X-ray guided drug delivery

• US 7,049,140 B1
• Filed: 04/28/2000
• Issued: 05/23/2006
• Est. Priority Date: 04/29/1999
• Status: Active Grant

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Hallahan, Dennis E.
• Primary Examiner(s): KETTER, JAMES S
• Application Number:
  US09/914,605
• Time in Patent Office: 2,216 Days
• Field of Search: 435/372, 514/44, 424/450
• US Class Current: 435/372
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61K 51/1203 in a form not provided for by groups A61K51/1206 - A61K51/1296, e.g. cells, cell fragments, viruses, virus capsides, ghosts, red blood cells, viral vectors

Abstract

A method of delivering an active agent to a target tissue, particularly neoplastic tissue, vascular anomaly or tumor tissue, in a vertebrate subject. The method includes the steps of exposing the target tissue to ionizing radiation; and administering a delivery vehicle to the vertebrate subject before, after, during, or combinations thereof, exposing the target tissue to the ionizing radiation. The delivery vehicle includes the active agent and delivers the agent to the target tissue. Representative delivery vehicles include platelets; leukocytes; proteins or peptides which bind activated platelets; antibodies which bind activated platelets; microspheres coated with proteins or peptides which bind activated platelets; liposomes conjugated to proteins or peptides, platelets, or leukocytes which bind activated platelets, or antibodies which bind activated platelets; and combinations thereof.

Claims

1. A delivery vehicle for use in targeted delivery of an active agent, the delivery vehicle comprising:

(i) a targeting agent that preferentially binds a radiation inducible target selected from the group consisting of ICAM-1, P-selectin, β

₃ Integrin, an activated platelet, and combinations thereof in a target tissue;

(ii) a pharmaceutically acceptable diluent or excipient; and

(iii) an active agent comprising a toxin, a radiosensitizing agent, or combinations thereof.

2. The delivery vehicle of claim 1, wherein the targeting agent is selected from the group consisting of a protein;

a peptide;

an antibody;

a genetic construct; and

combinations thereof.

3. The delivery vehicle of claim 1, comprises fibrinogen or a peptide fragment or analog thereof.

4. The delivery vehicle of claim 3, wherein the peptide fragment of fibrinogen is a gamma subunit peptide fragment of fibrinogen.

5. The delivery vehicle of claim 4, wherein the gamma subunit peptide fragment of fibrinogen comprises any of SEQ ID NOs:

1–

10, or comprises an analog or fragment of any of SEQ ID NOs;

1–

10.

7. The delivery vehicle of claim 1, wherein the delivery vehicle further comprises an imaging agent.

8. The delivery vehicle of claim 7, wherein the imaging agent is selected from the group consisting of a paramagnetic imaging agent, a radioactive imaging agent, and a fluorogenic imaging agent.

9. The delivery vehicle of claim 8, wherein the radioactive imaging agent is selected from the group consisting of gamma-emitters, positron-emitters and x-ray-emitters.

10. The delivery vehicle of claim 7, wherein the radioactive imaging agent is selected from the group consisting of ⁴³K, ⁵²Fe, ⁵⁷Co, ⁶⁷Cu, ⁶⁸Ga, ⁷⁷Ga, ⁸¹Br, Rb/^81M Kr, ^87MSr, ^99MTc, ¹¹¹In, ¹¹³In, ¹²³I, ¹²⁵I, ¹²⁷Cs, ¹²⁹Cs, ¹³¹I, ¹³²I, ¹⁹⁷Hg, ²⁰³Pb and ²⁰⁶Bi.

11. The delivery vehicle of claim 7, wherein the radioactive imaging agent is present in the delivery vehicle in an amount ranging from about 0.1 to about 100 millicuries.

12. The delivery vehicle of claim 11, wherein the radioactive imaging agent is present in the delivery vehicle in an amount ranging from about 1 to about 10 millicuries.

13. The delivery vehicle of claim 12, wherein the radioactive imaging agent is present in the delivery vehicle in an amount ranging from about 2 to about 5 millicuries.

14. The delivery vehicle of claim 13, wherein the radioactive imaging agent is present in the delivery vehicle in an amount ranging from about 1 to about 5 millicuries.

15. The delivery vehicle of claim 1, wherein the delivery vehicle further comprises a therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a radiotherapeutic agent, a and combinations thereof.

16. The delivery vehicle of claim 15, wherein the chemotherapeutic agent is selected from the group consisting of an anti-tumor drug, a cytokine, an anti-metabolite, an alkylating agent, a hormone, methotrexate, doxorubicin, daunorubicin, cytosine arabinoside, etoposide, 5–

4 fluorouracil, melphalan, chlorambucil, a nitrogen mustard, cyclophosphamide, cis-platinum, vindesine, vinca alkaloids, mitomycin, bleomycin, purothionin, macromomycin, 1,4-benzoquinone derivatives, trenimon, steroids, aminopterin, anthracyclines, demecolcine, etoposide, mithramycin, doxorubicin, daunomycin, vinblastine, neocarzinostatin, macromycin, α

-amanitin, and combinations thereof.

17. The delivery vehicle of claim 1, wherein the toxin is selected from the group consisting of Russell'"'"'s Viper Venom, activated Factor IX, activated Factor X, thrombin, phospholipase C, cobra venom factor, ricin, ricin A chain, Pseudomonas exotoxin, diphtheria toxin, bovine pancreatic ribonuclease, pokeweed antiviral protein, abrin, abrin A chain, gelonin, saporin, modeccin, viscumin, volkensin and combinations thereof.

18. The delivery vehicle of claim 15, wherein the radiotherapeutic agent is selected from the group consisting of ⁴⁷Sc, ⁶⁷Cu, ₉₀Y, ₁₀₉Pd, ¹²³I, ¹²⁵I, ¹³¹I, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁹⁹Au, ²¹¹At, ²¹²Pb, ²¹²Bi, ³²P, ³³P, ⁷¹Ge, ⁷⁷As, ¹⁰³Pb, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹⁹Sb, ¹²¹Sn, ¹³¹Cs, ¹⁴³Pr, ¹⁶¹Tb, ¹⁷⁷Lu, ¹⁹¹Os, ^193MPt, and ¹⁹⁷Hg.

19. The delivery vehicle of claim 1, wherein the radiosensitizing agent is selected from the group consisting of an anti-angiogenic agent;

a DNA protein kinase inhibitor;

a tyrosine kinase inhibitor;

a DNA repair enzyme inhibitor;

nitroimidazole;

metronidazole;

misonidazole;

a genetic construct comprising an enhancer-promoter region which is responsive to radiation, and at least one structural gene whose expression is controlled by the enhancer-promoter;

boron-neutron capture reagents; and

combinations thereof.

20. The delivery vehicle of claim 19, wherein the genetic construct comprises a viral vector.

21. The delivery vehicle of claim 15, wherein the therapeutic agent is a chemotherapeutic agent, and the delivery vehicle comprising the chemotherapeutic agent is administered in an amount ranging from about 10 to about 1000 mg.

22. The delivery vehicle of claim 21, wherein the delivery vehicle comprising the chemotherapeutic agent is administered in an amount ranging from about 50 to about 500 mg.

23. The delivery vehicle of claim 22, wherein the delivery vehicle comprising the chemotherapeutic agent is administered in an amount ranging from about 100 to about 250 mg.

24. The delivery vehicle of claim 1, wherein the active agent is a toxin, and the delivery vehicle comprising the toxin is administered in an amount ranging from about 1 to about 500 μ

g.

25. The delivery vehicle of claim 24, wherein the delivery vehicle comprising the toxin is administered in an amount ranging from about 10 to about 100 μ

g.

26. The delivery vehicle of claim 25, wherein the delivery vehicle comprising the toxin is administered in an amount ranging from about 20 to 50 μ

g.

27. The delivery vehicle of claim 15, wherein the therapeutic agent is a radiotherapeutic agent, and the delivery vehicle comprising the radiotherapeutic agent is administered in an amount ranging from about 0.5 to about 100 mg.

28. The delivery vehicle of claim 27, wherein the delivery vehicle comprising the radiotherapeutic agent is administered in an amount ranging from about 1 to about 50 mg.

29. The delivery vehicle of claim 28, wherein the delivery vehicle comprising the radiotherapeutic agent is administered In an amount ranging from about 5 to about 10 mg.

30. The delivery vehicle of claim 1, further comprising a carrier.

31. The delivery vehicle of claim 30, wherein the carrier and the targeting agent are the same.

32. The delivery vehicle of claim 30, wherein the carrier is selected from the group consisting of a platelet;

a leukocyte;

a protein;

a peptide;

an antibody;

a microsphere;

a liposome;

a genetic construct; and

combinations thereof.

33. A The delivery vehicle of claim 32, wherein the carrier comprises

a liposome.

34. The delivery vehicle of claim 33, wherein the liposome comprises a lipid selected from the group consisting of phosphatidylcholines (lecithins) (PC), phosphatidylethanolamines (PE), lysolecithins, lysophosphatidylethanolamines, phosphatidylserines (PS), phosphatidylglycerols (PG), phosphatidylinositol (PI), sphingomyelins, cardiolipin, phosphatidic acids (PA), fatty acids, gangliosides, glucolipids, glycolipids, mono-, di or triglycerides, ceramides, cerebrosides and combinations thereof.

35. The delivery vehicle of claim 34, wherein the liposome comprises a cationic lipid selected from the group consisting of 1,2-dioleyloxy-3-(trimethylamino) propane (DOTAP);

N-[1-(2,3, -ditetradecyloxy)propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE);

N-[1-(2,3,-dioleyloxy)propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE);

N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA);

3β

[N-(N′

,N′

-dimethylaminoethane)carbamoly] cholesterol (DC-Choi); and

dimethyldioctadecylammonium (DDAB);

dioleoylphosphatidyl ethanolamine (DOPE), cholesterol-containing DOPC, and combinations thereof.

36. The delivery vehicle of claim 33, wherein the liposome comprises a hydrophilic polymer coating and the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and combinations thereof.

37. The delivery vehicle of claim 33, wherein the targeting agent preferentially binds an activated platelet.

38. The delivery vehicle of claim 33, wherein the targeting agent is selected from the group consisting of a protein;

a peptide;

an antibody;

a genetic construct; and

combinations thereof.

39. The delivery vehicle of claim 33

wherein the targeting agent is fibrinogen or a peptide fragment or analog thereof.

40. The delivery vehicle of claim 39, wherein the peptide fragment of fibrinogen is a gamma subunit peptide fragment of fibrinogen.

41. The delivery vehicle of claim 40, wherein the gamma subunit peptide fragment of fibrinogen comprises any of SEQ ID NOs:

1–

10, or comprises an analog or fragment of any of SEQ ID NOs;

1–

10.

43. The delivery vehicle of claim 1, wherein the radiation inducible target is a cell adhesion molecule.

6. A delivery vehicle for use in targeted delivery of an active agent, the delivery vehicle comprising a targeting agent and a pharmaceutically acceptable diluent or excipient, wherein the targeting agent comprises a gamma subunit peptide fragment of fibrinogen and preferentially binds a radiation inducible target in a target tissue, wherein the gamma subunit peptide fragment of fibrinogen comprises HHLGGAKQAGDV (SEQ ID NO:

1).

42. A delivery vehicle for use in targeted delivery of an active agent, the delivery vehicle comprising a targeting agent and a pharmaceutically acceptable diluent or excipient, wherein the targeting agent preferentially binds a radiation inducible target selected from the group consisting of ICAM-1, P-selectin, β

₃ integrin, and combinations thereof, wherein the targeting agent is a gamma subunit peptide fragment of fibrinogen that comprises HHLGGAKQAGDV (SEQ ID NO;

1).

44. The delivery vehicle of 2, wherein the targeting agent is an antibody or derivative thereof.

45. The delivery vehicle of claim 44, wherein the antibody or derivative thereof preferentially binds a radiation inducible target selected from the group consisting of ICAM-1, P-selectin, β

₃ integrin, and combinations thereof.

46. A delivery vehicle for use in targeted delivery of an active agent, the delivery vehicle comprising:

(a) a liposome carrier;

(b) a targeting agent that preferentially binds a radiation inducible target; and

(c) a pharmaceutically acceptable diluent or excipient,

wherein the targeting agent is an antibody or derivative thereof selected from the group consisting of an intact immunoglobulin molecule, a single chain immunoglobulin molecule, an Fab fragment, an Fab′

fragment, an F(ab′

)₂ fragment, an F(v) fragment, a single-chain Fv antibody (scFv), a humanized antibody, and a monoclonal antibody.

47. A delivery vehicle, for use in targeted delivery of an active agent, the delivery vehicle comprising a targeting agent and a pharmaceutically acceptable diluent or excipient, wherein the targeting agent preferentially binds a radiation inducible target selected from the group consisting of ICAM-1, P-selectin, β

₃ integrin, and combinations thereof wherein the active agent comprises a genetic construct comprising a viral vector, an enhancer promoter region which is responsive to radiation, and at least one structural gene whose expression is controlled by the enhancer promoter.