Encapsulated contrast agents

• US 8,258,190 B2
• Filed: 04/30/2008
• Issued: 09/04/2012
• Est. Priority Date: 04/30/2007
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin N.
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): LAMBERSKI, JENNIFER A
• Application Number:
  US12/112,799
• Publication Number:
  US 20090092554A1
• Time in Patent Office: 1,588 Days
• Field of Search: None
• US Class Current: 514/772.1
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1887 Agglomerates, clusters, i.e. more than one (super)(para)magnetic microparticle or nanoparticle are aggregated or entrapped in the same maxtrix
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention relates to the field of polymer chemistry and more particularly to encapsulated contrast agents and methods for using the same.

Claims

1. A micelle, having a contrast agent encapsulated therein, comprising a multiblock copolymer of formula I:

2. The micelle according to claim 1, wherein R³ is an optionally substituted aliphatic group.

3. The micelle according to claim 1, wherein R³ is an azide-containing group or an alkyne-containing group.

4. The micelle according to claim 1, wherein Q is a valence bond.

5. The micelle according to claim 1, wherein Q is a bivalent, saturated C_1-12 alkylene chain, wherein 0-6 methylene units of Q are independently replaced by -Cy-, —

O—

, —

NH—

, —

S—

, —

OC(O)—

, —

C(O)O—

, or —

C(O)—

, wherein -Cy- is an optionally substituted 5-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The micelle according to claim 1, wherein R^x is a natural or unnatural amino acid side-chain group selected from a glutamic acid side-chain, an aspartic acid side-chain, a cysteine side-chain, a serine side-chain, an aldehyde containing side-chain, an imidazole containing side-chain, a benzimidazole containing side-chain, a lysine side-chain, an arginine side-chain, or a histidine side-chain.

7. The micelle according to claim 1, wherein R^y is a hydrophobic amino acid side-chain selected from a suitably protected aspartic acid, a suitably protected glutamic acid, a suitably protected tyrosine side-chain, a suitably protected serine side-chain, a suitably protected threonine side-chain, a phenylalanine side-chain, an alanine side-chain, a valine side-chain, a leucine side-chain, a tryptophan side-chain, a proline side-chain, or a mixture thereof.

8. The micelle according to claim 1, wherein R^y comprises a mixture of hydrophobic and hydrophilic amino acid side-chain groups such that the overall poly(amino acid) block comprising R^y is hydrophobic.

9. The micelle according to claim 1, wherein R^y consists of a mixture of D-hydrophobic and L-hydrophilic amino acid side-chain groups such that the overall poly(amino acid) block comprising R^y is hydrophobic and is a mixture of D- and L-configured amino acids.

10. The micelle according to claim 1, wherein R^y consists of a mixture of hydrophobic amino acid side-chain groups selected from D-leucine, D-phenylalanine, D-alanine, D-benzyl aspartate, or D-benzyl glutamate, and one or more of L-tyrosine, L-cysteine, L-aspartic acid, L-glutamic acid, L-DOPA, L-histidine, L-lysine, or L-ornithine.

11. The micelle according to claim 9, wherein the mixture of D-hydrophobic and L-hydrophilic amino acid side-chain groups is selected from D-leucine/L-tyrosine, D-leucine/L-aspartic acid, D-leucine/L-glutamic acid, D-phenylalanine/L-tyrosine, D- phenylalanine/L-aspartic acid, D-phenylalanine/L-glutamic acid, D-phenylalanine/L-serine, D-benzyl aspartate/L-tyrosine, D-benzyl aspartate/L-aspartic acid, D-benzyl aspartate/L-glutamic acid, D-benzyl glutamate/L-tyrosine, D-benzyl glutamate/L-aspartic acid.

12. The micelle according to claim 2, wherein R^2a is —

NHC(O)R⁴, —

NHR⁴ or —

N(R⁴)₂, wherein each R⁴ is an optionally substituted aliphatic group.

13. The micelle according to claim 1, wherein R^2a is —

NHR⁴ or —

N(R⁴)₂, wherein each R⁴ is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-(tetrahydropyran-2-yloxy)ethyl, pyridin-2-yldisulfanylmethyl, methyldisulfanylmethyl, (4-acetylenylphenyl)methyl, 3-(methoxycarbonyl)-prop-2-ynyl, methoxycarbonylmethyl, 2-(N-methyl-N-(4-acetylenylphenyl)carbonylamino)-ethyl, 2-phthalimidoethyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-iodobenzyl, 4-propargyloxybenzyl, 2-nitrobenzyl, 4-(bis-4-acetylenylbenzyl)aminomethyl-benzyl, 4-propargyloxy-benzyl, 4-dipropargylamino-benzyl, 4-(2-propargyloxy-ethyldisulfanyl)benzyl, 2-propargyloxy-ethyl, 2-propargyldisulfanyl-ethyl, 4-propargyloxy-butyl, 2-(N-methyl-N-propargylamino)ethyl, 2-(2-dipropargylaminoethoxy)-ethyl, vinyl, allyl, crotyl, 2-propenyl, but-3-enyl, —

CH₂CN, —

CH₂CH₂CN, —

CH₂CH(OCH₃)₂, 4-(bisbenzyloxymethyl)phenylmethyl, —

CC≡

CH, —

CH₂C≡

CH, —

CH₂C≡

CCH₃, or —

CH₂CH₂C≡

CH.

14. The micelle according to claim 1, wherein the contrast agent is selected from a magnetic nanoparticle or a semiconductor nanoparticle.

15. The micelle according to claim 1, wherein the contrast agent is selected from Fe, Fe₂O₃, Fe₃O₄, MnFe₂O₄, CoFe₂O₄, NiFe₂O₄, Co, Ni, FePt, CoPt, CoO, Fe₃Pt, Fe₂Pt, CO₃Pt, CO₂Pt, or FeOOH.