Immunotherapeutic nanoparticles and methods relating thereto
Compositions containing lipid nanoparticles and nucleic acid therapeutic agents are disclosed. For example, calcium phosphate nanoparticles having a lipid coating are provided, wherein the calcium phosphate nanoparticles include a cyclic dinucleotide and the lipid coating includes phosphatidylserine. The compositions can be formulated for administration to the lungs of a subject via inhalation, or for administration via injection. Methods for the treatment of lung cancer and other cancers are also described. Targeted delivery of therapeutic agents such as cyclic dinucleotides to antigen presenting immune cells via the disclosed methods can elicit beneficial antitumor immunity.
1 . A composition comprising a calcium phosphate nanoparticle having a lipid coating, wherein the lipid coating comprises a bilayer containing anionic phosphatidylserine, a phosphatidylcholine, and a sterol, wherein the anionic phosphatidylserine is present in both layers of the bilayer, wherein the calcium phosphate nanoparticle targets antigen presenting cells, and wherein the composition can be used as an inhalable nanoparticle immunotherapy that can be aerosolized during use, wherein the calcium phosphate nanoparticle comprises a nucleic acid therapeutic agent, and wherein the nucleic acid therapeutic agent is 2′3′ cyclic guanosine monophosphate-adenosine monophosphate (2′3′ cGAMP).
2 . The composition of claim 1 , wherein the composition has a ratio of the total lipids to 2′3′ cGAMP that ranges from about 10:1 to about 1000:1 by weight.
3 . The composition of claim 1 , wherein the composition has a ratio of the total lipids to 2′3′ cGAMP that ranges from about 20:1 to about 40:1 by weight.
4 . The composition of claim 1 , wherein the phosphatidylserine is present in an amount that ranges from about 10 mol % to about 80 mol % based on a total amount of lipids in the lipid coating.
5 . The composition of claim 1 , wherein the phosphatidylserine comprises a stearoyl (18:0) moiety, an oleoyl (18:1) moiety, an eicosatetraenoyl (20:4) moiety, a docosahexaenoyl (22:06) moiety, or a combination thereof.
6 . The composition of claim 1 , wherein the calcium phosphate nanoparticle, inclusive of the lipid coating, has a size range from about 50 nm to about 200 nm in diameter.
7 . The composition of claim 1 , wherein the composition is formulated for administration to the lungs of a subject.
8 . A method for treating cancer, the method comprising:
administering to a subject in need thereof a therapeutically effective amount of a composition of claim 1 wherein administering comprises inhalation of the composition;
co-administering to the subject in need thereof one or more immune checkpoint inhibitors; and
administering radiotherapy to the subject following administration of the therapeutically effective amount of the composition and the immune checkpoint inhibitor.
9 . The method of claim 8 , wherein the cancer is a lung cancer, a head and neck cancer, or an esophageal cancer.
10 . The method of claim 8 , wherein the cancer comprises one or more metastatic tumors.
11 . The method of claim 8 , wherein the composition has a ratio of the total lipids to the 2′3′ cGAMP that ranges from about 10:1 to about 1000:1 by weight.
12 . The method of claim 8 , wherein the calcium phosphate nanoparticle, inclusive of the lipid coating, has a size range from about 50 nm to about 150 nm in diameter.
13 . The method of claim 8 , wherein the composition is aerosolized during administration.
14 . A liquid composition comprising a calcium phosphate nanoparticle having a lipid coating, wherein the lipid coating comprises a bilayer containing anionic phosphatidylserine, phosphatidylcholine, and a sterol, wherein the anionic phosphatidylserine is present in both layers of the bilayer, wherein the calcium phosphate nanoparticle targets antigen presenting cells, wherein the liquid composition can be aerosolized prior to administration, wherein the calcium phosphate nanoparticle comprises a nucleic acid therapeutic agent, and wherein the nucleic acid therapeutic agent is 2′3′ cyclic guanosine monophosphate-adenosine monophosphate (2′3′ cGAMP).
15 . The composition of claim 1 , wherein the anionic phosphatidylserine, the phosphatidylcholine, and the sterol are present in a molar ratio of 5:4:1.