Nanoparticles encapsulating soluble biologics, therapeutics, and imaging agents
AssigneeThe Trustees of Princeton University
InventorsRobert F. Pagels, Robert K. PRUD'HOMME
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Abstract
An “inverse” precipitation route to precipitate aqueous soluble species with copolymers as nanoparticles having a hydrophilic, polar core and a less polar shell is described.
Claims21
-34. (canceled)
A nanoparticle comprising:
- a core comprising a more polar region of a copolymer and a water-soluble agent;
- and
- a shell comprising a less polar region of the copolymer,
- wherein the copolymer comprises a backbone and a pendant group covalently attached to the backbone,
- wherein the copolymer is selected from the group consisting of a graft copolymer and a branched-comb copolymer,
- wherein the graft copolymer comprises one or more pendant groups covalently attached to and at random intervals along the backbone,
- wherein the branched-comb copolymer comprises one or more pendant groups covalently attached to and at regular intervals along the backbone, and
- wherein the more polar region of the copolymer comprises the backbone and the less polar region of the copolymer comprises the pendant group or
- wherein the more polar region of the copolymer comprises the pendant group and the less polar region of the copolymer comprises the backbone.
The nanoparticle of claim 1, wherein the copolymer is the graft copolymer.
The nanoparticle of claim 1, wherein the copolymer is the branched-comb copolymer.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises the backbone and the less polar region of the copolymer comprises the pendant group.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises the pendant group and the less polar region of the copolymer comprises the backbone.
The nanoparticle of claim 1, wherein the copolymer is biodegradable.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises an anionic more polar region.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises a polypeptide.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises a polysaccharide.
The nanoparticle of claim 1, wherein the more polar region of the copolymer comprises poly(aspartic acid), poly(glutamic acid), dextran, or a combination.
The nanoparticle of claim 1, wherein the more polar region of the copolymer in the core is crosslinked.
The nanoparticle of claim 1, wherein the more polar region of the copolymer in the core is crosslinked with an alkaline earth, calcium, magnesium, or a combination.
The nanoparticle of claim 1, wherein the less polar region of the copolymer comprises a polyester, poly(lactic acid) (PLA), poly(lactic-co-glycolic) acid (PLGA), poly(caprolactone) (PCL), or a combination.
The nanoparticle of claim 1, wherein the water-soluble agent is selected from the group consisting of a biologic material, an amino acid, a peptide, a protein, DNA, RNA, a saccharide, glutathione, tryptophan, a lysozyme, glucagon-like peptide-I (GLP-1), a small molecule therapeutic, tobramycin, vancomycin, an imaging agent, eosin, eosin Y, tartrazine, a metal chelate, a gadolinium chelate, gadolinium diethylene triamine pentaacetic acid (GD-DTPA), and a combination.
The nanoparticle of claim 1, wherein the water-soluble agent is selected from the group consisting of RNA, an RNA salt, an RNA alkaline earth salt, an RNA calcium salt, an RNA magnesium salt, an RNA that produces an enzyme, DNA, a DNA salt, a DNA alkaline earth salt, a DNA calcium salt, a DNA magnesium salt, a DNA that produces an enzyme, a DNA that produces an imaging enzyme, a peptide, glucagon-like peptide-I (GLP-1), a glucagon-like peptide-I (GLP-1) analog, and a combination.
The nanoparticle of claim 1, further comprising a coating,
- wherein the coating comprises an inner region and an outer region,
- wherein the inner region comprises a hydrophobic region of an amphiphilic polymer, and
- wherein the outer region comprises a hydrophilic region of the amphiphilic polymer.
The nanoparticle of claim 1,
- wherein the copolymer is the graft copolymer comprising pendant groups covalently attached to and at random intervals along the backbone,
- wherein the more polar region of the copolymer comprises the backbone and the less polar region of the copolymer comprises the pendant group,
- wherein the backbone comprises a polysaccharide and/or a polypeptide,
- wherein the pendant group comprises a polyester, and
- wherein the water-soluble agent is selected from the group consisting of RNA, an RNA salt, DNA, a DNA salt, a peptide, glucagon-like peptide-I (GLP-1), a glucagon-like peptide-I (GLP-1) analog, and a combination.
A method for synthesizing the nanoparticle of claim 1, comprising:
- providing a hydrophobic hydroxy-final pendant group;
- providing the backbone, which comprises at least one carboxyl and is hydrophilic;
- carbodiimide coupling the hydrophobic hydroxy-final pendant group to the at least one carboxyl of the backbone to form the copolymer as a graft copolymer wherein the more polar region of the copolymer comprises the backbone and the less polar region of the copolymer comprises the pendant group;
- dissolving the water-soluble agent and the copolymer in a polar process solvent to form a first process solution;
- and
- continuously mixing the first process solution with a nonprocess solvent to form a mixed solution from which the nanoparticle assembles and precipitates,
- wherein the less polar region is soluble in the nonprocess solvent,
- wherein the nonprocess solvent is less polar than the polar process solvent, and
- wherein the mixing causes no more than 20 percent by volume of the polar process solvent to phase separate from the mixed solution.
A method for synthesizing the nanoparticle of claim 1, comprising:
- providing a hydrophobic carboxyl-final pendant group;
- providing the backbone, which comprises a hydroxy and is hydrophilic;
- carbodiimide coupling the hydrophobic carboxyl-final pendant group to the hydroxy of the backbone to form the copolymer as a graft copolymer wherein the more polar region of the copolymer comprises the backbone and the less polar region of the copolymer comprises the pendant group;
- dissolving the water-soluble agent and the copolymer in a polar process solvent to form a first process solution;
- and
- continuously mixing the first process solution with a nonprocess solvent to form a mixed solution from which the nanoparticle assembles and precipitates,
- wherein the less polar region is soluble in the nonprocess solvent,
- wherein the nonprocess solvent is less polar than the polar process solvent, and
- wherein the mixing causes no more than 20 percent by volume of the polar process solvent to phase separate from the mixed solution.
Dependencies are inferred from the claim text.