United States Patent:  6,020,457

Assignee:  Dendritech Inc. (Midland, MI)

Filed:  September 30, 1997

Dendritic polymers containing disulfide functional groups which are essentially inert under non-reducing conditions, but which form sulfhydryl groups upon being subjected to a reducing agent are prepared by synthesizing dendritic polymers having a core with a disulfide linkage or by reacting a dendritic polymer with a molecule containing a disulfide linkage and reactive terminal groups. In one aspect of the invention, dendritic polymers having a single disulfide functional group at the core are provided. The single disulfide group at the core can be reduced to form two sulfhydryl groups to which other molecules, such as proteins, oligonucleotides, peptides, hormones, other dendritic polymers, non-dendritic polymers, etc., can be bound. Applications for the disulfide functionalized dendritic polymers include formation of differentiated dendrimers, formation of binding reagents for diagnostics, drug delivery, gene therapy and magnetic resins imaging, and in the preparation of self-assembled dendrimer monolayers on a quartz crystal resonators to provide dendrimer-modified electrodes which are useful for detecting various ions or molecules. In another aspect of the invention, dendritic polymers having sulfhydryl terminals are provided. The sulfhydryl terminated dendritic polymers can be used to prepare stable, curable resins composition which can undergo cross linking when subjected to a reducing agent.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with one aspect of the invention, dendritic polymers having a single disulfide functional group at the core are provided. These dendritic polymers having a single disulfide functional group at the core can be of generally any desired generation and can include any of a variety of different surface functional groups. The single disulfide group at the core can be reduced to form two sulfhydryl groups and split the dendritic polymer molecule into two parts, each having a single reactive sulfhydryl group to which other molecules, such as proteins, oligonucleotides, peptides, hormones, other dendritic polymers, non-dendritic (e.g., linear or branched) polymers, etc., can be bound. The remaining surface groups (which can, for example, be amines, carboxylates, hydroxyl, etc.) may be used for signal amplification, attachment to surfaces, analyte interaction, further conjugation, etc.

Because dendritic polymers, especially dendrimers of generally any generation, can be prepared having a very narrow molecular weight distribution, and hence a very narrow particle size distribution, and can be readily subjected to surface modification, it is possible to produce disulfide functionalized dendritic polymers having properties customized to provide optimum performance in a variety of specific applications. Applications for the disulfide functionalized dendritic polymers include formation of differentiated dendrimers having heterogeneous surface-group topology confined in a fixed region on the surface, formation of ultrathin dendritic polymer-containing films for use in biological sensing devices, formation of binding reagents for diagnostics, drug delivery, gene therapy, and magnetic resonance imaging, and in the preparation of self-assembled dendritic monolayers on a quartz crystal resonator to provide dendritic polymer-modified electrodes useful for detecting various ions or molecules which can selectively bind to the dendrimer surface.

In accordance with another aspect of the invention, dendritic polymers having sulfhydryl terminal or surface groups are provided. The sulfhydryl terminated dendritic polymers may be prepared by terminating a dendritic polymer with a compound containing a disulfide functional group and subsequently reducing the disulfide group or by reacting with a reagent that produces a free thio group (such as Traut's reagent). The dendritic polymers having terminals containing disulfide functional groups can be used to prepare stable, curable resin compositions which can undergo cross-linking when subjected to a relatively mild reducing agent and subsequent oxidation to form inter-molecular disulfide linkage.

The dendritic polymers of this invention can, in general, be prepared using either of the well-known synthesis schemes, i.e., the convergent approach or the divergent approach. Any of the known reaction methods including the one-pot method, the protect-deprotect method, or the excess reagent method can be employed in the preparation of the dendritic polymers of this invention. The one-pot method tends to produce imperfect dendritic molecules having a relatively high polydispersity as compared to the nearly perfect dendrimers having a polydispersity near unity which can be prepared using the protect-deprotect method or excess reagent method. The resulting disulfide-functionalized dendritic polymers of this invention include generally any of the known dendritic architectures including, dendrimers, controlled hyperbranched polymers, dendrigrafts, and random hyperbranched polymers.

The preparation of dendrimers, random hyperbranched polymers, controlled hyperbranched polymers and dendrigrafts is well-known. Methods of synthesizing dendrimers are set forth in U.S. Pat. Nos. 4,507,466; 4,558,120; 4,568,737; 4,587,329; 4,631,337; 4,694,064; 4,713,975; 4,737,550; 4,871,779 and 4,857,599. Examples of hyperbranched polymers and methods of preparing the same are set forth, for example in U.S. Pat. No. 5,418,301. The dendritic polymers of this invention are characterized by a relatively high degree of branching, which is defined as the number average fraction of branching groups per molecule, i.e., the ratio of terminal groups plus branch monomer units to the total number of terminal groups, branch monomer units and linear monomer units. For ideal dendrons and dendrimers, the degree of branching is one. For linear polymers, the degree of branching is zero. Hyperbranched polymers have a degree of branching which is intermediate that of linear polymers and ideal dendrimers. A degree of branching of at least about 0.5 is preferred. The dendritic polymers of this invention may also include macromolecules commonly referred to as cascade molecules, arborols, arborescent grafted molecules, and the like. Also included within the scope of this invention are bridged dendritic polymers, i.e., dendritic macromolecules linked together either through surface functional groups or through a linking molecule connecting surface functional groups together, and dendritic polymer aggregates. The dendritic polymers of this invention can be generationally monodisperse or generationally polydisperse. Dendritic polymers in a monodisperse solution are substantially all of the same generation, and hence of uniform size and shape. The dendritic polymers in the polydisperse solution comprise a distribution of different generation polymers.

Claim 1 of 49 Claims

1. A dendritic polymer having a core containing a disulfide moiety and at least two dendrons emanating from the core, each dendron having at least two terminal groups.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.