Nanoalum particles comprising a PAA sizing agent
Provided herein are nanoalum particles comprising an aluminum salt and a sizing agent, wherein the size of the particle ranges from about 1 nm to 450 nm. Such nanoalum particles are stable and are amenable to a terminal sterilization step prior to vialing. Compositions comprising the nanoalum particles, and the making and using of the nanoalum particles are also provided.
1. A nanoalum particle comprising:
(a) an aluminum salt; and
(b) a sizing agent comprises PAA;
wherein the size of the nanoalum particle ranges from about 1 nm to about 450 nm, and wherein a weight ratio of the aluminum salt to the sizing agent is about 1:2-1:3.
2. The nanoalum particle of claim 1 , wherein the average size of the particles is the Z-average as determined by dynamic light scattering.
3. The nanoalum particle of claim 1 , wherein the aluminum salt is selected from the group consisting of aluminum hydroxide, aluminum hydroxide gel, AlPO 4 , AlO(OH), Al(OH)(PO 4 ), and KAl(SO 4 ) 2 .
4. The nanoalum particle of claim 1 , wherein an average molecular weight of the PAA is from about 750 Daltons to about 5000 Daltons.
5. The method of making the nanoalum particle of claim 1 comprising:
milling the aluminum salt in the presence of the sizing agent at the weight ratio of about 1:2-1:3; and
adjusting the pH to a value of less than 7.0, whereby the nanoalum particle is produced.
6. The method of claim 5 , further comprising mixing the sizing agent with the nanoalum particle within about 30 minutes after subjecting the aluminum salt to the high energy source.
7. The method of claim 5 , wherein the high energy source is generated from one, two, or more of a microfluidizer, an extruder, a sonicator, a high shear mixer, or a homogenizer.
8. The method of claim 5 , wherein the high energy source is generated from a microfluidizer and a high shear mixer, and a mixture comprising the aluminum salt and sizing agent is passed through the microfluidizer from one pass to about 30 passes or the high energy source is generated from a microfluidizer, and the mixture comprising the aluminum salt and sizing agent is passed through the microfluidizer from one pass to about 15 passes.
9. The method of claim 5 , wherein the aluminum salt is comprised of particles from 0.5 to 10 μm in size or 0.5 to 20 μm in size.
10. A composition comprising the nanoalum particle of claim 1 and a bioactive agent.
11. The composition of claim 10 , wherein the bioactive agent is a polypeptide, a fusion protein, a full-length protein, a peptide, a peptide mimetic, a polynucleotide, an antigen, a Rig-I agonist, ID97, an adjuvant, a diagnostic agent, a therapeutic agent, or an organism.
12. The composition of claim 10 , wherein the composition further comprises an adjuvant selected from the group consisting of a AS-2, monophosphoryl lipid A, 3-de-O-acylated monophosphoryl lipid A, IFA, QS21, CWS, TOM, AGPs, CpG-containing oligonucleotides, Toll-like receptor (TLR) agonists, Leif, saponins, saponin mimetics, biological and synthetic lipid A, imiquimod, gardiquimod, resiquimod, polyI:C, flagellin, GLA, SLA, STING, and combinations thereof.
13. A method of stimulating an immune response in a subject comprising administering the composition of claim 10 to a subject, thereby stimulating an immune response in the subject.
14. The method of claim 13 , wherein the immune response is primarily a TH1 immune response, primarily a TH2 immune response, or both a TH1 and a TH2 immune response or the immune response involves activation of B-cells, activation of T cells, production of antibodies, or release of cytokines.
15. A method of delivering a bioactive agent to a cell in a subject comprising administering to the subject a composition comprising (a) the nanoalum particle of claim 1 and (b) a bioactive agent, thereby delivering the bioactive agent to the cell in the subject.
16. The nanoalum particle of claim 4 , wherein the average molecular weight of the PAA is about 2000 Daltons.
17. The nanoalum particle of claim 1 , wherein the nanoalum particle is stable:
in a liquid formulation at about 0° C. to about 8° C. for at least about 1 month;
after repeated freeze-thaw cycles; or
in a liquid formulation at about 37° C. for at least about 1 month.
18. The nanoalum particle of claim 1 , wherein a size of the nanoalum particle ranges from about 70 nm to about 85 nm.
19. The method of claim 8 , wherein the high energy source is generated from a microfluidizer, and the mixture comprising the aluminum salt and sizing agent is passed through the microfluidizer from 10 passes to about 15 passes.