Histidine copolymer and methods for using same
First Claim
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1. A pharmaceutical agent delivery composition comprising:
- (a) a transport polymer comprising a peptide, characterized as having at least 10 amino acid residues, and wherein at least 10% of said amino acid residues are histidine, and wherein at least 10% of said amino acid residues are selected from the group consisting of non-histidine amino acids with a side-group that carries a positive charge at physiological pH, and wherein the molecular structure of said peptide is selected from the group consisting of;
linear, with the proviso that said peptide does not comprise a hexa-peptide having the sequence His-His-His-His-His-His, unless at least 10% of the remaining amino acid residues of said peptide are histidine; and
branched, with a backbone peptide of 1 or more amino acid residues and at least one peptide branch of 1 or more amino acid residues covalently attached to a side-group of an amino acid residue of said backbone peptide, with the proviso that each peptide branch can consist of a single histidine residue only if the backbone peptide does not consist solely of lysine residues;
with the proviso that said transport polymer does not consist of;
a random histidine copolymer;
ora block copolymer of histidine and a non-histidine amino acid with a side-group that carries a positive charge at physiological pH;
(b) a pharmaceutical agent associated with said transport polymer; and
(c) optionally, at least one intracellular delivery component associated with said transport polymer and/or said pharmaceutical agent.
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Abstract
The invention provides a pharmaceutical agent delivery composition comprising: (i) a transport polymer comprising a linear or branched peptide having from about 10 to about 300 amino acid residues, having from about 5 to 100% histidine residues, and optionally having from 0 to about 95% non-histidine amino acid residues; (ii) at least one pharmaceutical agent; and optionally (iii) one or more intracellular delivery components in association with the transport polymer. The invention also provides methods for using such composition to deliver the pharmaceutical agent to the interior of cells.
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Citations
51 Claims
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1. A pharmaceutical agent delivery composition comprising:
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(a) a transport polymer comprising a peptide, characterized as having at least 10 amino acid residues, and wherein at least 10% of said amino acid residues are histidine, and wherein at least 10% of said amino acid residues are selected from the group consisting of non-histidine amino acids with a side-group that carries a positive charge at physiological pH, and wherein the molecular structure of said peptide is selected from the group consisting of; linear, with the proviso that said peptide does not comprise a hexa-peptide having the sequence His-His-His-His-His-His, unless at least 10% of the remaining amino acid residues of said peptide are histidine; and branched, with a backbone peptide of 1 or more amino acid residues and at least one peptide branch of 1 or more amino acid residues covalently attached to a side-group of an amino acid residue of said backbone peptide, with the proviso that each peptide branch can consist of a single histidine residue only if the backbone peptide does not consist solely of lysine residues;
with the proviso that said transport polymer does not consist of;a random histidine copolymer;
ora block copolymer of histidine and a non-histidine amino acid with a side-group that carries a positive charge at physiological pH; (b) a pharmaceutical agent associated with said transport polymer; and (c) optionally, at least one intracellular delivery component associated with said transport polymer and/or said pharmaceutical agent. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
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29. A method for producing a pharmaceutical agent delivery composition comprising the steps of:
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a. providing a transport polymer comprising a peptide characterized as having at least 10 amino acid residues, and wherein at least 10% of said amino acid residues are histidine, and wherein at least 10% of said amino acid residues are selected from the group consisting of non-histidine amino acids with a side-group that carries a positive charge at physiological pH, and wherein the molecular structure of said peptide is selected from the group consisting of; linear, with the proviso that said peptide does not comprise a sequence His-His-His-His-His-His, unless at least 10% of the remaining amino acid residues of said peptide are histidine; and
branched, with a backbone peptide of 1 or more amino acid residues and at least one peptide branch of 1 or more amino acid residues covalently attached to a side-group of an amino acid residue of said backbone peptide, with the proviso that each peptide branch can consist of a single histidine residue only if the backbone peptide does not consist solely of lysine residues;with the proviso that said transport polymer does not consist of; a random histidine copolymer;
ora block copolymer of histidine and a non-histidine amino acid with a side-group that carries a positive charge at physiological pH; b. providing a pharmaceutical agent capable of associating with said transport polymer; c. combining said transport polymer with said pharmaceutical agent to form a polymer/pharmaceutical agent complex; and d. mixing said complex with an intracellular delivery component. - View Dependent Claims (30)
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31. A pharmaceutical agent delivery composition comprising:
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(a) a pharmaceutical agent; (b) a transport polymer in association with the pharmaceutical agent, the transport polymer comprising a peptide characterized as having at least 10% of the amino acid residues are histidine and at least 10% of the amino acid residues are non-histidine, wherein the non-histidine residues are selected so as to tailor the transport polymer to the pharmaceutical agent and a method of association between the pharmaceutical agent and the transport polymer, and wherein the molecular structure of the peptide is selected from the group consisting of; linear and having at least 13 amino acids, with the proviso that; a. the entire sequence of said peptide cannot be described by the formula;
(XHHX)n, wherein H is histidine, X is a hydrophobic amino acid, and n is an integer greater than or equal to 4;b. the entire sequence of said peptide cannot be described by the formula;
(XHXH)n, wherein H is histidine, X is a hydrophobic amino acid, and n is an integer greater than or equal to 4; andc. said peptide does not comprise a hexa-peptide having the sequence His-His-His-His-His-His, unless at least 10% of the remaining amino acid residues of said peptide are histidine; and branched and having at least 40 amino acids, with a backbone of 1 or more amino acid residues and at least one branch of 1 or more amino acid residues covalently attached to a side-group of an amino acid residue of said backbone, with the proviso that each branch can consist of a single histidine residue only if the backbone does not consist solely of lysine residues;
with the proviso that said transport polymer does not consist of;a random histidine copolymer;
ora block copolymer of histidine and a non-histidine amino acid with a side-group that carries a positive charge at physiological pH; and (c) optionally, at least one intracellular delivery component associated with said transport polymer and/or said pharmaceutical agent. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)
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Specification