Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2001-03-26
2003-12-30
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S054110, C525S263000, C525S273000, C522S001000
Reexamination Certificate
active
06670427
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to novel template-textured materials in the form of template-textured polymers (TTPs, (TGP)) from aqueous solutions, as well as TTPs on a solid carrier (e.g. membranes), methods for the production and use thereof for substance-specific separation of materials.
In biotechnology, for products such as enzymes, monoclonal antibodies or recombinant proteins, new and efficient separation and cleaning strategies are required. This is equally valid for synthetic drugs, in particular when these exhibit a more complex structure and/or a higher molecular weight or a restricted stability.
For all of these fields of application, substance-specific high-performance materials are searched for, a high flexibility in adapting to the specific targets being required. Solid materials (particles, films) are preferably used so as to facilitate phase separation of solid and fluid substance flows. Contrary to separation methods based on different physical properties, the chemical affinity to the carrier is the prerequisite for substance-specific separations. Substance-specificity may be obtained by biological or biomimetical receptors. For affinity separations, either specific but very sensitive biological ligands (e.g. antibodies, enzymes), or relatively unspecific synthetic ligands (e.g. dyes, metal chelates) are being used so far; examples being chromatography, solid phase extraction, membrane separation, solid phase assays or sensors (D. Sii, A. Sadana,
J. Biotechnol
. 19 (1991) 83).
Nonporous films, respectively layers or particles comprising affine ligands on their surfaces possess a restricted binding capacity with porous materials having a higher specific surface and binding capacity, restrictions of the binding capacity typically occur due to diffusion limitations. Directionally permeable porous membranes are therefore particularly attractive alternative materials. Established membrane methods using membranes such as micro-filtration or ultra-filtration (MF or UF) work according to the size-exclusion principle (W. Ho, K. Sirkar (Eds.),
Membrane Handbook
, van Nostrand Reinhold, New York, 1992). The separation of substances having a similar molecular size with porous membranes, additionally requires specific (affinity) interactions with the membrane (E. Klein, Affinity Membranes, John Wiley & Sons, New York, 1991).
The main motivation for applying affinity membranes consist in the possibility of a directional flow towards separation-specific groups (ligands/receptors), which are present in the pores in a high density. This allows for a radical improvement of efficiency (decrease in pressure, shorter turnover times, higher throughput rates, scarcely diffusion limitations in pores, faster equilibration) as compared to analogous processes using particles (D. K. Roper, E. N. Lightfoot,
j. Chromatogr
. A 702 (1995)3). Such affinity membranes can be used for separations of materials, preferably of proteins, but also of many other substances (e.g. peptides, nucleic acid derivates, carbohydrate or various toxins, herbicides, pesticides) and even up to cells (U.S. Pat. No. 5,766,908). Furthermore, there exist multiple application possibilities in analytics, such as, for example, for the highly selective enriching of samples or even for the decontamination of material flows (DE 19609479).
A very attractive alternative for biological or biomimetic affinity ligands/receptors, e.g. for chromatography or analytics has been developed in the past years. This is the use of specific, yet highly robust functional cavities (“molecular imprints”) in synthetic polymers produced by molecularly texturing polymerization (G. Wulff,
Angew. Chem
. 107 (1995) 1958; K. Mosbach, O. Ramström,
Bio/Technology
14 (1996) 163; A. G. Mayes, K. Mosbach,
Trends Anal. Chem
. 16 (1997) 321). For this purpose, a polymerization of monomers is realized in the presence of template molecules (e.g. protein, nucleic acid, low-molecular organic substance), which are able to form a relatively stable complex with a functional monomer during polymerization. After the extraction of the template, the so produced materials are able to specifically bind template molecules again. The so synthezised polymers are called template-textured polymers (TTPs, (TGP))/molecularly textured polymers (WIPs, (MIP)) or “fingerprint” polymers (cf.
FIG. 1
, FIG.
2
).
In this manner, for example, the production of polymeric sorbents in the presence of smaller organic molecules (U.S. Pat. No. 5,110,833), respectively of macromolecular substances (U.S. Pat. No. 5,372,719), or the synthesis of acrylamide gels or agarose gels in the presence of proteins have been described (U.S. Pat. Nos. 5,728,296, 5,756,717). Even peptide sorbents, respectively protein-specific sorbents produced by “surface-texturing” of metal chelate structures on specifically functionalized particles have been described (U.S. Pat. No. 5786428). In all cases, high affinities were obtained for the respective templates. The application of artificial antibodies and receptors produced by molecular texturing, has enormous advantages, since these structures are much more stable than their natural equivalents. Moreover, they can be synthesized for each substance (even for those having less distinct antigen properties, such as small molecules or immunodepressiva), and can be produced in a considerably simpler and more cost-efficient manner than the corresponding biomolecules.
The selection of the components for the synthesis of a TTP is mainly based the interactions between template and functional monomer. Bearing the target in mind to “fix” these interactions as efficiently as possible and in a way accessible to affinity interactions, suitable cross-linkers and solvents are additionally selected.
Each substance having a defined three-dimensional structure (shape) may be used as a template for the synthesis of TTP. Substance classes consequently extend from small molecules having molecular weights of below or about 100 Da (e.g. herbicides) up to particles such as viruses, bacteria or cells. However, compounds having a biological function such as proteins, peptides, nucleic acids or carbohydrates are of particularly great interest. The recognition of templates by TTP is based on a combination of various factors such as reversible covalent or non-covalent binding, electrostatic and hydrophobic interactions, as well as the complementarity of the structure (shape). Which one of these factors is dominant depends on the polymeric structure, the template properties, as well as the binding conditions. In hydrophobic solvents, for example, electrostatic interactions for template recognition based on TTP are frequently dominant. In polar solvents, however, hydrophobic interactions as well as specificity of structure are most important for the template recognition. TTPs should preferably be synthesized under conditions favouring the strong, yet reversible interactions between the polymer and the template. For large molecules (100 . . . 100,000 Da), however, a combination of a plurality of weaker bonds including hydrogen bonds and hydrophobic interactions can be advantageous. For smaller molecules (50 . . . 100 Da), less strong interactions such as, for example ionic bonds, are necessary for obtaining a TTP with high affinity.
Water as solvent or aqueous systems in general are, of course, of special interest in conjunction with the above-mentioned applications. Ligand/receptor systems “optimized” by nature, operate perfectly under these conditions. However, the synthesis of TTP for applications in aqueous systems, has only recently achieved an initial success (L. Andersson,
Anal. Chem
. 68 (1996) 111; S. Hjerten, J. L. Liao, K. Nakazato, Y. Wang, G. Zamaratskaia, H. X. Zhang,
Chromatographia
44 (1997) 227). Syntheses of TTP receptors for smaller molecules cause particular problems. Up to the present moment, it is obvious that in those attempts to control not just the selection of suitable interaction agents but also the detailed arrangement of the functional
Matuschewski Heike
Piletski Sergiy
Schedler Uwe
Ulbricht Mathias
Asinovsky Olga
Kriegsman & Kriegsman
Poly-Am GmbH
Seidleck James J.
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