Preparation of Soluble and Colloidal Molecularly Imprinted Polymers by Living Polymerization

• US 20080311072A1
• Filed: 06/01/2006
• Published: 12/18/2008
• Est. Priority Date: 06/01/2005
• Status: Active Grant

• Current Assignee: MIP Diagnostics Limited
• Original Assignee: Cranfield University
• Inventors: Piletsky, Sergey Anatoliyovich, Karim, Khalku, Piletska, Olena Volodimirivna, Turner, Anthony Peter Francis, Chianella, Iva, Guerriero, Antonio Ricardo Leonardo
• Granted Patent: US 8,192,762 B2
• Time in Patent Office: Days
• US Class Current: 424/78.36
• CPC Class Codes: B01J 20/26 Synthetic macromolecular compounds
• CPC Class Codes: B01J 20/268 Polymers created by use of a template, e.g. molecularly imprinted polymers
• CPC Class Codes: C08F 2/38 Polymerisation using regulators, e.g. chain terminating agents , e.g. telomerisation
• CPC Class Codes: C08F 2438/03 Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
• CPC Class Codes: C08F 293/005 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
• CPC Class Codes: C08F 4/00 Polymerisation catalysts

Abstract

The present invention describes a method for synthesis of relatively low molecular weight imprinted polymers using living polymerization, and their application in analytical chemistry, pharmacology, medicine and the food industry. Specifically the low-molecular weight polymers are synthesized by the polymerization of functional monomers in the presence of a template, such as a biological receptor, enzyme, nucleic acid, cell, virus, microorganism, tissue sample or drug using living initiator. The conditions of living polymerization ensure a relatively small size of synthesized molecules. Synthesized in this way molecules (dimers, oligomers, polymers, or their mixture) have a higher affinity to the template than the original monomers and can rebind it in vitro and/or in vivo. As a further aspect of the present invention, polymers synthesized as described above can be used as drugs in pharmacology and medicine, as receptor-specific ligands in analytical chemistry (sensors, assays), and for separations in the biotechnology, pharmaceutical and food industries.

Claims

1. A process for the preparation of a solution or colloidal suspension of a polymer comprising template-directed living polymerisation of functional monomers performed in the presence of a molecular template, thereby producing a complementary polymer at least a part of which is complementary to at least a part of the template, and the process including terminating the living polymerisation when complementary polymer particles suitable for preparation of the solution or colloidal suspension have formed.

2. A process according to claim 1, in which the process includes a step of modifying the complementary polymer particles to produce derived polymer particles, at least a part of which is complementary to at least a part of the template, for preparation of the solution or colloidal suspension.

3. A process according to claim 1, wherein the living polymerisation technique is selected from iniferter polymerisation, stable free radical-mediated polymerisation, atom transfer radical polymerisation (ATRP), and reversible addition-fragmentation chain transfer (RAFT) polymerisation.

4. A process according to claim 3, wherein the living polymerisation technique is a nitroxide-mediated radical polymerisation.

5. A process according to claim 3, wherein the living polymerisation technique is an iniferter polymerisation and the iniferter is selected from:

photo iniferters bearing a dithiocarbamyl group; and

thermal iniferters bearing an azo group.

6. A process according to claim 1, wherein the living polymerisation is initiated by an initiator selected from:

2-bromopropionitrile with Cu(I)Br complexed with N,N,N′

,N″

,N″

-pentamethyldiethylenetriamine;

polystyrene bromo macroinitiator with Cu(I)Cl/PMDETA;

ethyl 2-bromoisobutyrate with CuCl/bipyridine;

1,4-bis(2,6-diisopropylphenyl)acenaphatenediiminenickel (II) dibromide;

2,2-dimethoxy-2-phenylacephenone in combination with tetraethylthiuram disulfide;

tetraphenyl biphosphine;

tertiary peroxides (e.g., di-tert-butyl peroxide);

SmMe(C₅Me₅)₂(THF);

styrene-based epoxides in conjunction with TiCl₄;

methylstyrene tetramer disodium;

MoOCl₄-n-BuSn-EtOH;

HCl/ZnCl₂;

methyl p-toluenesulphonate;

2,10,15,20-tetraphenylporphinato aluminium methyl;

3-methyl-1,1-diphenylpentyllithium;

butyllithium in THF;

molybdenum alkylidine compounds;

bifunctional organolanthanide(III);

Mo(CH-t-Bu)(NAr)(OCMe₃)₂;

Mo(CHCPhMe₂)(NAr)(OCMe(CF₃)₂)₂;

HI/l₂;

Zr, Ti and Hf complexes combined with either methylaluminoxane or phenyl borates;

diimide complexes of Pd, Ni, Fe or Co;

homogeneous Ta, Ti, Mo, W carbene complexes;

rare earth metal complexes composed of metallocene type or non-metallocene type complexes;

cationic monocyclopentadienyl zirconium acetamidinate complexes;

esterified fluorinated telomers with one or two hydroxyl groups; and

Yb[C(SiMe₃)₃]₂.

7. A process according to claim 1, wherein the complementary polymer has a molecular weight of 500-1,000,000 Da.

8. A process according to claim 1, in which the process includes the steps of:

separating from the polymerisation system a complex comprising the template and complementary polymer; and

subsequent removal of the template.

9. A process according to claim 8, wherein removal of the template involves separation of the template from the polymer by means of one or more of change in pH of the solution, change in the ionic strength of the solution, and adding urea, guanidine, or a substance which interacts with the template stronger than does the polymer.

10. A process according to claim 8, wherein the removal of the template employs one or more of filtration, electrophoresis, chromatographic separation, washing, centrifugation, and dialysis.

11. A process according to claim 1, in which the process further comprises the use of affinity separation to isolate a complementary polymer fraction having a specific affinity to the template.

12. A process according to claim 1, wherein the living polymerisation is performed under one or more of the following conditions:

i) a stoichiometric ratio between initiator and monomers;

ii) cooling the reaction or stopping irradiation of the reaction to terminate radical formation after an initial initiation period which is shorter than the duration of the polymerisation reaction;

iii) removal of monomers from contact with the growing complementary polymer;

iv) addition of inhibitors to the reaction; and

v) a dilute reaction solution.

13. A process according to claim 1, wherein the functional monomers are selected from:

vinyl monomers;

allyl monomers;

acetylenes;

acrylates;

methacrylates;

derivatives of amino acids;

nucleosides;

nucleotides; and

carbohydrates.

14. A process according to claim 1, wherein the living polymerisation includes the steps of:

a) template-directed living polymerisation of a functional monomer in the presence of a template;

b) stopping polymerisation;

c) re-starting polymerisation in the presence of a different functional monomer;

thereby producing a complementary polymer which is a block copolymer, at least a part of which is complementary to at least a part of the template; and

d) optionally repeating steps a) to c).

15. A process according to claim 1, further comprising the step of cross-linking the functional monomers.

16. A process according to claim 15, wherein the cross-linking is effected by one or more cross linkers selected from:

ethylene glycol dimethacrylate;

methylene bisacrylamide; and

N,N′

-bisacryloylpiperazine.

17. A process according to claim 1 including a further step of contacting the solution or colloidal suspension of a polymer with a surface;

and restarting the living polymerisation to effect reaction between the polymer and the surface.

18. A product having a surface with an attached polymer, the polymer being attached to the surface according to claim 17.

19. A method of performing separations in biotechnology, or the pharmaceutical or food industries comprising the use of a product according to claim 18.

20. A polymer, solution of a polymer, or colloid of a polymer prepared according to the process of claim 1.

21. A pharmaceutical method comprising administering a polymer, solution of a polymer, or colloid of a polymer according to claim 20 as a drug.

23. Use of a polymer solution of a polymer, or colloid of a polymer prepared according to claim 1 as a contrasting agent, catalyst, or sensor element.

24. A process according to claim 1 including a further step of using the solution or colloidal suspension of polymer or a polymer isolated from said solution or suspension as a receptor-specific ligand.

25. A process according to claim 1 including a further step of using the solution or colloidal suspension of polymer or a polymer isolated from said solution or suspension as a separation matrix.

26. A process according to claim 1 including a further step of using the solution or colloidal suspension of polymer or a polymer isolated from said solution or suspension as a contrasting agent, catalyst or sensor element.

22. (canceled)