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Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing
Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing , et al. Nat. Biotechnol.,2023,41(10):1410-1415. DOI: 10.1038/s41587-023-01679-x PubMed ID: 36997680
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Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.
Purchased from AmBeed: 14916-80-4 ; 294-90-6 ; 13093-04-4 ; 65604-89-9 ; 22366-98-9 ; 143-28-2 ; 1484-84-0 ; 112-92-5 ; 3433-37-2 ; 34803-66-2 ; 622-26-4 ; 934-98-5 ; 3529-08-6 ; 123-70-6 ; 23356-96-9 ; 534-26-9 ; 4730-54-5 ; 108-00-9 ; 51388-00-2 ; 6711-48-4 ; 506-43-4 ; 2038-03-1 ; 142-25-6 ; 27578-60-5 ; 67980-77-2 ; 4572-03-6 ; 14156-95-7 ; 10563-26-5 ; 4097-88-5 ; 111-33-1 ; 123-12-6 ; 6261-22-9 ; 496808-04-9 ; 3644-18-6 ; 764-60-3 ; 1002-36-4 ; 51-45-6 ; 112086-54-1 ; 22104-79-6 ; 67529-83-3 ; 10563-29-8 ; 294-90-6 ; 506-43-4 ; 20739-58-6 ; 13901-38-7 ; 938459-02-0 ; 7209-38-3 ; 51721-39-2 ; 18128-28-4 ; 105-83-9 ; 877-96-3 ; 14712-23-3 ; 915922-79-1 ; 205059-32-1 ; 5298-72-6 ; 22763-69-5 ...More
CAS No. : | 112-92-5 | MDL No. : | MFCD00002823 |
Formula : | C18H38O | Boiling Point : | - |
Linear Structure Formula : | CH3(CH2)16CH2OH | InChI Key : | GLDOVTGHNKAZLK-UHFFFAOYSA-N |
M.W : | 270.49 | Pubchem ID : | 8221 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 | 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 |
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[0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLES [0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes). |
Yield | Reaction Conditions | Operation in experiment |
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73% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | Method B: To a 500 mL, three neck, round bottom flask equipped with a stir bar, nitrogen sweep, and thermocouple was charged with <strong>[3543-75-7]bendamustine</strong> HC1 (5.04g, 12.8 mmol), 1- octadecanol (4.15g, 15.3mmol), Nu,Nu'-Dicyclohexylcarbodiimide ( DCC, 3.17g, 15.4 mmol), 4- Dimethylaminopyridine (DMAP, 0.3 lg, 2.56 mmol) and methylene chloride (250 mL). The resulting slurry was stirred at room temperature for 16 hours. A solid was produced and removed from the reaction mixture by filtration. The filtrate was washed with water (150 mL). After phase separation, the organic phase dried over MgS04. The drying agent was removed by filtration and the filtrate was concentrated and subjected to ISCO chromatographic purification with a mixture of EtOAc and heptanes, giving a white solid 5.68g (73% yield) with 99A% purity. |
Yield | Reaction Conditions | Operation in experiment |
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99% | With triphenylphosphine-sulfur trioxide adduct; In neat (no solvent); at 110.0℃; for 2.0h;Green chemistry; | General procedure: In order to perform the esterification reaction, into a single-necked reaction flask, at equivalent quantities stearic acid (0.50 g, 1.76 mmol) and myristyl alcohol (0.48 g, 1.77 mmol) were added. After addition of the catalyst (5 mg), the mixture was heated with stirring in an oil bath at 110 C (bath temperature) for 2 h. Finally the reaction mixture was cooled and the obtained solid was crystallized from methanol/acetone/tetrahydrofuran to afford pure crystalline product. |