Methods for tumor treatment using dendrimer conjugates

• US 20060204443A1
• Filed: 03/09/2006
• Published: 09/14/2006
• Est. Priority Date: 03/11/2005
• Status: Abandoned Application

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Choyke, Peter L., Kobayashi, Hisataka
• Application Number:
  US11/371,780
• Publication Number:
  US 20060204443A1
• Time in Patent Office: Days
• US Class Current: 424/9.320
• CPC Class Codes: A61K 41/009 Neutron capture therapy, e.g. using uranium or non-boron material
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61N 2005/109 Neutrons
• CPC Class Codes: A61N 2005/1098 Enhancing the effect of the particle by an injected agent or implanted device

Abstract

Methods are disclosed for treating a tumor. A dendrimer conjugate is administered to a subject having a tumor. The dendrimer of the dendrimer conjugate is a generation 5 DAB, generation 2 polylysine, or generation 6-8 PAMAM dendrimer. The dendrimer conjugate comprises an effective amount of an anti-tumor agent. The anti-tumor agent is selectively concentrated in the lymphatic system to treat metastatic disease. In certain examples, the anti-tumor agent is an activatable anti-tumor agent and is activated once the anti-tumor agent is selectively concentrated in the lymphatic system.

Claims

1. A method of treating a tumor in the lymphatic system, comprising:

administering to a subject who has been identified as having a tumor a dendrimer conjugate that selectively concentrates in the lymphatic system of the subject, wherein the dendrimer conjugate comprises a generation 5 DAB or generation 3-10 PAMAM dendrimer conjugated to an amount of an anti-tumor agent effective to treat the identified tumor, but the dendrimer conjugate does not include a tumor specific targeting agent; and

treating the tumor with the anti-tumor agent.

2. The method of claim 1, wherein the anti-tumor agent is a cytotoxic agent that acts on a tumor without requiring activation.

3. The method of claim 1, wherein the cytotoxic agent is an activatable cytotoxic agent, and the cytotoxic agent is activated by application of physical energy from outside the body.

4. The method of claim 3, wherein the activatable cytotoxic agent comprises an agent activatable by a neutron beam, and the agent is activated by selectively directing a neutron beam at the lymphatic system of the subject.

5. The method of claim 4, wherein the activatable cytotoxic agent further comprises an imaging agent that is activatable by the neutron beam to be a cytotoxic agent.

6. The method of claim 4, wherein the dendrimer conjugate further comprises an imaging agent, and selectively directing a neutron beam at the lymphatic system of the subject comprises imaging the dendrimer conjugate in the lymphatic system, and directing the neutron beam at the imaged dendrimer conjugate.

7. The method of claim 6, wherein imaging the dendrimer conjugate comprises determining whether a tumor is present in an imaged lymph node, and directing the neutron beam at the imaged lymph node if the tumor is detected in the lymph node.

8. The method of claim 6, wherein the dendrimer conjugate comprises a gadolinium contrast agent that also acts as an activatable cytotoxic agent.

9. The method of claim 1, further comprising identifying a subject as having a tumor.

10. The method of claim 9, wherein identifying the subject as having a tumor comprises identifying the subject as having the tumor prior to administering the dendrimer conjugate.

11. The method of claim 9, wherein identifying the subject as having a tumor comprises identifying the subject as having a tumor that spreads through the lymphatic system, and administering the dendrimer conjugate comprises treating potential micrometastatic disease.

12. The method of claim 1, wherein administering the dendrimer conjugate comprises injecting the agent into or near a tumor.

13. The method of claim 1, wherein administering the dendrimer conjugate comprises injecting the agent directly into the afferent lymphatic system of a tumor.

14. The method of claim 1, wherein administering the dendrimer conjugate comprises selecting the dendrimer conjugate which selectively concentrates in a component of the lymphatic system in which the tumor is located.

15. The method of claim 1, wherein administering the dendrimer conjugate comprises peritumoral injection, intratumor injection, or intradermal injection.

16. The method of claim 1, wherein the dendrimer conjugate has a diameter of about 4 nanometers to about 15 nanometers.

17. The method of claim 1, wherein the dendrimer conjugate comprises a generation 4-8 PAMAM dendrimer.

18. The method of claim 1, wherein the dendrimer conjugate comprises a generation 6-8 PAMAM dendrimer.

19. A method of inhibiting metastatic disease in a subject, comprising:

identifying a subject as having a tumor that spreads through the lymphatic system;

administering a dendrimer conjugate in the lymphatic system of the subject who has been identified as having a tumor, wherein the dendrimer conjugate comprises a generation 5 DAB or generation 3-10 PAMAM dendrimer and is capable of selectively concentrating in lymphatic structures and is conjugated to an amount of a gadolinium imaging agent that can be activated by a neutron beam to treat the identified tumor, wherein the dendrimer conjugate does not include a tumor specific targeting agent;

imaging the lymphatic system to detect the gadolinium imaging agent in the lymphatic system; and

selectively activating the gadolinium imaging agent by directing a neutron beam at a portion of the imaged lymphatic system, thereby treating metastatic disease that may be in the lymphatic system.

20. A method of inhibiting metastatic disease in a subject, comprising:

selecting a dendrimer conjugate having a diameter of about 4 nanometers to about 15 nanometers for administration to a subject who has been identified as having a tumor;

administering the dendrimer conjugate in the lymphatic system of the subject, wherein the dendrimer conjugate comprises a generation 5 DAB or generation 3-10 PAMAM dendrimer and is capable of selectively concentrating in lymphatic structures and is conjugated to an amount of a gadolinium imaging agent that can be activated by a neutron beam to treat the identified tumor;

imaging the lymphatic system to detect the gadolinium imaging agent in the lymphatic system; and

selectively activating the gadolinium imaging agent by directing a neutron beam at a portion of the imaged lymphatic system, thereby treating metastatic disease that may be in the lymphatic system.

21. The method of claim 20, wherein the dendrimer conjugate does not include a tumor specific targeting agent.