Imageable polymers
阅读说明：本技术 可成像聚合物 (Imageable polymers ) 是由 S·霍恩 A·L·路易斯 S·L·威利斯 M·R·德雷尔 K·哈瑞法 Y·唐 于 2014-09-05 设计创作，主要内容包括：本发明涉及可成像聚合物,尤其包含聚乙烯醇的那些,以及涉及用于制备所述聚合物的方法以及包含所述聚合物的栓子微球。所述微球在栓塞程序期间可成像并且可负载药物或其它治疗剂以提供可成像药物递送系统。(This invention relates to imageable polymers, particularly those comprising polyvinyl alcohol, and to methods for making the polymers and embolic microspheres comprising the polymers. The microspheres are imageable during embolization procedures and may be loaded with drugs or other therapeutic agents to provide an imageable drug delivery system.)
1. A hydrogel comprising PVA or a copolymer of PVA wherein the PVA backbone comprises at least two side chains comprising crosslinkable ethylenically unsaturated functional groups, the crosslinkable groups being crosslinked by a vinylic comonomer, wherein the hydrogel further comprises a 1, 3-diol group of the PVA backbone acetalized with a radiopaque species comprising an iodinated phenyl group, wherein the vinylic comonomer is 2-acrylamido-2-methylpropane sulfonic acid, the radiopaque species being linked to the copolymer by a cyclic acetal linkage such that the hydrogel copolymer comprises a structure according to general formula I
Wherein X is a group of the formula
Wherein Z is a linking group bound to the cyclic acetal or is absent such that the phenyl group is bound to the cyclic acetal;
if Z is present, then Z is C1-6Alkylene radical, C1-6Alkyleneoxy or C1-6An alkoxy alkylene group;
hal is 1,2, 3 or 4 covalently linked iodides; and
j is a group-CH2-。
2. The hydrogel of claim 1, wherein the side chain containing the crosslinkable ethylenically unsaturated functional group is linked to the 1, 3-diol group of the PVA backbone via a cyclic acetal linkage.
3. The hydrogel of claim 1, wherein the crosslinkable ethylenically unsaturated functional group is an acrylate group.
4. The hydrogel of claim 1, wherein the copolymer is acrylamido polyvinyl alcohol-co-acrylamido-2-methylpropane sulfonate.
5. The hydrogel of claim 1, wherein Z is methylene or ethylene or is a group- (CH)2)p-O-(CH2)q-, where q is 0, 1 or 2, and p is 1 or 2.
6. The hydrogel of claim 1, wherein Z is-CH2OCH2-or-CH2O; or Z is absent.
7. The hydrogel of claim 1, wherein Hal is 3 covalently linked iodides or 4 covalently linked iodides.
8. The hydrogel of claim 1, wherein the hydrogel comprises greater than 10% iodine by dry weight.
9. The hydrogel of claim 1, wherein the hydrogel is in the form of microparticles or microspheres.
10. The hydrogel of claim 9, wherein the hydrogel is in the form of microspheres having a mean diameter size range of 10 μ ι η to 2000 μ ι η.
11. A hydrogel according to claim 9 in the form of microspheres having an average iodine content of greater than 15mg/ml microcapsules fully hydrated in normal saline as the fill volume.
12. The hydrogel of claim 9 in the form of microspheres having an average radiopacity greater than 500 HU.
13. The hydrogel of claim 9, wherein the hydrogel is in the form of microspheres having a net negative charge at ph 7.4.
14. A hydrogel according to any one of claims 1 to 13 for use in the embolization of a blood vessel.
15. Use of a hydrogel according to any one of claims 9 to 13 in the form of microspheres in the manufacture of a medicament for the treatment of a solid tumour, wherein the hydrogel microspheres are administered into a blood vessel associated with the solid tumour in a patient to embolize the blood vessel.
16. The use of claim 15, wherein the solid tumor is an angio-rich liver tumor.
17. A composition comprising hydrogel microspheres of any one of claims 9 to 13 and a therapeutic agent, wherein the therapeutic agent is adsorbed into the hydrogel matrix.
18. The composition of claim 17, wherein the therapeutic agent is camptothecin.
19. The composition of claim 17, wherein the therapeutic agent is an anthracycline.
20. The composition of claim 17, wherein the therapeutic agent is selected from irinotecan, topotecan, doxorubicin, daunorubicin, idarubicin, epirubicin, sorafenib, vandetanib, and sunitinib.
21. The composition of claim 17, wherein the therapeutic agent is miboplatin.
22. The composition of claim 17, wherein the therapeutic agent is held in the hydrogel by static electricity.
23. The composition of any one of claims 17 to 22, for use in embolization of a blood vessel.
24. Use of a composition according to any one of claims 17 to 22 in the manufacture of a medicament for the treatment of a solid tumour, wherein:
the hydrogel is in the form of microspheres; and wherein
The composition is administered into a blood vessel of a patient associated with the solid tumor to embolize the blood vessel.
25. The use of claim 24, wherein the solid tumor is an angio-rich liver tumor.
26. A method of making a radiopaque hydrogel copolymer comprising PVA or a copolymer of PVA, the method comprising reacting a hydrogel copolymer comprising PVA or a copolymer of PVA with a radiopaque species capable of forming a cyclic acetal with a 1,3 diol under acidic conditions, wherein the PVA backbone comprises at least two side chains comprising a crosslinkable ethylenically unsaturated functional group, the crosslinkable group being crosslinked by a vinylic comonomer, the copolymer comprising a 1, 3-diol group, wherein the radiopaque species comprises an iodinated phenyl group, wherein the vinylic comonomer is 2-acrylamido-2-methylpropane sulfonic acid, the radiopaque species being linked to the copolymer by a cyclic acetal linkage such that the hydrogel copolymer comprises a structure according to general formula I
Wherein X is a group of the formula
Wherein Z is a linking group bound to the cyclic acetal or is absent such that the phenyl group is bound to the cyclic acetal;
if Z is present, then Z is C1-6Alkylene radical, C1-6Alkyleneoxy or C1-6An alkoxy alkylene group;
hal is 1,2, 3 or 4 covalently linked iodides; and
j is a group-CH2-。
27. The method of claim 26, wherein the side chain containing the crosslinkable ethylenically unsaturated functional group is linked to the 1, 3-diol group of the PVA backbone via a cyclic acetal linkage.
28. The method of claim 26, wherein the crosslinkable ethylenically unsaturated functional group is an acrylate group.
29. The method of claim 26, wherein the copolymer is acrylamido polyvinyl alcohol-co-acrylamido-2-methylpropane sulfonate.
30. The method of claim 26, wherein the radiopaque substance is an iodinated aldehyde.
31. The method of claim 26, wherein the radiopaque substance is a compound of formula IV:
wherein:
a is selected from-CHO, -CHOR1OR2、-CHOR1OH、-CHSR1OH or-CHSR1SR2Wherein R is1And R2Independently selected from C1-4An alkyl group;
z is a linking group or is absent; if Z is present, then Z is C1-6Alkylene radical, C1-6Alkyleneoxy or C1-6An alkoxy alkylene group; and
hal is 1,2, 3 or 4 covalently linked iodides.
32. The method of claim 31, wherein Z is methylene or ethylene or is a group- (CH)2)p-O-(CH2)q-, where q is 0, 1 or 2, and p is 1 or 2.
33. The method of claim 32, wherein Z is selected from-CH2O-、-CH2OCH2-and- (CH)2)2A group of O-; or Z is absent.
34. The method of claim 31, wherein Hal is 3 or 4 iodides.
35. The method of claim 26, wherein the radiopaque substance is iodinated benzyl aldehyde, iodinated phenyl aldehyde, or iodinated phenoxy aldehyde.
36. The method of claim 26, wherein the copolymer is a hydrogel in the form of microspheres.
37. A method of making the radiopaque hydrogel microspheres of claim 36, comprising the steps of:
(a) swelling preformed hydrogel microspheres in a solvent capable of swelling said microspheres; and
(b) mixing the swollen microspheres with a solution of a radiopaque substance capable of forming a cyclic acetal with a 1,3 diol under acidic conditions; and
(c) and extracting the microspheres.
38. The method of claim 37, further comprising the step of drying the extracted microspheres.
39. The method of claim 37, wherein the radiopaque substance is 2,3, 5-triiodobenzaldehyde, 2,3,4, 6-tetraiodobenzaldehyde, or 2- (2,4, 6-triiodophenoxy) acetaldehyde.
examples