Aptamer Conjugates for Targeting of Therapeutic and/or Diagnostic Nanocarriers
The present invention provides targeted delivery compositions and their methods of use in treating and diagnosing a disease state in a subject.
1 . A targeted delivery composition, comprising:
(a) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and
(b) a conjugate having the formula:
A-[(EG)(P)] n -T;
wherein,
A is an attachment component for attaching said conjugate to said nanocarrier;
[(EG)(P)] n is a linking group, wherein the subscript n is an integer from 1 to about 40; and
each EG is independently selected from a group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and octaethylene glycol;
P is independently selected from a group consisting of phosphate and thiophosphate; and,
T is a targeting agent.
2 . The targeted delivery composition of claim 1 , wherein said nanocarrier is selected from the group consisting of a liposome, a micelle, a lipoprotein, a lipid-coated bubble, a block copolymer micelle, a polymersome, a noisome, an iron oxide particle, a gold particle, a silica particle, a dendrimer, and a quantum dot.
3 . The targeted delivery composition of claim 1 , wherein said nanocarrier comprises a stealth agent.
4 . The targeted delivery composition of claim 3 , wherein said stealth agent is poly(ethylene glycol).
5 . The targeted delivery composition of claim 1 , wherein said therapeutic or diagnostic agent is embedded in, encapsulated in, or tethered to said nanocarrier.
6 . The targeted delivery composition of claim 5 , wherein said nanocarrier is a liposome.
7 . The targeted delivery composition of claim 1 , wherein said nanocarrier is a liposome selected from the group consisting of SUVs, LUVs and MLVs.
8 . The targeted delivery composition of claim 1 , wherein said nanocarrier comprises a therapeutic agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane.
9 . The targeted delivery composition of claim 1 , wherein said diagnostic agent is a radioactive agent, a fluorescent agent, or a contrast agent.
10 . The targeted delivery composition of claim 1 , wherein said diagnostic agent is a radioactive agent selected from the group consisting of 111 In-DTPA, 99m Tc(CO) 3 -DTPA, and 99m Tc(CO) 3 -ENPy2.
11 . The targeted delivery composition of claim 1 , wherein said diagnostic agent is a fluorescent agent.
12 . The targeted delivery composition of claim 1 , wherein said diagnostic agent is a MR agent or a X-ray contrast agent.
13 . The targeted delivery composition of claim 1 , wherein said attachment component comprises a functional group for covalent attachment to said nanocarrier.
14 . The targeted delivery composition of claim 1 , wherein said attachment component is a lipid.
15 . The targeted delivery composition of claim 14 , wherein said lipid is a phospholipid, glycolipid, sphingolipid, or cholesterol.
16 . The targeted delivery composition of claim 1 , wherein the A portion of said conjugate is present in a lipid bilayer portion of said nanocarrier.
17 . The targeted delivery composition of claim 16 , wherein said nanocarrier is a liposome.
18 . The targeted delivery composition of claim 1 , wherein n is a number sufficient to allow said targeting agent to extend beyond the surface of said nanocarrier.
19 . The targeted delivery composition of claim 1 , wherein n is between 1 and 20.
20 . The targeted delivery composition of claim 1 , wherein n from 4 to 12.
21 . The targeted delivery composition of claim 1 , wherein n is 4, 5, 6, 7, 8, 9, 10, 11 or 12.
22 . The targeted delivery composition of claim 1 , wherein T is an aptamer.
23 . The targeted delivery composition of claim 1 , wherein T is an aptamer that targets a site present on a receptor selected from the group consisting of MUC-1, EGFR, FOL1R, Claudin 4, MUC-4, CXCR4, CCR7, somatostatin receptor 4, Erb-B2 (erythroblastic leukaemia oncogene homologue 2) receptor, CD44 receptor, VEGF receptor-2 kinase, and nucleolin.
24 . A conjugate having the formula:
A-[(EG)(P)] n -T;
wherein,
A is an attachment component;
[(EG)(P)] n is a linking group, wherein the subscript n is an integer from 1 to about 40; and
each EG is independently selected from a group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and octaethylene glycol;
P is independently selected from a group consisting of phosphate and thiophosphate; and,
T is a targeting agent.
25 . The conjugate of claim 24 , wherein said attachment component comprises a functional group for covalent attachment to a nanocarrier.
26 . The conjugate of claim 24 , wherein said attachment component is a lipid.
27 . The conjugate of claim 26 , wherein said lipid is selected from the group consisting of a phospholipid, glycolipid, sphingolipid, and cholesterol.
28 . The conjugate of claim 24 , wherein n is between 1 and 20.
29 . The targeted delivery composition of claim 24 , wherein n is from 4 to 12.
30 . The targeted delivery composition of claim 24 , wherein n is 4, 5, 6, 7, 8, 9, 10, 11, or 12.
31 . The conjugate of claim 24 , wherein n is 8.
32 . The conjugate of claim 24 , wherein T is an aptamer.
33 . A conjugate having the formula:
(DT)-[(EG)(P)] m -T;
wherein,
DT is a diagnostic agent, a therapeutic agent, or a combination thereof;
[(EG)(P)] m is a linking group, wherein the subscript m is an integer from 1 to about 40; and
each EG is independently selected from a group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and octaethylene glycol;
P is independently selected from a group consisting of phosphate and thiophosphate; and,
T is a targeting agent.
34 . The conjugate of claim 33 , wherein said diagnostic agent is a radioactive agent, a fluorescent agent, or a contrast agent.
35 . The conjugate of claim 33 , wherein said diagnostic agent is a radioactive agent is selected from the group consisting of 111 In-DTPA, 99m Tc(CO) 3 -DTPA, and 99m Tc(CO) 3 -ENPy2.
36 . The conjugate of claim 34 , wherein said diagnostic agent is a fluorescent agent.
37 . The targeted delivery composition of claim 33 , wherein said diagnostic agent is a MR agent or a X-ray contrast agent.
38 . The conjugate of claim 33 , wherein said therapeutic agent is an anticancer agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane.
39 . The conjugate of claim 33 , wherein m is between 1 and 20.
40 . The conjugate of claim 33 , wherein T is an aptamer.
41 . The targeted delivery composition of claim 33 , wherein T is an aptamer that targets a site present on a receptor selected from the group consisting of MUC-1, EGFR, FOL1R, Claudin 4, MUC-4, CXCR4, CCR7, somatostatin receptor 4, Erb-B2 (erythroblastic leukaemia oncogene homologue 2) receptor, CD44 receptor, VEGF receptor-2 kinase, and nucleolin.
42 . A method of preparing a targeted delivery composition, comprising attaching a nanocarrier including a therapeutic or diagnostic agent to a conjugate having the formula:
A-[(EG)(P)] n -T;
wherein,
A is an attachment component for attaching said conjugate to said nanocarrier;
[(EG)(P)] n is a linking group, wherein the subscript n is an integer from 1 to about 40; and
each EG is independently selected from a group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and octaethylene glycol;
P is independently selected from a group consisting of phosphate and thiophosphate; and,
T is a targeting agent.
43 . The method of claim 42 , wherein said attachment component is a lipid.
44 . The method of claim 43 , wherein said lipid is a phospholipid, glycolipid, sphingolipid, cholesterol, or a cholesterol derivative.
45 . The method of claim 42 , wherein the A portion of said conjugate is present in a lipid bilayer portion of said nanocarrier.
46 . The method of claim 45 , wherein said nanocarrier is a liposome.
47 . The method of claim 42 , wherein n is between 1 and 20.
48 . The targeted delivery composition of claim 42 , wherein n is from 4 to 12.
49 . The targeted delivery composition of claim 42 , wherein n is 4, 5, 6, 7, 8, 9, 10, 11 or 12.
50 . The method of claim 42 , wherein T is an aptamer.
51 . A method for treating or diagnosing a cancerous condition in a subject, comprising administering to said subject a targeted delivery composition of claim 1 , wherein said therapeutic or diagnostic agent is sufficient to treat or diagnose said condition.
52 . The method of claim 51 , wherein T is an aptamer that targets a site present on a receptor selected from the group consisting of MUC-1, EGFR, Claudin 4, MUC-4, CCR7, somatostatin receptor 4, Erb-B2 (erythroblastic leukaemia oncogene homologue 2) receptor, CD44 receptor, VEGF receptor-2 kinase, and nucleolin.
53 . The method of claim 51 , wherein said nanocarrier has embedded in, encapsulated in, or tethered to an anticancer agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane.
54 . A method of determining the suitability of a subject for a targeted therapeutic treatment, comprising administering to said subject a targeted delivery composition of claim 1 , wherein said nanocarrier comprises a diagnostic agent, and imaging said subject to detect said diagnostic agent.
55 . A method for delivering a therapeutic agent to a subject, comprising administering to said subject a conjugate of claim 33 , wherein DT is a therapeutic agent.
56 . A method of determining the suitability of a subject for a targeted therapeutic treatment, comprising administering to said subject a conjugate of claim 33 , wherein DT is a diagnostic agent, and imaging said subject to detect said diagnostic agent.