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

Patent metadata

Field	Value
Publication number	US-2017266325-A1
Application number	US-201515310395-A
Country	US
Kind code	A1
Filing date	May 13, 2015
Priority date	May 13, 2014
Publication date	Sep 21, 2017
Grant date	—

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

1 . Nanoparticles comprising one or more polymers having encapsulated thereon one or more moieties comprising a plurality of high Z-elements.

2 . The nanoparticles of claim 1 , wherein the one or more moieties comprising a plurality of high Z-elements are selected from the group consisting of hyperbranched polymers, dendrimers, multifunctional linear polymers, and combinations thereof.

3 . The nanoparticles of claim 1 , wherein the one or more polymers are amphiphilic.

4 . The nanoparticles of claim 3 , wherein the one or more amphiphilic polymer comprise one or blocks of a hydrophobic or more hydrophobic polymer and a one or more blocks of a hydrophilic or more hydrophilic polymer.

5 . The nanoparticles of claim 4 , wherein the hydrophobic or more hydrophobic block is a polyester.

6 . The nanoparticles of claim 5 , wherein the polyester is selected from the group consisting of polycaprolactone, polylactic acid, polyglycolic acid, and copolymers thereof.

7 . The nanoparticles of claim 6 , wherein the one or more amphiphilic polymers is selected from the group consisting of PLA-PEG, PGA-PEG, and PLGA-PEG.

8 . The nanoparticles of claim 7 , wherein the amphiphilic polymer is PLGA-PEG.

9 . The nanoparticles of claim 1 , wherein the high Z-element is selected from the group consisting of iodine, barium, gadolinium, technetium, gold, bismuth, and combinations thereof.

10 . The nanoparticles of claim 9 , wherein the high Z-element is iodine.

11 . The nanoparticles of claim 1 , wherein the dendrimer is PAMAM.

12 . The nanoparticles of claim 1 , wherein the enhancement in CT at pH 7.4 is at least 2-fold, three-fold, four-fold, 5-fold or greater compared to the unencapsulated dendrimer.

13 . The nanoparticles of claim 1 , wherein the particle have an average diameter from about 50 to about 150 nm, preferably from about 60 to about 140 nm, more preferably from about 70 about 140 nm, most preferably from about 70 to about 135 nm.

14 . The nanoparticles of claim 10 , wherein the concentration of iodine is from about 20 to about 10,000 μg/ml, preferably from about 40 to about 8000 μg/ml, more preferably from about 100 to about 7000 μg/ml, most preferably from about 500 to about 7000 μg/ml.

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

16 . The nanoparticles of claim 1 , wherein the particles further contain a targeting moiety.

17 . A pharmaceutical composition comprising the particles of claim 1 and one or more pharmaceutically acceptable carriers.

18 . A conjugate comprising a moiety comprising a plurality of high Z-elements, wherein the moiety is covalently bound to a material which gels in upon contact with biological fluids.

19 . The conjugate of claim 18 , wherein the one or more moieties comprising a plurality of high Z-elements are selected from the group consisting of hyperbranched polymers, dendrimers, multifunctional linear polymers, and combinations thereof.

20 . The conjugate of claim 18 , wherein the high Z-element is selected from the group consisting of iodine, barium, gadolinium, technetium, gold, bismuth, and combinations thereof.

21 . The conjugate of claim 20 , wherein the high Z-element is iodine.

22 . The conjugate of claim 19 , wherein the dendrimer is PAMAM.

23 . The conjugate of claim 18 , wherein the material which gels up contact with bodily fluids is a polymer.

24 . The conjugate of claim 23 wherein the polymer is selected from the group consisting of alginates, cellulosic polymers, such as carboxymethyl cellulose, and hyaluronan.

25 . The conjugate of claim 24 , wherein the polymer is alginate having a molecular weight from about 120,000 to about 190,000 Daltons.

26 . The conjugate of claim 18 , wherein the particles further comprise one or more therapeutic agents, prophylactic agents, nutraceuticals, or combinations thereof.

27 . The conjugate of claim 18 , wherein the particles further contain a targeting moiety.

28 . A pharmaceutical composition comprising the conjugate of claim 18 and one or more pharmaceutically acceptable carriers.

29 . A method for imaging soft tissue using computing tomography, the method comprising administering an effective amount of nanoparticles comprising one or more polymers having encapsulated thereon one or more moieties comprising a plurality of high Z-elements or a conjugate comprising a moiety comprising a plurality of high Z-elements, wherein the moiety is covalently bound to a material which gels in upon contact with biological fluids, and imaging the tissue.

30 . The method of claim 29 , wherein the particles, compositions, or conjugates are administered parenterally.

Assignees

• Univ Yale

Inventors

• Fahmy Tarek
• Sinusas Albert
• Kim Dongin

Classifications

• A61K49/0442

  Polymeric X-ray contrast-enhancing agent comprising a halogenated group · CPC title

• A61K49/0438

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

• A61K49/0423

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