body weight changes; 6) Euthanize animals 24-72 hours post-administration, collect tissues such as liver and spleen, and assess nucleic acid organ distribution and expression efficiency by flow cytometry or fluorescence imaging.
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| ADME/Pharmacokinetics |
As a component of LNPs, its pharmacokinetic behavior is closely associated with the overall properties of the LNP formulation. This compound has a high LogP value of 20.4, a topological polar surface area (tPSA) of 76.2 Ų, and 52 rotatable bonds, reflecting its highly flexible long-chain alkyl structure. Due to its pKa of 6.27, it remains neutral at physiological pH, which helps reduce plasma protein adsorption and prolong circulation time. The compound is typically supplied as a solution in ethanol (10 mg/mL) and should be stored at -20°C, with stability for at least 2 years.
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| Toxicity/Toxicokinetics |
In animal studies, LNPs containing Lipid A9 cause body weight reduction in mice, suggesting potential metabolic or immune-mediated adverse effects. The same study also reported innate immune activation (elevated CCL2 levels). Additional shipping charges may apply for transport of this compound, though it remains stable for several days at room temperature. Standard chemical safety practices should be followed during handling and storage.
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| References | |
| Additional Infomation |
The recent success of mRNA vaccines in SARS-CoV-2 clinical trials is partly due to the development of lipid nanoparticle delivery systems. These systems can not only efficiently express mRNA-encoded immunogens after intramuscular injection, but also act as adjuvants and influence vaccine reactivity. This article first provides an overview of mRNA delivery systems, and then focuses on lipid nanoparticles currently used in SARS-CoV-2 vaccine clinical trials. Finally, this article analyzes the determinants of lipid nanoparticle performance in mRNA vaccines. [1]
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| Molecular Formula |
C57H112N2O5
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|---|---|
| Molecular Weight |
905.51
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| Exact Mass |
904.857
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| CAS # |
2036272-50-9
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| PubChem CID |
122666762
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| Appearance |
Colorless to light yellow liquid
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| LogP |
20.4
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
52
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| Heavy Atom Count |
64
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| Complexity |
964
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(OCC(CCCC)CCCCCC)(=O)CCCCCCCCC(N(CCCN(C)C)C(=O)CCCCCCCC)CCCCCCCCC(OCC(CCCC)CCCCCC)=O
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| InChi Key |
XNEHCOKBKFCJSM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C57H112N2O5/c1-8-13-18-21-28-35-45-55(60)59(49-38-48-58(6)7)54(43-33-26-22-24-29-36-46-56(61)63-50-52(39-16-11-4)41-31-19-14-9-2)44-34-27-23-25-30-37-47-57(62)64-51-53(40-17-12-5)42-32-20-15-10-3/h52-54H,8-51H2,1-7H3
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| Chemical Name |
bis(2-butyloctyl) 10-[3-(dimethylamino)propyl-nonanoylamino]nonadecanedioate
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| Synonyms |
1,19-Bis(2-butyloctyl) 10-[[3-(dimethylamino)propyl](1-oxononyl)amino]nonadecanedioate; Lipid A9; 2036272-50-9; 1,19-Bis(2-butyloctyl) 10-[[3-(dimethylamino)propyl](1-oxononyl)amino]nonadecanedioate; Bis(2-butyloctyl) 10-(N-(3-(dimethylamino)propyl)nonanamido)nonadecanedioate; Lipid A9?; starbld0002660; SCHEMBL18202060;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~110.44 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1044 mL | 5.5218 mL | 11.0435 mL | |
| 5 mM | 0.2209 mL | 1.1044 mL | 2.2087 mL | |
| 10 mM | 0.1104 mL | 0.5522 mL | 1.1044 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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