CARBON NANOPARTICLE COMPOSITIONS AND METHODS FOR DELIVERING THERAPEUTICS TO SPECIFIC TARGET SITES
Described herein are nanoparticle compositions and methods for pH-specific release and targeted delivery of therapeutics with enhanced bioavailability. In some embodiments, methods are described for generating carbon nanoparticles (CNPs) that can release payload in acidic pH environments.
1 . A composition comprising graphene oxide nanoparticles (CNP) comprising a plurality of graphene sheets having a plurality of carboxylic acid groups and hydroxyl groups and interconvertible open and closed forms; the open form having a size of about 40 nm to 200 nm in breadth and length in open sheet form; the closed form having a diameter of about 50 nm to 80 nm; wherein the closed form can be converted to the open form at a pH of about 6.8 or lower; and the open form can be converted to the closed form at a pH of about 7.0 or greater.
2 . The composition of claim 1 , wherein the carboxylic acid groups comprise at least about 25-35% of the total mass of the CNP.
3 . The method of claim 1 , wherein the hydroxyl groups comprise at least about 15% of the total mass of the CNP.
4 . The composition of claim 1 , wherein the CNP has a solubility in aqueous solution at a concentration of about 1 mg CNP/mL.
5 . The composition of claim 1 , wherein the CNP displays fluorescence in the blue, green, red, and infrared spectra.
6 . The composition of claim 1 , wherein the CNP has amphiphilic properties.
7 . A method for reversible encapsulation of a molecule within the CNP of claim 1 , the method comprising:
contacting the open form CNP with a molecule to be encapsulated;
converting the open form CNP to the closed form CNP with the molecule encapsulated therein by adjusting the pH to about 7.0 or greater; and
releasing the encapsulated molecule from the closed form CNP by converting back to the open form CNP at a pH of about 6.8 or lower.
8 . The method of claim 7 , wherein the molecule is one or more of a small molecule pharmaceutical, a protein, a peptide, a nucleic acid, a single strand DNA, a double strand DNA, an RNA, an siRNA, an oligonucleotide, a gene, a gene fragment, an imaging agent, a lanthanide, or a combination thereof.
9 . The method of claim 8 , wherein the molecule is no more than about 500 kDa in size.
10 . A composition comprising a water-soluble carbon nanoparticle (CNP) having an encapsulated molecule therein, the CNP comprising a plurality of graphene sheets having a plurality of carboxylic acid groups and hydroxyl groups and interconvertible open and closed forms; the open form having a size of about 40 nm to 200 nm in breadth and length in open sheet form; the closed form having a diameter of about 50 nm to 80 nm; wherein the closed form can be converted to the open form at a pH of about 6.8 or lower; and the open form can be converted to the closed form at a pH of about 7.0 or greater.
11 . The composition of claim 10 , wherein the carboxylic acid groups comprise at least about 25-35% of the total mass of the CNP.
12 . The method of claim 10 , wherein the hydroxyl groups comprise at least about 15% of the total mass of the CNP.
13 . The composition of claim 10 , wherein the encapsulated molecule is an imaging agent or a therapeutic agent.
14 . The composition of claim 10 , wherein the encapsulated molecule is a therapeutic agent for the treatment of cancer.
15 . The composition of claim 10 , wherein the encapsulated molecule is one or more of a small molecule pharmaceutical, a protein, a peptide, a nucleic acid, a single strand DNA, a double strand DNA, an RNA, an siRNA, an oligonucleotide, a gene, a gene fragment, an imaging agent, a lanthanide, or a combination thereof.
16 . The composition of claim 10 , wherein the molecule is no more than about 500 kDa in size.
17 . The composition of claim 10 , further comprising one or more biomolecules or divalent metals for targeted delivery of the CNP with the encapsulated molecule to a cell, tissue, brain, or organ.
18 . The composition of claim 17 , wherein the biomolecule is a protein, a receptor, an aptamer, a ligand, or an antibody; and the divalent metal is manganese (Mn).
19 . A method for treating a subject with cancer, the method comprising:
delivering to the subject a pH-sensitive water-soluble carbon nanoparticle (CNP) having an encapsulated molecule therein,
wherein the CNP comprises a plurality of graphene sheets having a plurality of carboxylic acid groups and hydroxyl groups and interconvertible open and closed forms; the open form having a size of about 40 nm to 200 nm in breadth and length in open sheet form; the closed form having a diameter of about 50 nm to 80 nm; wherein the closed form can be converted to the open form at a pH of about 6.8 or lower; and the open form can be converted to the closed form at a pH of about 7.0 or greater; and
wherein the encapsulated molecule is released from the CNP at a pH of 6.8 or lower after delivery to the subject.
20 . The method of claim 19 , wherein delivering comprises parenteral administration, oral administration, or inhalation.
21 . The method of claim 19 , wherein the molecule is one or more of a small molecule pharmaceutical, a protein, a peptide, a nucleic acid, a single strand DNA, a double strand DNA, an RNA, an siRNA, an oligonucleotide, a gene, a gene fragment, an imaging agent, a lanthanide, or a combination thereof.
22 . The method of claim 21 , wherein the small molecule pharmaceutical is paclitaxel.
23 . The method of claim 19 , wherein the cancer is breast, ovarian, lung, bladder, prostate, melanoma, esophageal, stomach, other solid tumor cancers, combinations thereof.
24 . The method of claim 19 , wherein the subject has glioblastoma.
25 . The method of claim 19 , wherein the CNP further comprises one or more biomolecules or divalent metals for targeted delivery of the CNP with the encapsulated molecule to a cell, tissue, organ, or organ system.
26 . The method of claim 25 , wherein the biomolecule is a protein, a receptor, an aptamer, a ligand, or an antibody; and the divalent metal is manganese (Mn).
27 . The method of claim 19 , wherein the molecule is delivered across the blood brain barrier (BBB) of the subject.
28 . A method for producing a pH-sensitive water-soluble carbon nanoparticle (CNP), the method comprising:
treating a material comprising one or a combination of wood, charcoal, low grade coal, or carbonized plant biomass with a dilute acidic solution to form a mixture of components including insoluble material and a second solution;
separating the second solution from the insoluble material;
neutralizing the second solution to form a precipitate; and
separating the precipitate from the neutralized second solution;
wherein the precipitate comprises the CNP, the CNP comprising a plurality of graphene sheets having a plurality of carboxylic acid groups and interconvertible open and closed forms; the open form having a size of about 40 nm to 200 nm in breadth and length in open sheet form; the closed form having a diameter of about 50 nm to 80 nm; wherein the closed form can be converted to the open form at a pH of about 6.8 or lower; and the open form can be converted to the closed form at a pH of about 7.0 or greater.
29 . The method of claim 28 , wherein the dilute acidic solution is diluted HNO 3 .
30 . The method of claim 28 , wherein the carboxylic acid groups comprise at least about 25-35% of the total mass of the CNP.
31 . The method of claim 28 , wherein the hydroxyl groups comprise at least about 15% of the total mass of the CNP.