Compositions for nanoconfinement induced contrast enhancement and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-10898593-B2
Application number	US-201515310395-A
Country	US
Kind code	B2
Filing date	May 13, 2015
Priority date	May 13, 2014
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

Multivalent CT or MR contrast agents and methods of making and using thereof are described herein. The agents contain a moiety, such as a polymer, that provides multivalent attachment of CT or MR contrast agents. Examples include, but are not limited to, multivalent linear polymers, branched polymers, or hyperbranched polymers, such as dendrimers, and combinations thereof. The dendrimer is functionalized with one or more high Z-elements, such as iodine. The high Z-elements can be covalently or non-covalently bound to the dendrimer. The dendrimers are confined in order to enhance CT contrast. In some embodiments, the moiety is confined by encapsulating the dendrimers in a material to form particles, such as nanoparticles. In other embodiments, the dendrimer is confined by conjugating the moiety to a material, such as a polymer, which forms a gel upon contact with bodily fluids.

First claim

We claim:

1. A pharmaceutical composition comprising polymeric nanoparticles having an average diameter between about 50 and about 150 nm, wherein the nanoparticles comprise
one or more encapsulating polymers selected from the group consisting of polycaprolactone, polylactic acid, polyglycolic acid, and copolymers thereof and amphiphilic polymers selected from the group consisting of poly(lactic acid)-polyethylene glycol (PLA-PEG), poly(glycolic acid)-polyethylene glycol (PGA-PEG), and poly(lactide -co-glycolide)-polyethylene glycol (PLGA-PEG); and
one or more multifunctional polymers selected from the group consisting of hyperbranched polymers, dendrimers, multifunctional linear polymers, and combinations thereof, the multifunctional polymers having attached covalently or non-covalently thereto one or more elements selected from the group consisting of iodine, barium, gadolinium, gold, bismuth, dysprosium, platinum, and combinations thereof;
wherein the multifunctional polymers are encapsulated within the polymeric nanoparticles such that the elements are clustered at distances of between about 1 and about 100 nm, and
wherein the concentration of the elements in the polymeric nanoparticles is between about 500 and about 10,000 μg/ml,
wherein the elements within the polymeric nanoparticles are at an effective amount and clustering distance to enhance computed tomography contrast, as compared to a control composition having the same concentration of the elements not in the same clustering distances.

2. The composition of claim 1 , wherein the one or more multifunctional polymers are hyperbranched polymers.

3. The composition of claim 1 , wherein the nanoparticles comprise amphiphilic polymers and are formed by self-assembly.

4. The composition of claim 3 , wherein the amphiphilic polymers are pegylated copolymers of polymers selected from the group consisting of polycaprolactone, polylactic acid, polyglycolic acid, and copolymers thereof.

5. The composition of claim 4 , wherein the pegylated copolymers are selected from the group consisting of poly(lactic acid) -polyethylene glycol (PLA-PEG), poly(glycolic acid)-polyethylene glycol (PGA-PEG), and poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG).

6. The composition of claim 3 , wherein the amphiphilic polymer comprises pegylated polycaprolactone.

7. The composition of claim 1 , wherein the elements comprise iodine.

8. The composition of claim 1 , wherein the multifunctional polymers are polyamidoamine (PAMAM) dendrimers.

9. The composition of claim 1 , wherein contrast enhancement by the nanoparticles in computing tomography at pH 7.4 is at least two-fold, three-fold, four-fold, five-fold or greater as compared to the control composition.

10. The composition of claim 1 , wherein the nanoparticles further comprise one or more therapeutic agents, prophylactic agents, nutraceuticals, or combinations thereof.

11. The composition of claim 1 , wherein the nanoparticles further contain a targeting moiety.

12. The composition of claim 1 , further comprising one or more pharmaceutically acceptable carriers.

13. A method for imaging soft tissue using computing tomography, comprising
administering to the soft tissue an effective amount of the composition of claim 1 , and imaging the soft tissue using computing tomography.

14. The method of claim 13 , wherein the composition is administered parenterally.

15. The nanoparticles of claim 1 , wherein the elements within the polymeric nanoparticles are at distances of between about 1 and about 75 nm.

16. The composition of claim 1 , wherein the elements within the polymeric nanoparticles are clustered at distances of between about 1 and about 50 nm.

17. The composition of claim 1 , wherein the elements within the polymeric nanoparticles are clustered at distances of between about 1 and about 25 nm.

18. The composition of claim 1 , wherein the elements within the polymeric nanoparticles are clustered at distances less than about 8, 7, 6, 5, 4, 3, or 2 nm.

Assignees

• Univ Yale

Inventors

• Fahmy Tarek
• Sinusas Albert
• Kim Dongin

Classifications

• A61K49/1887

  Agglomerates, clusters, i.e. more than one (super)(para)magnetic microparticle or nanoparticle are aggregated or entrapped in the same maxtrix · CPC title

• C08J3/124

  Treatment for improving the free-flowing characteristics · CPC title

• C08K9/10

  Encapsulated ingredients · CPC title

• A61K49/0485 Primary

  Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer · CPC title

• A61K49/0438

  Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol · CPC title