Responsive MRI contrast agents

• US 8,734,761 B2
• Filed: 04/21/2006
• Issued: 05/27/2014
• Est. Priority Date: 04/26/2005
• Status: Expired due to Fees

• Current Assignee: Koninklijke Philips N.V.
• Original Assignee: Koninklijke Philips N.V.
• Inventors: Willard, Nicolaas Petrus, Wegh, Rene Theodorus, Pikkemaat, Jeroen Alphons, Gruell, Holger
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): PERREIRA, MELISSA JEAN
• Application Number:
  US11/912,694
• Publication Number:
  US 20080193384A1
• Time in Patent Office: 2,958 Days
• Field of Search: None
• US Class Current: 424/9.3
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61K 49/1821 coated or functionalised microparticles or nanoparticles

Abstract

The invention provides MRI contrast agents which provide a high sensitivity and which have an optimised body retention time. These agents enable the mapping of the local pH, temperature, oxygen concentration or other metabolites in a patient'"'"'s body by the use of Chemical Exchange Saturation Transfer (CEST). Particularly pH and temperature mapping are useful for the detection of small cancer lesions and localized inflammation respectively.

Claims

1. The MRI contrast agent, comprising:

a carrier selected from the group consisting of liposomes, particles, and micelles, wherein the carrier includes a linking molecule comprising a phosphatidylcholine derivative;

a plurality of CEST-active paramagnetic complexes linked to the carrier and including at least one exchangeable entity for enabling CEST;

wherein at least one of the plurality of CEST-active paramagnetic complexes is covalently attached to the carrier via a nitrogen atom of the linking molecule, the linking molecule including an “

R”

group moiety covalently bonded to the nitrogen atom and a phosphate head group of the linking molecule, the “

R”

group moeity selected from the group consisting of;

CH₂(OCH₂CH₂)_n, and CH₂(OCH₂CH₂)_nCONHCH₂CH₂.

2. The MRI contrast agent of claim 1, wherein at least one of the plurality of CEST-active paramagnetic complexes has a paramagnetic ion attached to a cheating ligand, and the plurality of CEST-active paramagnetic complexes includes at least two different CEST-active paramagnetic complexes attached to the carrier.

3. The MRI contrast agent according to claim 1, wherein:

at least one of the CEST-active paramagnetic complexes has a first paramagnetic ion, a first chelating ligand, and at least one first exchangeable entity; and

at least one of the CEST-active paramagnetic complexes has the second CEST-active paramagnetic complex having a second paramagnetic ion, a second chelating ligand, and at least one second exchangeable entity;

wherein the first and second paramagnetic ions are different from each ether and first and second chelating ligands are different hem each other.

4. The MRI contrast agent of claim 3, wherein the first paramagnetic ion includes a first lanthanide ion and the second paramagnetic ion includes a second lanthanide ion different from the first lanthanide ion.

5. The MRI contrast agent of claim 3, wherein the first chelating ligand is a DOTAM-G1 derivative and the second chelating ligand is a DOTAM-G3 derivative.

6. The MRI contrast agent of claim 3, wherein the first and second CEST-active paramagnetic complexes include an asymmetric Yb-DOTAM complex.

7. The MRI contrast agent of claim 2, wherein one of the plurality of CEST-active paramagnetic complexes has a superparamagnetic iron oxide particle embedded in an organic material which includes the exchangeable entity.

8. The MRI contrast agent of claim 3, wherein the carrier has at least four surface groups to which the plurality of the CEST-active paramagnetic complexes are linked.

9. The MRI contrast agent of claim 1, wherein the carrier includes a linear polymer with a weight less than 20 kDa.

15. The MRI contrast agent of claim 1, wherein the carrier is a liposome configured to carry up to 100,000 CEST-active paramagnetic complexes.

10. A CEST MRI contrast agent comprising:

a common carrier selected from the group consisting of liposomes, particles, and micelles;

a plurality of paramagnetic complexes, each including;

a first chelating ligand linked to the common carrier;

a second chelating ligand linked to the common carrier;

a first and second paramagnetic ion;

a first complex forming a first exchangeable entity between the first paramagnetic ion and the first chelating ligand;

a second complex forming a second exchangeable entity between the second paramagnetic ion and the second chelating ligand;

wherein the first and second chelating ligands are dendrimers of a different generation.

11. The MRI contrast agent of claim 10, wherein

the first and second exchangable entities include amide protons;

and

the first and second chelating ligands include at least one of a DOTAM-G1 complex and a DOTAM-G3 complex.

12. The MRI contrast agent of claim 10, wherein:

the first chelating ligand includes a DOTAM-G3 complex with 16 surface amino groups.

13. The MRI contrast agent of claim 10, wherein:

the first and second chelating ligands are each covalently linked to a phospholipid included in the carrier, to incorporate at least one of the first and second chelating ligand into a shell of the carrier.

14. The MRI contrast agent of claim 10, wherein:

the first and second chelating ligands are each covalently attached to a linker molecule comprising a phosphatidylcholine or phosphatidycholine derivative, the linker molecule including a phosphate head group for forming a hydrophilic shell of the liposome, micelle, or particle.