Heteromultivalent nanoparticle compositions

Patent metadata

Field	Value
Publication number	US-9107963-B2
Application number	US-201313863005-A
Country	US
Kind code	B2
Filing date	Apr 15, 2013
Priority date	Apr 13, 2012
Publication date	Aug 18, 2015
Grant date	Aug 18, 2015

Abstract

A composition for use in diagnostic and therapeutic applications includes a heteromultivalent nanoparticle having an outer surface and a plurality of targeting moieties conjugated to the surface of the nanoparticle, the targeting moieties includes a first activated platelet targeting moiety and a second activated platelet targeting moiety.

First claim

Having described the invention, we claim:

1. A composition for use in diagnostic and therapeutic applications comprising a heteromultivalent nanoparticle having an outer surface and a plurality of targeting moieties conjugated to the surface of the nanoparticle, the targeting moieties comprising a GPIb-IIIa-binding peptide and a p-selectin binding peptide, and wherein the nanoparticle remains attached to activated platelets at a thrombus site under a hemodynamic shear environment.

2. The composition of claim 1 , the nanoparticle comprising a liposome.

3. The composition of claim 1 , the GPIIb-IIIa-binding peptide comprising a RGD small peptide and the p-selectin binding peptide comprising SEQ ID NO: 1.

4. The composition of claim 3 , the RGD small peptide having SEQ ID NO: 3.

5. The composition of claim 1 , wherein the targeting moieties are conjugated to the nanoparticle surface with PEG linkers.

6. The composition of claim 1 , wherein the targeting moieties are spatially or topographically arranged on the nanoparticle surface such that the GPIIb-IIIa-binding peptide and the p-selectin binding peptide do not spatially mask each other and the nanoparticle is able to bind to an activated platelet with exposed activated platelet receptors thereby enhancing retention of the nanoparticle construct onto activated platelets under hemodynamic flow.

7. The composition of claim 1 , wherein the ratio of GPIIb-IIIa-binding peptide to p-selectin binding peptide provided on the nanoparticle surface is about 80:20 to about 20:80.

8. composition of claim 1 , wherein the GPIIb-IIIa-binding peptide and p-selectin binding peptide provided on the nanoparticle surface have a total mol % of about 5 to about 20 with respect to total lipid content.

9. The composition of claim 1 , further comprising a therapeutic and/or imaging agent, the agent encapsulated within the nanoparticle construct.

10. The composition of claim 9 , the therapeutic agent selected from the group consisting of an anti-thrombotic agent and a thrombolytic agent.

11. The composition of claim 9 , wherein the therapeutic agent includes tissue plasminogen activator (tPA).

12. The composition of claim 9 , the nanoparticle further comprising Golden Nanorods (GNRs) conjugated to the surface, the GNRs allowing photothermal destabilization of the nanoparticle and therapeutic and/or imaging agent release in response to near-infrared (NIR) light.

13. A method of delivering a therapeutic and/or imaging agent to activated platelets in a subject, the method comprising administering to the subject the composition of claim 1 .

14. The method of claim 13 , the nanoparticle construct comprising a liposome.

15. The method of claim 13 , the GPIIb-IIIa-binding peptide comprising a RGD small peptide and the p-selectin binding peptide comprising a EWVDV (SEQ ID NO: 1) small peptide.

16. The method of claim 13 , the RGD small peptide having SEQ ID NO:3 and the p-selectin binding peptide having SEQ ID NO: 1.

17. The method of claim 13 , wherein the first and second activated platelet targeting moieties are conjugated to the nanoparticle surface with PEG linkers.

18. The method of claim 13 , wherein the first and second activated platelet targeting moieties can be spatially or topographically arranged on the nanoparticle surface such that the first and second activated platelet targeting moieties do not spatially mask each other and the nanoparticle is able to bind to an activated platelet with exposed activated platelet receptors and enhance retention of the nanoparticle onto activated platelets under hemodynamic flow.

19. The method of claim 13 , wherein the ratio of GPIIb-IIIa-binding peptide to p-selectin binding peptide provided on the nanoparticle surface is about 80:20 to about 20:80.

20. The method of claim 13 , wherein the GPIIb-IIIa-binding peptide and p-selectin binding peptide provided on the nanoparticle surface have a total mol % of about 5 to about 20 with respect to total lipid content.

21. The method of claim 13 , wherein the therapeutic agent is a thrombolytic agent and the subject is afflicted with an occlusive vascular disease selected from the group consisting of stroke, myocardial infarction, peripheral arterial diseases and deep vein thrombosis.

22. The method of claim 13 , the nanoparticle construct further comprising a plurality of Golden Nanorods (GNRs) conjugated to the surface, the GNRs allowing photothermal destabilization of the nanoparticle construct and release of the therapeutic and/or imaging agent in response to near-infrared (NIR) light.

Assignees

• Univ Case Western Reserve

Inventors

• Sen Gupta Anirban
• Ravikumar Madhumitha
• Modery Christa

Classifications

• A61K47/48815 Primary

  Human Necessities · mapped topic

• A61K49/0041

  Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N) · CPC title

• A61K47/48238

  Human Necessities · mapped topic

• A61K38/49

  Urokinase; Tissue plasminogen activator · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title