US20050070721A1
Expired / Lapsed
US
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PH-sensitive polymeric micelles for drug delivery
Assignee: University of Utah Research Foundation Inc
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Filing: 2003-05-19
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Granted: —
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Expires: 2023-05-19
Abstract
Abstract Mixed micelles containing poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) block copolymer are a pH-sensitive drug carrier that release the drug in an acidic microenvironment, but not in the blood. Since the microenvironment of solid tumors is acidic, these mixed micelles are useful for treating cancer, including those cancers exhibiting multidrug resistance. Targeting ligands, such as folate, can also be attached to the mixed micelles for enhancing drug delivery into cells. Methods of making poly(L-histidine), synthetic intermediates, and block copolymers are also described.
Inventors
- 👤 You Bae
- 👤 Kun Na
- 👤 Eun Lee
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 04:09
CPC Classifications
C; C07; C07D; C07D233/00; C07D233/54; C07D233/64; A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0019; A61K9/10; A61K9/107; A61K9/1075; C07D413/00; C07D413/02; C07D413/06; C08; C08F; C08F8/00; C08F8/30
Claims Analysis
Total Claims: 97
Claim 1
Independent Claim
67 words
1 . A method of making an imidazole-protected L-histidine N-carboxyanhydride comprising: (a) reacting L-histidine, which comprises an α-amino group and an imidazole group, with an amino-group protecting reagent, resulting in an α-amino-protected L-histidine; (b) reacting the α-amino-protected L-histidine with an imidazole-protecting reagent, resulting in an α-amino-protected and imidazole-protected L-histidine; and (c) reacting the α-amino-protected and imidazole-protected L-histidine with an anhydride-forming reagent, resulting in the imidazole-protected L-histidine N-carboxyanhydride.
Claim 2
Dependent Claim
67 words
1 . A method of making an imidazole-protected L-histidine N-carboxyanhydride comprising: (a) reacting L-histidine, which comprises an α-amino group and an imidazole group, with an amino-group protecting reagent, resulting in an α-amino-protected L-histidine; (b) reacting the α-amino-protected L-histidine with an imidazole-protecting reagent, resulting in an α-amino-protected and imidazole-protected L-histidine; and (c) reacting the α-amino-protected and imidazole-protected L-histidine with an anhydride-forming reagent, resulting in the imidazole-protected L-histidine N-carboxyanhydride.
Claim 3
Dependent Claim
23 words
2 . The method of claim 1 wherein the amino-group protecting reagent comprises benzyl chloroformate and the α-amino-protected L-histidine comprises N α -carbobenzoxy-L-histidine.
Claim 4
Dependent Claim
13 words
3 . The method of claim 1 wherein the imidazole-protecting reagent comprises 2,4-dinitrofluorobenzene.
Claim 5
Dependent Claim
23 words
4 . The method of claim 2 wherein the imidazole-protecting reagent comprises 2,4-dinitrofluorobenzene and the α-amino-protected and imidazole-protected L-histidine comprises N-carbobenzoxy-N im -dinitrophenyl-L-histidine.
Claim 6
Dependent Claim
14 words
5 . The method of claim 1 wherein the anhydride-forming reagent comprises thionyl chloride.
Claim 7
Dependent Claim
17 words
6 . The method of claim 1 wherein the imidazole-protected L-histidine N-carboxyanhydride comprises N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 8
Dependent Claim
56 words
7 . A method of making N im -dinitrophenyl-L-histidine N-carboxyanhydride comprising: (a) reacting L-histidine with benzyl chloroformate, resulting in an N α -carbobenzoxy-L-histidine; (b) reacting the N α -carbobenzoxy-L-histidine with 2,4-dinitrofluorobenzene, resulting in an N α -carbobenzoxy-N im -dinitrophenyl-L-histidine; and (c) reacting the Nα-carbobenzoxy-N im -dinitrophenyl-L-histidine with thionyl chloride, resulting in the N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 9
Dependent Claim
56 words
7 . A method of making N im -dinitrophenyl-L-histidine N-carboxyanhydride comprising: (a) reacting L-histidine with benzyl chloroformate, resulting in an N α -carbobenzoxy-L-histidine; (b) reacting the N α -carbobenzoxy-L-histidine with 2,4-dinitrofluorobenzene, resulting in an N α -carbobenzoxy-N im -dinitrophenyl-L-histidine; and (c) reacting the Nα-carbobenzoxy-N im -dinitrophenyl-L-histidine with thionyl chloride, resulting in the N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 10
Dependent Claim
103 words
8 . A method of making an imidazole-protected poly(L-histidine) comprising: (a) reacting L-histidine, which comprises an α-amino group and an imidazole group, with an amino-group protecting reagent, resulting in an α-amino-protected L-histidine; (b) reacting the α-amino-protected L-histidine with an imidazole-protecting reagent, resulting in an α-amino-protected and imidazole-protected L-histidine; (c) reacting the α-amino-protected and imidazole-protected L-histidine with an anhydride-forming reagent, resulting in an imidazole-protected L-histidine N-carboxyanhydride; and (d) converting the imidazole-protected L-histidine N-carboxyanhydride to an acid addition salt thereof and then polymerizing the imidazole-protected L-histidine N-carboxyanhydride acid addition salt by ring-opening polymerization in the presence of an initiator to result in the imidazole-protected poly(L-histidine).
Claim 11
Dependent Claim
103 words
8 . A method of making an imidazole-protected poly(L-histidine) comprising: (a) reacting L-histidine, which comprises an α-amino group and an imidazole group, with an amino-group protecting reagent, resulting in an α-amino-protected L-histidine; (b) reacting the α-amino-protected L-histidine with an imidazole-protecting reagent, resulting in an α-amino-protected and imidazole-protected L-histidine; (c) reacting the α-amino-protected and imidazole-protected L-histidine with an anhydride-forming reagent, resulting in an imidazole-protected L-histidine N-carboxyanhydride; and (d) converting the imidazole-protected L-histidine N-carboxyanhydride to an acid addition salt thereof and then polymerizing the imidazole-protected L-histidine N-carboxyanhydride acid addition salt by ring-opening polymerization in the presence of an initiator to result in the imidazole-protected poly(L-histidine).
Claim 12
Dependent Claim
23 words
9 . The method of claim 8 wherein the amino-group protecting reagent comprises benzyl chloroformate and the α-amino-protected L-histidine comprises N α -carbobenzoxy-L-histidine.
Claim 13
Dependent Claim
13 words
10 . The method of claim 8 wherein the imidazole-protecting reagent comprises 2,4-dinitrofluorobenzene.
Claim 14
Dependent Claim
25 words
11 . The method of claim 9 wherein the imidazole-protecting reagent comprises 2,4-dinitrofluorobenzene and the α-amino-protected and imidazole-protected L-histidine comprises N α -carbobenzoxy-N im -dinitrophenyl-L-histidine.
Claim 15
Dependent Claim
14 words
12 . The method of claim 8 wherein the anhydride-forming reagent comprises thionyl chloride.
Claim 16
Dependent Claim
17 words
13 . The method of claim 8 wherein the imidazole-protected L-histidine N-carboxyanhydride comprises N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 17
Dependent Claim
26 words
14 . The method of claim 8 wherein the acid addition salt of the imidazole-protected L-histidine N-carboxyanhydride comprises a hydrochloride salt of the imidazole-protected L-histidine N-carboxyanhydride.
Claim 18
Dependent Claim
14 words
15 . The method of claim 8 wherein the initiator comprises a primary amine.
Claim 19
Dependent Claim
13 words
16 . The method of claim 15 wherein the primary amine comprises n-hexylamine.
Claim 20
Dependent Claim
13 words
17 . The method of claim 15 wherein the primary amine comprises isopropylamine.
Claim 21
Dependent Claim
92 words
18 . A method of making poly(N im -dinitrophenyl-L-histidine) comprising: (a) reacting L-histidine with benzyl chloroformate, resulting in N-carbobenzoxy-L-histidine; (b) reacting the N α -carbobenzoxy-L-histidine with 2,4-dinitrofluorobenzene, resulting in N α -carbobenzoxy-N im -dinitrophenyl-L-histidine; (c) reacting the N α -carbobenzoxy-N im -dinitrophenyl-L-histidine with thionyl chloride, resulting in an N im -dinitrophenyl-L-histidine N-carboxyanhydride; and (d) converting the N im -dinitrophenyl-L-histidine N-carboxyanhydride to N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride and then polymerizing the N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride by ring-opening polymerization in the presence of n-hexylamine or isopropylamine to result in the poly(N im -dinitrophenyl-L-histidine).
Claim 22
Dependent Claim
92 words
18 . A method of making poly(N im -dinitrophenyl-L-histidine) comprising: (a) reacting L-histidine with benzyl chloroformate, resulting in N-carbobenzoxy-L-histidine; (b) reacting the N α -carbobenzoxy-L-histidine with 2,4-dinitrofluorobenzene, resulting in N α -carbobenzoxy-N im -dinitrophenyl-L-histidine; (c) reacting the N α -carbobenzoxy-N im -dinitrophenyl-L-histidine with thionyl chloride, resulting in an N im -dinitrophenyl-L-histidine N-carboxyanhydride; and (d) converting the N im -dinitrophenyl-L-histidine N-carboxyanhydride to N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride and then polymerizing the N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride by ring-opening polymerization in the presence of n-hexylamine or isopropylamine to result in the poly(N im -dinitrophenyl-L-histidine).
Claim 23
Dependent Claim
41 words
19 . A method of making poly(L-histidine) comprising: (a) polymerizing N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride by ring-opening polymerization in the presence of an initiator to result in poly(N im -dinitrophenyl-L-histidine); and (b) deprotecting the poly(N im -dinitrophenyl-L-histidine) to result in poly(L-histidine).
Claim 24
Dependent Claim
41 words
19 . A method of making poly(L-histidine) comprising: (a) polymerizing N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride by ring-opening polymerization in the presence of an initiator to result in poly(N im -dinitrophenyl-L-histidine); and (b) deprotecting the poly(N im -dinitrophenyl-L-histidine) to result in poly(L-histidine).
Claim 25
Dependent Claim
14 words
20 . The method of claim 19 wherein the initiator comprises a primary amine.
Claim 26
Dependent Claim
13 words
21 . The method of claim 20 wherein the primary amine comprises n-hexylamine.
Claim 27
Dependent Claim
13 words
22 . The method of claim 20 wherein the primary amine comprises isopropylamine.
Claim 28
Dependent Claim
24 words
23 . The method of claim 19 wherein the deprotecting the poly(N im -dinitrophenyl-L-histidine) comprises reacting the poly(N im -dinitrophenyl-L-histidine) with a thiolysis reagent.
Claim 29
Dependent Claim
13 words
24 . The method of claim 23 wherein the thiolysis reagent comprises 2-mercaptoethanol.
Claim 30
Dependent Claim
113 words
24 . The method of claim 19 wherein the N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride is made by reacting L-histidine, which comprises an α-amino group and an imidazole group, with an amino-group protecting reagent, resulting in an α-amino-protected L-histidine; reacting the α-amino-protected L-histidine with an imidazole-protecting reagent, resulting in an α-amino-protected and imidazole-protected L-histidine; reacting the α-amino-protected and imidazole-protected L-histidine with an anhydride-forming reagent, resulting in an imidazole-protected L-histidine N-carboxyanhydride; and drying the imidazole-protected L-histidine N-carboxyanhydride to result in a dried imidazole-protected L-histidine N-carboxyanhydride, dissolving the dried imidazole-protected L-histidine N-carboxyanhydride in an anhydrous organic solvent to result in a dissolved imidazole-protected L-histidine N-carboxyanhydride, and then reacting the dissolved imidazole-protected L-histidine N-carboxyanhydride with thionyl chloride.
Claim 31
Dependent Claim
19 words
25 . The method of claim 19 wherein the poly(L-histidine) has a molecular weight of at least about 5,000.
Claim 32
Dependent Claim
109 words
26 . A method of making a poly(L-histidine)-poly(ethylene glycol) block copolymer comprising: (a) reacting monocarboxylic acid-poly(ethylene glycol), comprising a carboxylic acid group, with an activating reagent to result in an activated monocarboxylic acid-poly(ethylene glycol) wherein the carboxylic acid group is activated; (b) reacting poly(N im -dinitrophenyl-L-histidine), comprising a terminal α-amino group, with the activated monocarboxylic acid-poly(ethylene glycol) such that an amide bond is formed between the terminal α-amino group of poly(N im -dinitrophenyl-L-histidine) and the carboxylic group of activated monocarboxylic acid-poly(ethylene glycol), resulting in a poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer; and (c) deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer to result in the poly(L-histidine)-poly(ethylene glycol) block copolymer.
Claim 33
Dependent Claim
109 words
26 . A method of making a poly(L-histidine)-poly(ethylene glycol) block copolymer comprising: (a) reacting monocarboxylic acid-poly(ethylene glycol), comprising a carboxylic acid group, with an activating reagent to result in an activated monocarboxylic acid-poly(ethylene glycol) wherein the carboxylic acid group is activated; (b) reacting poly(N im -dinitrophenyl-L-histidine), comprising a terminal α-amino group, with the activated monocarboxylic acid-poly(ethylene glycol) such that an amide bond is formed between the terminal α-amino group of poly(N im -dinitrophenyl-L-histidine) and the carboxylic group of activated monocarboxylic acid-poly(ethylene glycol), resulting in a poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer; and (c) deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer to result in the poly(L-histidine)-poly(ethylene glycol) block copolymer.
Claim 34
Dependent Claim
22 words
27 . The method of claim 26 wherein the activating reagent comprises N-hydroxysuccinimide, and the activated monocarboxylic acid-poly(ethylene glycol) comprises N-hydroxysuccinimide-poly(ethylene glycol).
Claim 35
Dependent Claim
29 words
28 . The method of claim 26 wherein deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer comprises reacting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer with a thiolysis reagent.
Claim 36
Dependent Claim
13 words
29 . The method of claim 28 wherein the thiolysis reagent comprises 2-mercaptoethanol.
Claim 37
Dependent Claim
26 words
30 . The method of claim 26 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 38
Dependent Claim
27 words
31 . The method of claim 30 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 39
Dependent Claim
27 words
32 . The method of claim 26 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 40
Dependent Claim
95 words
33 . The method of claim 26 wherein the poly(N im -dinitrophenyl-L-histidine) is made by: reacting L-histidine with benzyl chloroformate, resulting in N α -carbobenzoxy-L-histidine; reacting the N α -carbobenzoxy-L-histidine with 2,4-dinitrofluorobenzene, resulting in N α -carbobenzoxy-N im -dinitrophenyl-L-histidine; reacting the N α -carbobenzoxy-N im -dinitrophenyl-L-histidine with thionyl chloride, resulting in an N im -dinitrophenyl-L-histidine N-carboxyanhydride; and converting the N im -dinitrophenyl-L-histidine N-carboxyanhydride to N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride and then polymerizing the N im -dinitrophenyl-L-histidine N-carboxyanhydride hydrochloride by ring-opening polymerization in the presence of n-hexylamine or isopropylamine to result in the poly(N im -dinitrophenyl-L-histidine).
Claim 41
Dependent Claim
105 words
34 . A method of making poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprising: (a) activating folic acid, which comprises a carboxyl group, to result in activated folic acid wherein the carboxyl group is activated; (b) reacting poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer, comprising a terminal hydroxyl group, with the activated folic acid such that an ester bond is formed between the terminal hydroxyl group of the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer and the carboxyl group of the activated folic acid, resulting in poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate; and (c) deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate to result in the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate.
Claim 42
Dependent Claim
105 words
34 . A method of making poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprising: (a) activating folic acid, which comprises a carboxyl group, to result in activated folic acid wherein the carboxyl group is activated; (b) reacting poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer, comprising a terminal hydroxyl group, with the activated folic acid such that an ester bond is formed between the terminal hydroxyl group of the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer and the carboxyl group of the activated folic acid, resulting in poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate; and (c) deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate to result in the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate.
Claim 43
Dependent Claim
15 words
35 . The method of claim 34 wherein the carboxyl group is activated with N,N′-dicyclohexylcarbodiimide.
Claim 44
Dependent Claim
30 words
36 . The method of claim 34 wherein the deprotecting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate comprises reacting the poly(N im -dinitrophenyl-L-histidine)-poly(ethylene glycol) block copolymer-folate with a thiolysis reagent.
Claim 45
Dependent Claim
13 words
37 . The method of claim 36 wherein the thiolysis reagent comprises 2-mercaptoethanol.
Claim 46
Dependent Claim
26 words
38 . The method of claim 34 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 47
Dependent Claim
27 words
39 . The method of claim 38 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 48
Dependent Claim
27 words
40 . The method of claim 34 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 49
Dependent Claim
11 words
41 . A composition of matter comprising N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 50
Dependent Claim
11 words
41 . A composition of matter comprising N im -dinitrophenyl-L-histidine N-carboxyanhydride.
Claim 51
Dependent Claim
10 words
42 . A composition of matter comprising poly(N im -dinitrophenyl-L-histidine).
Claim 52
Dependent Claim
10 words
42 . A composition of matter comprising poly(N im -dinitrophenyl-L-histidine).
Claim 53
Dependent Claim
23 words
43 . The composition of matter of claim 42 wherein the poly(N im -dinitrophenyl-L-histidine) has a molecular weight of at least about 5,000.
Claim 54
Dependent Claim
10 words
44 . A composition of matter comprising N α -carbobenzoxy-L-histidine.
Claim 55
Dependent Claim
10 words
44 . A composition of matter comprising N α -carbobenzoxy-L-histidine.
Claim 56
Dependent Claim
12 words
45 . A composition of matter comprising N α -carbobenzoxy-N im -dinitrophenyl-L-histidine.
Claim 57
Dependent Claim
12 words
45 . A composition of matter comprising N α -carbobenzoxy-N im -dinitrophenyl-L-histidine.
Claim 58
Dependent Claim
11 words
46 . A composition of matter comprising poly(L-histidine)-poly(ethylene glycol) block copolymer.
Claim 59
Dependent Claim
11 words
46 . A composition of matter comprising poly(L-histidine)-poly(ethylene glycol) block copolymer.
Claim 60
Dependent Claim
28 words
47 . The composition of matter of claim 46 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 61
Dependent Claim
29 words
48 . The composition of matter of claim 47 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 62
Dependent Claim
29 words
49 . The composition of matter of claim 46 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 63
Dependent Claim
11 words
50 . A composition of matter comprising poly(L-histidine)-poly(ethylene glycol) block copolymer-folate.
Claim 64
Dependent Claim
11 words
50 . A composition of matter comprising poly(L-histidine)-poly(ethylene glycol) block copolymer-folate.
Claim 65
Dependent Claim
28 words
51 . The composition of matter of claim 50 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 66
Dependent Claim
29 words
52 . The composition of matter of claim 51 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 67
Dependent Claim
29 words
53 . The composition of matter of claim 50 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 68
Dependent Claim
17 words
54 . A composition comprising mixed micelles comprising poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 69
Dependent Claim
17 words
54 . A composition comprising mixed micelles comprising poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 70
Dependent Claim
26 words
55 . The composition of claim 54 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 71
Dependent Claim
27 words
56 . The composition of claim 55 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 72
Dependent Claim
27 words
57 . The composition of claim 54 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 73
Dependent Claim
32 words
58 . The composition of claim 54 wherein the mixed micelles comprise a hydrophobic interior portion and wherein the mixed micelles further comprise a hydrophobic drug associated with the hydrophobic interior portion.
Claim 74
Dependent Claim
15 words
59 . The composition of claim 58 wherein the hydrophobic drug comprises an anticancer drug.
Claim 75
Dependent Claim
13 words
60 . The composition of claim 59 wherein the anticancer drug comprises adriamycin.
Claim 76
Dependent Claim
31 words
61 . The composition of claim 54 wherein the mixed micelles comprise about 60-90% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer and about 10-40% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 77
Dependent Claim
31 words
62 . The composition of claim 61 wherein the mixed micelles comprise about 75% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer and about 25% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 78
Dependent Claim
17 words
63 . A composition comprising mixed micelles comprising poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 79
Dependent Claim
17 words
63 . A composition comprising mixed micelles comprising poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 80
Dependent Claim
26 words
64 . The composition of claim 63 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(L-histidine) portion having a molecular weight of at least about 5,000.
Claim 81
Dependent Claim
27 words
65 . The composition of claim 64 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 82
Dependent Claim
27 words
66 . The composition of claim 63 wherein the poly(L-histidine)-poly(ethylene glycol) block copolymer-folate comprises a poly(ethylene glycol) portion having a molecular weight of at least about 2,000.
Claim 83
Dependent Claim
32 words
67 . The composition of claim 63 wherein the mixed micelles comprise a hydrophobic interior portion and wherein the mixed micelles further comprise a hydrophobic drug associated with the hydrophobic interior portion.
Claim 84
Dependent Claim
15 words
68 . The composition of claim 67 wherein the hydrophobic drug comprises an anticancer drug.
Claim 85
Dependent Claim
13 words
69 . The composition of claim 68 wherein the anticancer drug comprises adriamycin.
Claim 86
Dependent Claim
31 words
70 . The composition of claim 63 wherein the mixed micelles comprise about 60-90% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer and about 10-40% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 87
Dependent Claim
31 words
71 . The composition of claim 70 wherein the mixed micelles comprise about 75% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer and about 25% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 88
Dependent Claim
74 words
72 . A method for treating an animal with a drug comprising: (a) mixing the drug with a mixed micelle composition comprising (i) poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer or (ii) poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer, to result in drug-loaded mixed micelle composition; and (b) administering the drug-loaded mixed micelle composition to the animal such that the drug-loaded mixed micelle composition is systemically circulated in the animal.
Claim 89
Dependent Claim
74 words
72 . A method for treating an animal with a drug comprising: (a) mixing the drug with a mixed micelle composition comprising (i) poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer or (ii) poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer, to result in drug-loaded mixed micelle composition; and (b) administering the drug-loaded mixed micelle composition to the animal such that the drug-loaded mixed micelle composition is systemically circulated in the animal.
Claim 90
Dependent Claim
12 words
73 . The method of claim 72 wherein the drug is hydrophobic.
Claim 91
Dependent Claim
14 words
74 . The method of claim 72 wherein the drug is an anticancer drug.
Claim 92
Dependent Claim
12 words
75 . The method of claim 72 wherein the drug comprises adriamycin.
Claim 93
Dependent Claim
37 words
76 . The method of claim 72 wherein the mixed micelle composition comprises about 60-90% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer or poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and about 10-40% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 94
Dependent Claim
58 words
77 . A method for treating multidrug resistance in an animal comprising administering into the systemic circulation of the animal a drug-loaded mixed micelle composition comprising a mixture of a hydrophobic anticancer drug and mixed micelles comprising (i) poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer or (ii) poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 95
Dependent Claim
58 words
77 . A method for treating multidrug resistance in an animal comprising administering into the systemic circulation of the animal a drug-loaded mixed micelle composition comprising a mixture of a hydrophobic anticancer drug and mixed micelles comprising (i) poly(L-histidine)-poly(ethylene glycol) block copolymer and poly(L-lactic acid)-poly(ethylene glycol) copolymer or (ii) poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and poly(L-lactic acid)-poly(ethylene glycol) copolymer.
Claim 96
Dependent Claim
14 words
78 . The method of claim 77 wherein the hydrophobic anticancer drug comprises adriamycin.
Claim 97
Dependent Claim
36 words
79 . The method of claim 79 wherein the mixed micelles comprise about 60-90% by weight of poly(L-histidine)-poly(ethylene glycol) block copolymer or poly(L-histidine)-poly(ethylene glycol) block copolymer-folate and about 10-40% by weight of poly(L-lactic acid)-poly(ethylene glycol) copolymer.
References Cited (Backward Citations)
US5849839A
Cited
US20030072794A1
Cited
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