Cerium oxide nanoparticle-based device for the detection of reactive oxygen species and monitoring of chronic inflammation

• US 8,795,731 B1
• Filed: 10/08/2010
• Issued: 08/05/2014
• Est. Priority Date: 10/12/2009
• Status: Active Grant

• Current Assignee: University of Central Florida Research Foundation Inc. (State University System of Florida)
• Original Assignee: University of Central Florida Research Foundation Inc. (State University System of Florida)
• Inventors: Perez, Jesus Manuel, Asati, Atul, Santra, Santimukul, Kaittanis, Charalambos
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): Kim, Sun Y
• Application Number:
  US12/924,976
• Time in Patent Office: 1,397 Days
• US Class Current: 424/489
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• CPC Class Codes: A61B 5/686 Permanently implanted devices, e.g. pacemakers, other stimulators, biochips A61B5/6861 takes precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0019 characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0034 Indocyanine green, i.e. ICG, cardiogreen
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

A polymer-coated cerium oxide based device and system is disclosed for detecting reactive oxygen species and monitoring chronic inflammation. The device and system encapsulate free therapeutic nanoparticle elements not present in a living body in a prosthetic or implantable unit. Embodiment one is a two-chamber structure with a reactive oxygen species (ROS) scavenging component on one end and at the opposite end is an imaging agent consisting of at least one of a fluorophore capable of fluorescence emission, a chemiluminescent agent, a magnetic relaxation agent and an X-ray contrast agent. Embodiment two is a single chamber device consisting of a multifunctional nanocomposite with a ROS-scavenging nanoparticle constituent (nanoceria) and a multimodal reporting nanoparticle component (i.e. Dex-IO-DiR). The device and system are utilized in treatment of diseases with a pro-inflammatory component, including, but not limited to, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease, cystic fibrosis, arthritis, and cancer chemotherapy.

Claims

1. An implantable device for imaging detection of reactive oxygen species associated with aberrant clinical conditions, comprising

a first chamber having an interior cavity including therein a reactive oxygen species (ROS) scavenging component and an exterior semi-permeable membrane encapsulating the ROS scavenging component within the first chamber;

said ROS scavenging component being polymeric nanoparticles encapsulating a non-metallic ROS scavenging agent selected from the group consisting of catalase, superoxide dismutase, peroxidase, and glutathione, and said ROS scavenging component capable of scavenging reactive oxygen species under a normal physiological condition;

a second chamber having an interior cavity including therein nanoparticles containing one or more imaging agent and an exterior semi-permeable membrane encapsulating the nanoparticles containing imaging agent within the second chamber; and

the first chamber and the second chamber joined in a non-communicating manner, each chamber communicating with an aqueous environment through the semi-permeable membrane thereof, permitting diffusion of the reactive oxygen species therethrough, such that said ROS scavenging component in the first chamber protects the nanoparticles containing imaging agent in the second chamber from the reactive oxygen species under the normal physiological condition;

said nanoparticles containing imaging agent in the second chamber incurring an imaging detectable change in the presence of an elevated non-physiological level of the reactive oxygen species in vivo associated with an aberrant clinical condition when scavenging of the reactive oxygen species by the ROS scavenging component is insufficient, thereby indicating the presence of an elevated non-physiological level of the reactive oxygen species.

2. The device of claim 1, wherein the aberrant clinical condition includes inflammation, exposure to radiation, or changes in a tissue/cellular micro-environment.

3. The device of claim 1, wherein the device is a miniature device suitable for in vivo monitoring a potential induction of inflammation during medical treatments.

4. The device of claim 1, wherein the imaging agent comprises at least one of a fluorophore capable of fluorescence emission, a chemiluminescent agent, a magnetic relaxation agent and an X-ray contrast agent.

5. The device of claim 4, wherein the imaging agent is a hydrophobic fluorophore selected from at least one of octodecyl indocarbocyanine(DiI), indodicarbocyanine (DiD), and indotricarbocyanine (DiR).

6. The device of claim 4, wherein the imaging agent is a hydrophobic fluorophore selected from at least one of cyanine 5.5 (Cy5.5) and indocyanine green (ICG).

7. The device of claim 4, wherein the imaging agent is encapsulated in cavities of the nanoparticles in the second chamber.

8. The device of claim 4, wherein the nanoparticles containing imaging agent are nanoparticles of at least one of iron oxide, bismuth, europium, gadolinium and chelates thereof.

9. The device of claim 4, wherein the nanoparticles containing imaging agent are coated with at least one polymer selected from dextran, polyacrylic acid, hyper-branched polyester, poly-lactic-co-glycolic acid, and mixtures thereof.

10. The device of claim 4, wherein the nanoparticles containing imaging agent are polymer-coated nanoparticles of iron oxide for magnetic resonance imaging detection of the reactive oxygen species.

11. The device of claim 4, wherein the nanoparticles containing imaging agent are polymer-coated nanoparticles of iron oxide containing a fluorophore for magnetic resonance imaging and fluorescence imaging detections of the reactive oxygen species.

12. An implantable device for imaging detection of reactive oxygen species associated with aberrant clinical conditions, comprising

a first chamber having an interior cavity including therein polymer-coated cerium oxide nanoparticles and an exterior semi-permeable membrane encapsulating the polymer-coated cerium oxide nanoparticles within the first chamber;

said polymer-coated cerium oxide nanoparticles capable of scavenging reactive oxygen species under a normal physiological condition;

a second chamber having an interior cavity including therein nanoparticles containing one or more imaging agent and an exterior semi-permeable membrane encapsulating the nanoparticles containing imaging agent within the second chamber; and

the first chamber and the second chamber joined in a non-communicating manner, each chamber communicating with an aqueous environment through the semi-permeable membrane thereof, permitting diffusion of the reactive oxygen species therethrough, such that said polymer-coated cerium oxide nanoparticles in the first chamber protects the nanoparticles containing imaging agent in the second chamber from the reactive oxygen species under the normal physiological condition;

said nanoparticles containing imaging agent in the second chamber incurring an imaging detectable change in the presence of an elevated non-physiological level of the reactive oxygen species in vivo associated with an aberrant clinical condition when scavenging of the reactive oxygen species by the polymer-coated cerium oxide nanoparticles is insufficient, thereby indicating the presence of an elevated non-physiological level of the reactive oxygen species.

13. The device of claim 12, wherein the polymer-coated cerium oxide nanoparticles are coated with at least one polymer.

14. The device of claim 12, wherein the polymer-coated cerium oxide nanoparticles are coated with dextran or polyacrylic acid.

15. The device of claim 12, wherein the aberrant clinical condition includes inflammation, exposure to radiation, or changes in a tissue/cellular micro-environment.

16. The device of claim 12, wherein the device is a miniature device suitable for in vivo monitoring a potential induction of inflammation during medical treatments.

17. The device of claim 12, wherein the imaging agent comprises at least one of a fluorophore capable of fluorescence emission, a chemiluminescent agent, a magnetic relaxation agent, and an X-ray contrast agent.

18. The device of claim 17, wherein the imaging agent is a hydrophobic fluorophore selected from at least one of octodecyl indocarbocyanine(DiI), indodicarbocyanine (DiD), and indotricarbocyanine (DiR).

19. The device of claim 17, wherein the imaging agent is a hydrophobic fluorophore selected from at least one of cyanine 5.5 (Cy5.5) and indocyanine green (ICG).

20. The device of claim 17, wherein the imaging agent is encapsulated in cavities of the nanoparticles in the second chamber.

21. The device of claim 17, wherein the nanoparticles containing imaging agent are nanoparticles of at least one of iron oxide, bismuth, europium, gadolinium and chelates thereof.

22. The device of claim 17, wherein the nanoparticles containing imaging agent are coated with at least one polymer selected from dextran, polyacrylic acid, hyper-branched polyester, poly-lactic-co-glycolic acid, and mixtures thereof.

23. The device of claim 17, wherein the nanoparticles containing imaging agent are polymer-coated nanoparticles of iron oxide for magnetic resonance imaging detection of the reactive oxygen species.

24. The device of claim 17, wherein the nanoparticles containing imaging agent are polymer-coated nanoparticles of iron oxide containing a fluorophore for magnetic resonance imaging and fluorescence imaging detections of the reactive oxygen species.