Heat shock protein as a targeting agent for endothelium-specific in vivo transduction

• US 7,575,738 B2
• Filed: 08/13/2004
• Issued: 08/18/2009
• Est. Priority Date: 08/13/2004
• Status: Expired due to Fees

• Current Assignee: General Electric Company
• Original Assignee: General Electric Company
• Inventors: Zhao, Ming, Syud, Faisal A., Torres, Andrew S.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US10/917,326
• Publication Number:
  US 20060034761A1
• Time in Patent Office: 1,831 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/9.1, 424/9.2, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 530/350, 562/516
• US Class Current: 424/1.69
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 59/008 Peptides; Proteins

Abstract

The present invention relates to the use of Heat Shock Proteins and fragments thereof as targeting ligand. The Heat Shock Protein may be labeled with imaging agents that are capable of binding lectin-like oxidized low-density lipoprotein (LOX-1) or may be attached to a therapeutic agent. The sequences are useful for the diagnosis and monitoring of diseases as well as means for internalizing signaling moieties and therapeutics.

Claims

1. A compound having the formula S-(L)_n-H

wherein S is a signal moiety selected from the group consisting of a luminescent dye, a near infrared dye, a paramagnetic ion, a superparamagnetic particle, ¹¹ C, ¹⁸F, ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ^94mTc, ⁹⁴Tc, ^99mTc, ¹¹¹ In, ¹⁵⁴-¹⁵⁸Gd, and ¹⁷⁵Lu,

L links S to H, wherein L is a linker selected from the group consisting of a covalent bond, polypeptide, protein, organic radical having a valence of at least 2, and chelating agent,

H is HSP-70, or a fragment thereof that binds to LOX- 1, and

n is either 0 or 1.

3. The compound of claim 1, wherein the luminescent dye is fluorescein.

4. The compound of claim 1, wherein the paramagnetic ion is an isotope of gadolinium.

5. The compound of claim 1, wherein the superparamagnetic particle is a nanoparticle.

6. The compound according to claim 5, wherein the nanoparticle comprises at least one of iron oxide and elemental iron.

7. The compound according to claim 1, wherein the organic radical is covalently bound to both S and H.

8. The compound according to claim 1, wherein the organic radical is ionically bound to one of S and H.

9. The compound according to claim 1, wherein the organic radical is ionically bound to both S and H.

10. The compound according to claim 1, wherein the organic radical comprises between 1 and about 10,000 carbon atoms.

11. The compound according to claim 1, wherein the organic radical is selected from the group consisting of alkylene, arylene, cycloakylene, aminoaklylene, aminoarylene, aminocycloalkylene, thioalkylene, thioarylene, thiocycloalkylene, oxyalkylene, oxyarylene, oxycycloalkylene, acylalkylene, acylarylene, acylcycloalkylene units, and combinations thereof.

12. The compound of claim 11, wherein the acylarylene unit is a 4-acylphenylene group having the following structure:

13. The compound of claim 1, wherein the L is a metal chelating agent.

14. The compound according to claim 13, wherein the metal chelating agent binds at least one metal cation selected from the group consisting of cations of ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ^94mTc, ⁹⁴Tc, ^99mTc, ¹¹¹In, ^154-158Gd, and ¹⁷⁵Lu.

15. The compound of claim 13, wherein the metal chelating agent is selected from the group consisting of diethylene triamine pentaacetic acid (DTPA), 1,4,7-triaza-cyclononane-N,N′

,N″

-triacetic acid (NOTA), p-bromoacetamido-benyl-tetraethylaminetetraacetic acid (TETA), 1,4,7,10-tetraazacyclododecanetetraacetic acid(DOTA),ethylenediaminetetraacetic acid (EDTA), CHXA ({N-[2-amino-3-(p-isothiocyanatophenyl)]trans-cyclohexane-1,2-diaminen ,N,N′

,N″

,N′

″

,N″

″

-pentaacetic acid}).

16. The compound according to claim 1, wherein H is an N-terminus fragment of Heat Shock Protein 70.

2. A composition, comprising:

a compound having the formula S-(L)_n-H disposed in a pharmaceutically acceptable excipient,

wherein S is a signal moiety selected from the group consisting of a luminescent dye, a near infrared dye, a paramagnetic ion, a superparamagnetic particle, ¹¹ C, ¹⁸F, ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ^94mTc, ⁹⁴Tc, ¹¹¹ In, ¹⁵⁴-¹⁵⁸Gd, and ¹⁷⁵Lu,

L links S to H, wherein L is a linker,

H is HSP-70, or a fragment thereof that binds to LOX- 1, and

n is either 0 or 1.

17. A kit comprising the composition of claim 2.