Drug carrier providing MRI contrast enhancement

Patent metadata

Field	Value
Publication number	US-9795693-B2
Application number	US-200913062550-A
Country	US
Kind code	B2
Filing date	Sep 3, 2009
Priority date	Sep 10, 2008
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

Described are drug carriers useful in magnetic resonance imaging (MRI)-guided drug release comprising a shell capable of releasing an enclosed biologically active agent as a result of a local stimulus, e.g. energy input, such as heat, wherein the shell encloses a 19 F MR contrast agent. Preferably, the carrier also acts as a contrast enhancement agent for MRI based on the principle of Chemical Exchange-dependent Saturation Transfer (CEST). To this end the shell encloses a cavity that comprises a paramagnetic chemical shift reagent, a pool of proton analytes, and the 19 F contrast agent, and wherein the shell allows diffusion of the proton analytes.

First claim

The invention claimed is:

1. A carrier adapted for the localized delivery of a biologically active agent, comprising a shell capable of releasing an enclosed biologically active agent as a result of a local stimulus, wherein the shell encloses a 19F MR contrast agent and a 1H MR contrast agent in a cavity formed by the shell, wherein the 19F MR contrast agent undergoes a change in detectability and becomes detectable upon its release from the shell.

2. A carrier according to claim 1 , wherein the 19F contrast agent is selected from the group consisting of the compounds of

3. A carrier according to claim 1 , wherein the 1H MR contrast agent is selected from the group of T1 and/or T2 modifying contrast agents, Chemical Exchange-dependent Saturation Transfer (CEST) contrast agent, and combinations thereof.

4. A carrier according to claim 1 , wherein the shell comprises a thermosensitive material capable of affecting drug release.

5. A carrier according to claim 1 , wherein the shell is semipermeable, wherein the cavity further comprises a paramagnetic chemical shift reagent and a pool of proton analytes, and wherein the shell allows diffusion of the proton analytes.

6. A carrier according to claim 5 , having a non-spherical shape.

7. A carrier according to claim 5 , wherein the pool of proton analytes comprises water.

8. A carrier according to claim 1 , being a thermosensitive nanoparticle selected from the group consisting of liposomes, polymersomes, nanocapsules, and mixtures thereof.

9. A carrier according to claim 1 , comprising a metal complex having a metal ion and a ligand that is based on a multidentate chelate ligand, as a paramagnetic chemical shift reagent.

10. A carrier according to claim 9 , wherein the metal complex has at least one coordination site of the metal left open for the coordination of at least one water molecule.

11. A carrier according to claim 10 , wherein the paramagnetic shift reagent is selected from the group consisting of [Ln(hpdo3a)(H2O)], [Ln(dota)(H2O)]—, [Ln(dotma)H2O)]—, [Ln(dotam)(H2O)]3+, [Ln(dtpa)(H2O)]2-, derivatives thereof, and mixtures thereof, with Ln being a lanthanide ion.

12. A carrier according to claim 1 comprising a paramagnetic agent in or at its outer surface.

13. A carrier according to claim 12 , wherein the paramagnetic agent is selected from the group consisting of at least one of the lanthanide ions Dy3+, Ho3+, Er3+, Tm3+, or Yb3+ complexed by a multidentate chelating molecule bearing at least one hydrophobic group that comprises at least 6 carbon atoms.

14. A carrier according to claim 1 , comprising a drug in the treatment of cancer or cardiovascular disorders.

15. A carrier according to claim 1 , comprising a ligand for targeted binding exposed on the outer surface of the carrier.

16. A carrier according to claim 15 , wherein the ligand comprises a hydrophobic tail, the tail penetrating into a lipid bilayer shell of the carrier.

17. A carrier according to claim 15 , wherein the ligand is a disease-specific molecular probe.

18. A method for the MRI guided delivery of a bio-active agent to a subject, comprising the administration to said subject of a carrier according to claim 1 provided with the bio-active agent, allowing the carrier to release the bio-active agent, and rendering a 19F MR image using the contrast provided by the 19F MR contrast agent.

19. A method according to claim 18 , wherein the carrier comprises a CEST contrast agent, and wherein prior to and/or during release of the bioactive agent an MR image is rendered using the CEST contrast enhancement provided by said CEST contrast agent.

Assignees

• Langereis Sander
• Keupp Jochen
• Gruell Holger
• Burdinski Dirk
• Beelen Danielle
• Koninklijke Philips Nv

Inventors

• Langereis Sander
• Keupp Jochen
• Gruell Holger
• Burdinski Dirk
• Beelen Danielle

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K49/08 Primary

  characterised by the carrier · CPC title

• A61K49/12

  Macromolecular compounds · CPC title