Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof

• US 10,568,975 B2
• Filed: 02/05/2014
• Issued: 02/25/2020
• Est. Priority Date: 02/05/2013
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Yu, Tao, Patel, Himatkumar, Chan, Kannie M. Y., Oskolkov, Nikita, McMahon, Michael, Hanes, Justin
• Primary Examiner(s): Vu, Jake M
• Application Number:
  US14/765,881
• Publication Number:
  US 20160206760A1
• Time in Patent Office: 2,211 Days
• Field of Search: None
• CPC Class Codes: A61K 49/1833 having a (super)(para)magnetic core coated or functionalised with a small organic molecule oligomeric, polymeric, dendrimeric A61K49/1851
• CPC Class Codes: A61K 49/1878 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating

Abstract

Surface conjugated diamagnetic Chemical Exchange Saturation Transfer (diaCEST) agent carriers and methods of making and using are described herein. The particles are safe alternatives to conventional paramagnetic or superparamagnetic metal-based MRI contrast agents that are often toxic and therefore not biocompatible. The carriers described herein can provide simultaneous monitoring of multiple particle types labeled with ‘multicolor’ diaCEST contrast agents. In some embodiments, the carriers are micro- and/or nanoparticles. In other embodiments, the carriers are liposomes. In some embodiments, the particles and/or liposomes are mucus penetrating. In other embodiments, the particles and/or liposomes are not mucus penetrating.

Claims

1. A particle comprising

a biocompatible, hydrophobic polymeric core,

having covalently bound to the core surface altering polymeric agents comprising a polyalkylene oxide, the polymeric agents having a molecular weight between about 1,000 Daltons and about 10,000 Daltons,

wherein the density of the surface altering agent is between about 0.1 and about 1000 chains/blocks/moieties per 100 nm², and

a plurality of diamagnetic chemical exchange saturation transfer (diaCEST) agents covalently coupled to the surface altering polymeric agents,

wherein the diaCEST agent is selected from the group consisting of L-arginine;

barbituric acid;

substituted barbituric acid with F, COOH, carbonyl, phospholipid at one or more ring atoms or protons attached thereto;

salicylic acid;

4-amino-salicylic acid;

imidazole;

substituted imidazole with Br, COOH, carbonyl, phospholipid, peptide at one or more ring atoms or protons attached thereto, peptides rich in backbone NH, guanidyl NH₂, and/or OH protons; and

combinations thereof,

wherein the diaCEST agents are presented on the surface of the particles and the surface altering polymeric agents are of sufficient length to exhibit good temporal and spatial resolution of the diaCEST agent for in vivo imaging in the absence of a metal-based contrast agent.

2. The particle of claim 1, wherein the core comprises a polymer selected from the group consisting of polystyrenes;

poly(hydroxy acids);

poly(lactic acid);

poly(glycolic acid);

poly(lactic acid-co-glycolic acid);

polyanhydrides;

polyorthoesters;

polyamides;

polycarbonates;

polyalkylenes;

polyalkylene terephthalates;

polyvinyl ethers;

polyvinyl esters;

polyvinyl halides;

polysiloxanes;

polyurethanes;

co-polymers of polyurethanes;

alkyl cellulose;

cellulose esters;

polycarbonate-urethane polymers;

silicone-urethane polymers;

epoxy polymers;

polycarbonate urethane;

silicone urethane;

polyvinylpyridine copolymers;

polyether sulfones;

polydimethyl siloxane;

polyesters;

polyureas;

polyimides;

polysulfones;

polyacetylenes; and

combinations, copolymers and/or mixtures thereof.

3. The particle of claim 1, wherein the polyalkylene oxide is polyethylene glycol.

4. The particle of claim 1 wherein the diaCEST agent is L-arginine.

5. The particle of claim 1, wherein the diaCEST agent is barbituric acid.

6. The particle of claim 1, wherein the diaCEST agent is propargylglycine-W-(DYD)₆.

7. The particle of claim 1 wherein the particle further contains one or more therapeutic and/or prophylactic agents.

8. The particle of claim 7, wherein the one or more therapeutic and/or diagnostic agents are selected from the group consisting of, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antiopsychotic agents, neuroprotective agents, anti-proliferatives, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, nutraceuticals, and combinations thereof.

9. The particle of claim 8, wherein the therapeutic and/or diagnostic agent is a chemotherapeutic agent.

10. The particle of claim 9, wherein the chemotherapeutic agent is a taxane.

11. A population of particles comprising two or more particles of claim 1,

wherein the particles contain different diaCEST agents and/or different therapeutic or prophylactic agents.

12. A pharmaceutical composition comprising an effective amount for imaging of

particles of claim 1,

wherein the diaCEST agents are presented on the surface of the particles and the surface altering polymeric agents are of sufficient length to exhibit good temporal and spatial resolution of the diaCEST agent for in vivo imaging in the absence of a metal-based contrast agent, or

the population of these particles comprising two or more of these particles containing different diaCEST agents and/or different therapeutic or prophylactic agents,

in one or more pharmaceutically acceptable carriers.

13. The composition of claim 12 in the form of a solution.

14. The composition of claim 12 in the form of a suspension.

15. A method for CEST imaging in vivo comprising administering a pharmaceutical composition comprising an effective amount for imaging of

particles of claim 1,

wherein the diaCEST agents are presented on the surface of the particles and the surface altering polymeric agents are of sufficient length to exhibit good temporal and spatial resolution of the diaCEST agent for in vivo imaging in the absence of a metal-based contrast agent, or

the population of these particles comprising two or more of these particles containing different diaCEST agents and/or different therapeutic or prophylactic agents,

in one or more pharmaceutically acceptable carriers, and

imaging the particles using magnetic resonance imaging.

16. The method of claim 15, wherein the particles are administered parenterally.

17. The method of claim 15, wherein the particles are administered by injection.

18. The method of claim 15 comprising administering the population of particles of claim 11.

19. The method of claim 18, wherein the population contains two or more different types of particles containing different diaCEST agents and different therapeutic or prophylactic agents and wherein each specific pool of protons on the different diaCEST agents is saturated selectively using radiofrequency pulses to simultaneously image the different types of particles.

20. The particle of claim 3, wherein the polyethylene glycol has a molecular weight from about 1,000 Daltons to about 8,000 Daltons.

21. The particle of claim 3, wherein the polyethylene glycol has a molecular weight from about 1,000 Daltons to about 6,000 Daltons.

22. The particle of claim 3, wherein the polyethylene glycol has a molecular weight from about 4,000 Daltons to about 6,000 Daltons.

23. The particle of claim 2, wherein the polyester is a poly(hydroxy acid), copolymer, or mixture thereof.

24. The particle of claim 23, wherein the poly(hydroxy acid) is selected from the group consisting of poly(lactic acid) poly(glycolic acid), poly(lactic acid-co-glycolic acid), and a combination thereof.

25. The particle of claim 23, wherein the poly(hydroxy acid) or copolymer thereof is selected from the group consisting of poly(lactide-co-caprolactone), copolymer of poly(lactide-co-caprolactone), or mixtures of poly(lactide-co-caprolactone).

26. The particle of claim 2, wherein the polyalkylene is selected from the group consisting of polyethylenes, polypropylenes, and a combination thereof.

27. The particle of claim 1, wherein the polyalkylene oxide is polyoxypropylene (PPO) or copolymers thereof.