Substituted fullerene formulations and their use in ameliorating oxidative stress diseases or inhibiting cell death

1 . A composition, comprising:

a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and

at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

2 . The composition of claim 1 , wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

4 . The composition of claim 1 , further comprising at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

5 . The composition of claim 4 , wherein the excipient is included in the U.S. FDA EAFUS list or GRAS list.

6 . The composition of claim 1 , wherein the substituted fullerene comprises at least one of i-iv:

(i) m (>CX X ) groups bonded to the fullerene core, wherein:

(i-a) m is an integer from 1 to 6, inclusive,

(i-b) each X 1 and X 2 is independently selected from —H; —COOH; —CONH 2 ; —CONHR′; —CONR′ 2 ; —COOR′; —CHO; —(CH 2 ) d OR 11 ; a peptidyl moiety; —R; —RCOOH; —RCONH 2 ; —RCONHR′; —RCONR′ 2 ; —RCOOR′; —RCHO; —R(CH 2 ) d OR 11 ; a heterocyclic moiety; a branched moiety comprising one or more terminal —OH, —NH 2 , triazole, tetrazole, or sugar groups; or a salt thereof, wherein each R is a hydrocarbon moiety having from 1 to about 6 carbon atoms and each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol, and d is an integer from 0 to about 20, and each R 11 is independently —H, a charged moiety, or a polar moiety;

(ii) p —X 3 groups bonded to the fullerene core, wherein:

(ii-a) p is an integer from 1 to 18, inclusive; and

(ii-b) each —X 3 is independently selected from —N + (R 2 )(R 3 )(R 4 ), wherein R 2 , R 3 , and R 4 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20;

—N + (R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) t —COO − , wherein f is an integer from 1 to about 20; —C(R 5 )(R 6 )(R 7 ), wherein R 5 , R 6 , and R 7 are independently —COOH, —H, —CH(═O), —CH 2 OH, or a peptidyl moiety;

wherein each R 10 is independently >O, >C(R 2 )(R 3 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, >CHN + (R 2 )(R 3 )(R 4 ), wherein R 2 , R 3 , and R 4 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, or >CHN + (R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) f —COO − , wherein f is an integer from 1 to about 20;

—C(R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) f —COO − , wherein f is an integer from 1 to about 20; —(CH 2 ) e —COOH, —(CH 2 ) e —CONH 2 , —(CH 2 ) e —COOR′, wherein e is an integer from 1 to about 6 and each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol; a peptidyl moiety; or an aromatic heterocyclic moiety containing a cationic nitrogen;

(iii) q —X 4 — groups bonded to the fullerene core, wherein

(iii-a) q is an integer from 1 to 6, inclusive; and

(iii-b) each —X 4 —group is independently

wherein R 2 is independently —H or —(CH 2 ) d —CH 3 , d is an integer from 0 to about 20, and R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f PO 4 − , or —(CH 2 ) f —COO − , and f is an integer from 1 to about 20;

wherein each R 2 and R 3 is independently —H or —(CH 2 ) d —CH 3 and d is an integer from 0 to about 20;

wherein each R 2 is independently —H or —(CH 2 ) d —CH 3 , d is an integer from 0 to about 20, and each R 9 is independently —H, —OH, —OR′, —NH 2 , —NHR′, —NHR′ 2 , or —(CH 2 ) d OH, wherein each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol.

(iv) r dendrons bonded to the fullerene core and s nondendrons bonded to the fullerene core, wherein:

(iv-a) r is an integer from 1 to 6, inclusive;

(iv-b) s is an integer from 0 to 18, inclusive;

(iv-b) each dendron has at least one protic group which imparts water solubility, and

(iv-d) each nondendron independently comprises at least one drug, amino acid, peptide, nucleotide, vitamin, or organic moiety.

7 . The composition of claim 1 , wherein the substituted fullerene comprises a fullerene core (Cn) having 60 carbon atoms or 70 carbon atoms.

8 . The composition of claim 1 , wherein the substituted fullerene has the structure:

9 . A method of ameliorating an oxidative stress disease, comprising:

administering to a mammal via a transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, oral, buccal, rectal, or nasal route an effective amount of a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

10 . The method of claim 9 , wherein the mammal suffers or is susceptible to an oxidative stress disease selected from central nervous system (CNS) neurodegenerative diseases, stroke, atherosclerosis, myocardial ischemia, myocardial reperfusion, diabetes, complications of diabetes, circulatory impairment, retinopathy, blindness, kidney disease, pancreas disease, neuropathy, gum disease, cataracts, skin disease, skin damage, radiation damage, damage caused by tobacco use, excessive angiogenesis, insufficient angiogenesis, hearing loss, collateral damage of chemotherapy, mucositis, or senescence.

11 . The method of claim 10 , wherein the CNS neurodegenerative disease is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

12 . The method of claim 9 , wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

13 . The method of claim 9 , wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

14 . A method of inhibiting cell death, comprising:

administering to a mammal via a transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, oral, buccal, rectal, or nasal route an effective amount of a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

15 . The method of claim 14 , wherein the mammal suffers or is susceptible to cell death caused by heat, radiation, mechanical injury, a chemical toxin, a bacterial toxin, a viral toxin, a plant toxin, a biological toxin, or two or more thereof.

16 . The method of claim 14 , wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

17 . The method of claim 14 , wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

18 . A method of protecting cells in vitro, comprising:

administering to the cells a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core.

19 . The method of claim 18 , wherein the substituted fullerene comprises at least one of i-iv:

(i) m (>CX 1 X 2 ) groups bonded to the fullerene core, wherein:

(i-a) m is an integer from 1 to 6, inclusive,

(i-b) each X 1 and X 2 is independently selected from —H; —COOH; —CONH 2 ; —CONHR′; —CONR′ 2 ; —COOR′; —CHO; —(CH 2 ) d OR 11 ; a peptidyl moiety; —R; —RCOOH; —RCONH 2 ; —RCONHR′; —RCONR′ 2 ; —RCOOR′; —RCHO; —R(CH 2 ) d OR 11 ; a heterocyclic moiety; a branched moiety comprising one or more terminal —OH, —NH 2 , triazole, tetrazole, or sugar groups; or a salt thereof, wherein each R is a hydrocarbon moiety having from 1 to about 6 carbon atoms and each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol, and d is an integer from 0 to about 20, and each R 11 is independently —H, a charged moiety, or a polar moiety;

(ii) p —X 3 groups bonded to the fullerene core, wherein:

(ii-a) p is an integer from 1 to 18, inclusive; and

(ii-b) each —X 3 is independently selected from —N + (R 2 )(R 3 )(R 4 ), wherein R 2 , R 3 , and R 4 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20;

—N + (R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) f —COO − , wherein f is an integer from 1 to about 20; —C(R 5 )(R 6 )(R 7 ), wherein R 5 , R 6 , and R 7 are independently —COOH, —H, —CH(═O), —CH 2 OH, or a peptidyl moiety;

wherein each R 10 is independently >O, >C(R 2 )(R 3 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, >CHN + (R 2 )(R 3 )(R 4 ), wherein R 2 , R 3 , and R 4 are independently —H or —(CH2) d —CH 3 , wherein d is an integer from 0 to about 20, or >CHN + (R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) f —COO − , wherein f is an integer from 1 to about 20;

—C(R 2 )(R 3 )(R 8 ), wherein R 2 and R 3 are independently —H or —(CH 2 ) d —CH 3 , wherein d is an integer from 0 to about 20, and each R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f PO 4 − , or —(CH 2 ) f —COO − , wherein f is an integer from 1 to about 20; —(CH 2 ) e —COOH, —(CH 2 ) e —CONH 2 , —(CH 2 ) e —COOR′, wherein e is an integer from 1 to about 6 and each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol; a peptidyl moiety; or an aromatic heterocyclic moiety containing a cationic nitrogen;

(iii) q —X 4 — groups bonded to the fullerene core, wherein

(iii-a) q is an integer from 1 to 6, inclusive; and

(iii-b) each —X 4 — group is independently

wherein R 2 is independently —H or —(CH 2 ) d —CH 3 , d is an integer from 0 to about 20, and R 8 is independently —(CH 2 ) f —SO 3 − , —(CH 2 ) f —PO 4 − , or —(CH 2 ) f —COO − , and f is an integer from 1 to about 20;

wherein each R 2 and R 3 is independently —H or —(CH 2 ) d —CH 3 and d is an integer from 0 to about 20;

wherein each R 2 is independently —H or —(CH 2 ) d —CH 3 , d is an integer from 0 to about 20, and each R 9 is independently —H, —OH, —OR′, —NH 2 , —NHR′, —NHR′ 2 , or —(CH 2 ) d OH, wherein each R′ is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol.

(iv) r dendrons bonded to the fullerene core and s nondendrons bonded to the fullerene core, wherein:

(iv-a) r is an integer from 1 to 6, inclusive;

(iv-b) s is an integer from 0 to 18, inclusive;

(iv-b) each dendron has at least one protic group which imparts water solubility, and

(iv-d) each nondendron independently comprises at least one drug, amino acid, peptide, nucleotide, vitamin, or organic moiety.

20 . The method of claim 18 , wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, and azone-like compounds.