COMPOSITIONS AND METHODS FOR DELIVERY OF RNA
The disclosure provides nanoemulsion compositions and methods of making and using thereof to deliver a bioactive agent such as a nucleic acid to a subject. The nanoemulsion composition comprises a hydrophobic core based on inorganic nanoparticles in a lipid nanoparticle that allows imaging as well as delivering nucleic acids. Methods of using these particles for treatment and vaccination are also provided.
1 . A composition comprising a plurality of nanoparticles, wherein the plurality of nanoparticles comprise a hydrophobic core, the hydrophobic core comprising:
a mixture of liquid oil and a solid inorganic nanoparticle;
a cationic lipid;
a hydrophilic surfactant; and
a hydrophobic surfactant.
2 . The composition of claim 1 , wherein the hydrophobic core does not comprise glyceryl trimyristate.
3 . The composition of claim 1 , wherein the hydrophobic surfactant is selected from the group consisting of sorbitan monostearate, sorbitan monooleate, and sorbitan trioleate.
4 . The composition of claim 1 , wherein cationic lipid is selected from the group consisting of 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP); 3b-[N—(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC Cholesterol); dimethyldioctadecylammonium (DDA); 1,2-dimyristoyl-3-trimethylammoniumpropane (DMTAP), dipalmitoyl(C16:0)trimethyl ammonium propane (DPTAP); distearoyltrimethylammonium propane (DSTAP); N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC); 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (DOEPC); 1,2-dioleoyl-3-dimethylammonium-propane (DODAP); and 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA); and 1,r-((2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl) (2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethyl)azanediyl)bis(dodecan-2-ol) (C 12-200).
5 . The composition of claim 4 , wherein the cationic lipid is DOTAP.
6 . The composition of claim 1 , wherein the solid inorganic nanoparticle is selected from the group consisting of metal salts, metal oxides, metal hydroxides, and metal phosphates.
7 . The composition of claim 1 , wherein the solid inorganic nanoparticle comprises iron oxide.
8 . The composition of claim 7 , wherein the iron oxide is magnetite (Fe 3 O 4 ), maghemite (y-Fe 2 O 3 ), wüstite (FeO), or hematite (a-Fe 2 O 3 ), or a combination thereof.
9 . The composition of claim 1 , wherein the nanoparticles are associated with a bioactive agent.
10 . The composition of claim 9 , wherein the bioactive agent comprises a nucleic acid.
11 . The composition of claim 10 , wherein the nucleic acid is DNA.
12 . The composition of claim 10 , wherein the nucleic acid is RNA.
13 . The composition of claim 12 , wherein the RNA is mRNA.
14 . The composition of claim 13 , wherein the mRNA encodes for an antigen.
15 . The composition of claim 13 , wherein the mRNA encodes for an antibody.
16 . The composition of claim 13 , wherein the mRNA encodes for a Venezuelan equine encephalitis viral sequence.
17 . The composition of claim 1 , wherein the liquid oil is a vegetable oil, an animal oil or a synthetically prepared oil.
18 . The composition of claim 1 , wherein the liquid oil is capric/caprylic triglyceride, vitamin E, lauroyl polyoxylglyceride, monoacylglycerol, squalene, squalane, or any combination thereof.
19 . The composition of claim 1 , wherein the liquid oil is squalene, sunflower oil, soybean oil, olive oil, grapeseed oil, squalane, capric/caprylic triglyceride, or any combination thereof.
20 . The composition of claim 1 , wherein the liquid oil is squalene.
21 . The composition of claim 1 , wherein the hydrophilic surfactant comprises polyethylene oxide.
22 . The composition of claim 21 , wherein the polyethylene oxide comprises polyoxyethylene sorbitan ester.
23 . The composition of claim 1 , wherein the hydrophilic surfactant comprises polysorbate.
24 . The composition of claim 23 , wherein the polysorbate comprises polysorbate 80.
25 . The composition of claim 1 , wherein the solid inorganic nanoparticle has an average diameter from about 3 nm to about 50 nm.
26 . The composition of claim 1 , wherein the nanoparticles comprise an average diameter from about 40 nm to about 80 nm, wherein the average diameter is a z-average hydrodynamic diameter measured by dynamic light scattering.
27 . The composition of claim 1 , wherein the liquid oil comprises squalene, wherein the solid inorganic nanoparticle comprises iron oxide, wherein the cationic lipid comprises DOTAP, wherein the hydrophobic surfactant comprises sorbitan monostearate, and wherein the hydrophilic surfactant comprises polysorbate 80.
28 . The composition of claim 1 , wherein the liquid oil is squalene, wherein the solid inorganic nanoparticle is iron oxide, wherein the cationic lipid is DOTAP, wherein the hydrophobic surfactant is sorbitan monostearate, and wherein the hydrophilic surfactant is polysorbate 80.
29 . The composition of claim 28 , wherein the composition further comprises sodium citrate.
30 . The composition of claim 1 , wherein the liquid oil comprises from 2% to 40% w/v squalene, wherein the solid inorganic nanoparticle comprises from 0.001% to 10% w/v iron oxide, wherein the cationic lipid comprises from 0.2% to 10% w/v DOTAP, wherein the hydrophobic surfactant comprises from 0.25% to 5% w/v sorbitan monostearate, and wherein the hydrophilic surfactant comprises from 0.5% to 10% w/v polysorbate 80.