Imageable embolic microsphere
This invention concerns imageable, radiopaque embolic beads, which are particularly useful for monitoring embolization procedures. The beads comprise iodine containing compounds which are covalently incorporated into the polymer network of a preformed hydrogel bead. The beads are prepared by activating pre-formed hydrogel beads towards nucleophilic attack and then covalently attaching iodinated compounds into the polymer network. The radiopaque beads may be loaded with chemotherapeutic agents and used in methods of embolizing hyperplastic tissue or solid tumors.
1. A method of making a radiopaque hydrogel bead, comprising:
forming an activated hydrogel bead by reacting a preformed hydrogel bead with a carbonyldiimidazole or a carbodiimide; and
reacting functional groups on the activated hydrogel bead with an iodinated compound such at the iodinated compound is covalently coupled to the activated hydrogel bead, wherein the iodinated compound is an aromatic iodine containing compound.
2. The method according to claim 1 , wherein the aromatic iodine containing compound is an iodinated benzyl or phenyl alcohol or is an iodinated benzoic acid.
3. The method according to claim 1 , wherein the aromatic iodine containing compound is 2,3,5-triiodobenzoic acid.
4. The method according to claim 1 , comprising preforming the preformed hydrogel bead from a polymer which has alcoholic hydroxyl substituents or acylated derivatives thereof.
5. The method according to claim 1 , wherein the preformed hydrogel bead comprises a cross-linked polyhydroxy polymer selected from polyvinyl alcohol (PVA) or a copolymer of vinyl alcohol.
6. The method according to claim 1 , wherein the preformed hydrogel bead comprises a polymer backbone with a 1,2-diol and/or a 1,3-diol structure to enable crosslinking with an acrylic monomer.
7. The method according to claim 6 , wherein the acrylic monomer is 2-acrylamido-2-methylpropane sulfonic acid (AMPS).
8. The method according to claim 1 , wherein hydroxyl moieties on and/or within the preformed hydrogel bead are activated by reaction with the carbonyldiimidazole.
9. The method according to claim 1 , wherein the iodinated compound is an iodinated alcohol, an iodinated amine, or an iodinated carboxylic acid.
10. The method according to claim 1 , wherein the iodinated compound is an iodinated alcohol.
11. The method according to claim 10 , wherein the iodinated alcohol is a triiodobenzyl alcohol or a triiodophenyl alcohol.
12. The method according to claim 1 , having coupled to its imide or imidazole function, a terminally bifunctional linker which comprises an aliphatic carbon chain with at least 2 carbons.
13. The method according to claim 12 , wherein both functionalities of the terminally bifunctional linker are reactive with imide or imidazole.
14. The method according to claim 12 , wherein the functionality or reactive moieties of the bifunctional linker comprise one or more of an amine, carboxylic acid and alcohol.
15. The method according to claim 12 , wherein the bifunctional linker is a diamino alkane, optionally wherein bifunctional linker has general formula H 2 N(CH 2 ) n NH 2 wherein n includes any number between 2 and 20, 2 and 10, or 2 and 4.
16. The method according to claim 12 wherein the iodinated compound is covalently coupled through the bifunctional linker.
17. The method according to claim 1 , further comprising absorbing a pharmacologically active agent within the radiopaque hydrogel bead.
18. The method according to claim 1 , comprising:
adding the carbonyldiimidazole or the carbodiimide to a suspension that contains the preformed hydrogel bead, wherein the preformed hydrogel bead is swollen with an organic solvent, in the presence of a catalytic amount of a base and under anhydrous conditions to react with the preformed hydrogel bead such that it is activated towards nucleophilic substitution; and
covalently coupling the activated hydrogel bead with the iodinated compound which is reactive towards the imidazole or diimide functionality of the activated hydrogel bead.
19. The method according to claim 18 , wherein the preformed hydrogel bead comprises a cross-linked polyhydroxy polymer selected from polyvinyl alcohol (PVA) or a copolymer of vinyl alcohol.