Kidney-targeted drug delivery systems
A composition including an elastin-like polypeptide (ELP) coupled to a kidney targeting peptide and a therapeutic agent is provided.
1 . A pharmaceutical composition, comprising:
a therapeutically effective amount of elastin-like polypeptide (ELP) coupled to a therapeutic agent, the ELP including an amino acid sequence having between 5 and 320 repeats of the amino acid sequence GVPGX (SEQ ID NO: 1), wherein X in each repeat of the sequence GVPGX (SEQ ID NO: 1) is any amino acid except proline;
a pharmaceutically acceptable carrier;
a kidney targeting agent coupled to the ELP, wherein the kidney targeting agent comprises the amino acid sequence of SEQ ID NO: 5; and
a drug binding domain coupled to the ELP, wherein the drug binding domain is configured to bind to the therapeutic agent,
wherein the therapeutically effective amount of the ELP coupled to the therapeutic agent improves the deposition and retention of the therapeutic agent mostly in the renal cortex relative to a non-conjugated therapeutic, and wherein the pharmaceutical composition enhances the deposition and retention of the therapeutic agent in the kidney relative to the non-conjugated therapeutic.
2 . The pharmaceutical composition of claim 1 , wherein the therapeutic agent is selected from the group consisting of VEGF, HGF, b-FGF, TGF-β, and HIF.
3 . The pharmaceutical composition of claim 1 , wherein the therapeutic agent is VEGF.
4 . The pharmaceutical composition of claim 3 , wherein the VEGF is selected from the group consisting of VEGF 121 , VEGF 189 , VEGF 206 , VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PlGF.
5 . The pharmaceutical composition of claim 1 , wherein the X in the amino acid sequence GVPGX (SEQ ID NO: 1) is Val, Ala, and Gly in a ratio range of 0-1:0-8:0-8.
6 . The pharmaceutical composition of claim 5 , wherein X is selected from Val, Ala, and Gly in a 1:8:7 ratio or 1:4:3 ratio.
7 . The pharmaceutical composition of claim 1 , wherein the ELP comprises the amino acid sequence of SEQ ID NO: 2, 3, or 4.
8 . The pharmaceutical composition of claim 1 , wherein the drug binding domain comprises the amino acid sequence of SEQ ID NO: 9, 10, 11, 12, or combination thereof.
9 . A method of treating kidney disease in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1 .
10 . The method of claim 9 , wherein the therapeutic agent is selected from the group consisting of VEGF, HGF, b-FGF, TGF-β, and HIF.
11 . The method of claim 9 , wherein the X in the amino acid sequence GVPGX (SEQ ID NO: 1) is Val, Ala, and Gly in a ratio range of 0-1:0-8:0-8.
12 . A pharmaceutical composition, comprising:
a therapeutically effective amount of elastin-like polypeptide (ELP) coupled to a therapeutic agent, the ELP including an amino acid sequence having between 5 and 320 repeats of the amino acid sequence GVPGX (SEQ ID NO: 1), wherein X in the sequence GVPGX (SEQ ID NO: 1) is any amino acid except proline;
a pharmaceutically acceptable carrier; and
a kidney targeting agent coupled to the ELP, wherein the kidney targeting agent comprises an amino acid sequence of SEQ ID NO: 5;
wherein the therapeutically effective amount of the ELP coupled to the therapeutic agent improves the deposition and retention of the therapeutic agent mostly in the renal cortex relative to a non-conjugated therapeutic, and wherein the pharmaceutical composition enhances the deposition and retention of the therapeutic agent in the kidney relative to the non-conjugated therapeutic.
13 . A pharmaceutical composition, comprising:
a therapeutically effective amount of elastin-like polypeptide (ELP) coupled to a therapeutic agent, the ELP including an amino acid sequence having between 5 and 320 repeats of the amino acid sequence GVPGX (SEQ ID NO: 1), wherein X in each repeat of the sequence GVPGX (SEQ ID NO: 1) is any amino acid except proline, and wherein the ELP comprises the amino acid sequence of SEQ ID NO: 2, 3, or 4;
a pharmaceutically acceptable carrier; and
a kidney targeting agent coupled to the ELP, wherein the kidney targeting agent comprises an amino acid sequence of SEQ ID NO: 5;
wherein the therapeutically effective amount of the ELP coupled to the therapeutic agent improves the deposition and retention of the therapeutic agent mostly in the renal cortex relative to a non-conjugated therapeutic, and wherein the pharmaceutical composition enhances the deposition and retention of the therapeutic agent in the kidney relative to the non-conjugated therapeutic.
14 . A pharmaceutical composition, comprising:
a therapeutically effective amount of elastin-like polypeptide (ELP) coupled to a therapeutic agent, the ELP including an amino acid sequence having between 5 and 320 repeats of the amino acid sequence GVPGX (SEQ ID NO: 1), wherein X in each repeat of the sequence GVPGX (SEQ ID NO: 1) is any amino acid except proline;
a pharmaceutically acceptable carrier;
a kidney targeting agent coupled to the ELP, wherein the kidney targeting agent comprises an amino acid sequence of SEQ ID NO: 5; and
a drug binding domain coupled to the ELP, wherein the drug binding domain is configured to bind to the therapeutic agent and comprises the amino acid sequence of SEQ ID NO: 9, 10, 11, 12, or combination thereof, and
wherein the therapeutically effective amount of the ELP coupled to the therapeutic agent improves the deposition and retention of the therapeutic agent mostly in the renal cortex relative to a non-conjugated therapeutic, and wherein the pharmaceutical composition enhances the deposition and retention of the therapeutic agent in the kidney relative to the non-conjugated therapeutic.
15 . The pharmaceutical composition of claim 12 , wherein the therapeutic agent is selected from the group consisting of VEGF, HGF, b-FGF, TGF-β, and HIF.
16 . The pharmaceutical composition of claim 15 , wherein the therapeutic agent is VEGF.
17 . The pharmaceutical composition of claim 16 , wherein the VEGF is selected from the group consisting of VEGF 121 , VEGF 189 , VEGF 206 , VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PlGF.
18 . The pharmaceutical composition of claim 12 , wherein the X in the amino acid sequence GVPGX (SEQ ID NO: 1) is Val, Ala, and Gly in a ratio range of 0-1:0-8:0-8.
19 . The pharmaceutical composition of claim 18 , wherein X is selected from Val, Ala, and Gly in a 1:8:7 ratio or 1:4:3 ratio.
20 . The pharmaceutical composition of claim 12 , wherein the ELP comprises the amino acid sequence of SEQ ID NO: 2, 3, or 4.