Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2000-06-21
2002-06-25
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S332000, C528S363000, C528S422000, C528S425000, C528S482000, C424S001290, C424S001330
Reexamination Certificate
active
06410680
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to treating oxidative stress and, particularly, to treating disease conditions associated with a presence of superoxide and of reactive chemical species derived from superoxide.
BACKGROUND
The oxygen radicals (including for example “superoxide”, O
2
·−
; hydroxyl radical, OH
·
) and some non-radical derivatives of O
2
(including for example hydrogen peroxide, H
2
O
2
) are commonly known as reactive oxygen species [“ROS”]. During electron transport in redox reactions in all living organisms the reduction of molecular oxygen by a single electron generates the reactive oxy-radical, i.e., the superoxide anion (O
2
·−
). ROS, including superoxide and chemical species derived from it, can be damaging to living systems. In healthy aerobic organisms, production of ROS (and of reactive nitrogen species [“RNS”]) is balanced by antioxidant defenses. The balance is imperfect, however, and some ROS- and RNS-mediated damage is ongoing to greater or lesser degrees. In healthy organisms, damaged biomolecules are continually repaired or replaced.
A serious imbalance that arises between production of ROS/RNS and the antioxidant defenses is referred to as “oxidative stress”, and significant oxidative damage can be caused by oxidative stress. Oxidative stress can result from diminished antioxidants (for example by depletion or underproduction of antioxidants as a result of dietary insufficiency or genetically associated metabolic deficiency), or from increased production of ROS/RNS (for example by exposure to elevated O
2
or by metabolism of toxins or by excessive activation of ROS/RNS-producing pathways resulting from inflammatory disease processes).
Oxidative stress is associated with a wide variety of disease conditions. In some instances oxidative stress is a primary cause of the disease condition (e.g., radiation-induced damage, some cancers, some drug side effects, and sometimes atherosclerosis and hypertension); or probably is a primary cause (e.g., Vitamin E deficiency and Selenium deficiency). In other instances oxidative stress is secondary, but may contribute significantly to pathology (e.g., atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease, and possibly a significant number of other diseases).
Under normal circumstances in cytosol or on extracellular surfaces the superoxide radical is consumed by superoxide dismutases (SODs). SOD enzymes are oxoreductases (EC 1.1.5.1.1) that contain copper, iron, or manganese ion in the active site and catalyze the dismutation of O
2
·−
radicals to molecular oxygen and hydrogen peroxide, which is further converted to molecular oxygen and water by catalase. Many mammalian diseases may be characterized as conditions in which the body fails to contain an overproduction of the O
2
·−
radical and of the more harmfully reactive O
·
. radical which is consequently derived through Fenton chemistry between reduced metal ions (Cu
+
, Fe
2+
) and hydrogen peroxide.
In certain metabolic processes, the production of O
2
·−
is enhanced, resulting in tissue injury and disease. Examples of such oxidative stress-related diseases include perfusion injury, such as that which occurs after acute myocardial infarction or stroke, inflammatory processes such as arthritis, inflammatory bowel conditions and stomach ulcers.
Considerable effort has been directed toward developing pharmaceuticals that might be therapeutically useful in ameliorating tissue injury and disease associated with oxidative stress. In one general approach, an excess of reactive oxygen species would be corrected by administering an agent that would produce increased superoxide dismutase activity where oxidative stress is either underway or likely to occur. Attempts have been made, for example, to administer a superoxide dismutase (typically, a CuZn-SOD) enzyme of animal origin to a subject in need of treatment. The SOD may be used in the native state, but some have proposed modifying it in some manner, such as by treatment with albumin (see, e.g., L. G. Cleland et al. 1979
, Arthritis Rheum
., Vol. 22, p. 559) polyethylene glycol (see, e.g., J. M. McCord et al. 1979, in, “Excerpta Medica”,
Ciba Foundation Symposium
, Vol. 65, pp. 343-60), ficoll (see, e.g., W. F. Petrone et al. 1980
, Proc. Nat'l. Acad. Sci. USA
, Vol. 77, pp. 1159-63), polyalkylene glycol (see, e.g., Japanese Patent No. 61-249388 (Ajinomoto Co., 1985)) or liposome (see, e.g., A. M. Michelson 1982
, Agents Action
, Vol. 11, pp. 179-210). Modification of SOD enzymes may provide advantages for their use as drugs. A suitably modified SOD may, for example, have longer lifetime in vivo, or may have reduced toxicity as compared to the native enzyme, or may have reduced immunogenicity (see, e.g., A. Abuchowski et al. 1978
, Recl. Trav. Chim. Pays-Bas
, Vol. 97, pp. 293-95). However, such modified enzymes may be costly, and the modifications may reduce their effective catalytic activity.
Others have proposed administering synthetic lower molecular weight metal complexes, and a variety of small-molecule SOD “mimics” have been developed and tested for pharmaceutical efficacy (see, e.g., B. Halliwell et al. 1999
, Free Radicals in Biology and Medicine
, 3d Ed., Oxford, see particularly, pp. 831-32). Where such SOD mimics employ copper or iron as the metal, however, they may generate highly reactive OHM radicals, which can rapidly interact with surrounding living materials, resulting in tissue injury and aggravation of the disease state.
SUMMARY
In one general aspect the invention features a dendrimer construct having a core and two or more branched arms projecting outwardly from the core. The arms include internal branched units and terminal moieties; the terminal moieties constitute an outermost surface of the dendrimer construct. The arms include at least one metal ion binding site enclosed within the outermost surface. The outermost surface of the dendrimer construct is sufficiently densely packed to restrict the movement of larger molecules from the milieu into the dendritic construct, and the surface is sufficiently porous to permit free movement of smaller molecules from the milieu into the dendrimer construct and to the metal ion binding site and out from the dendrimer construct to the milieu.
In another general aspect the invention features a metal-dendrimer complex in which a metal active site is enclosed within the surface of the dendrimer construct. The dendrimer construct includes a core and two or more branched arms projecting outwardly from the core. The arms include internal branched units and terminal moieties; the terminal moieties constitute the outer surface of the dendrimer construct. The arms include at least one metal ion binding site associated with one or more internal branched units and enclosed within the outermost surface, and a metal ion is complexed at the metal ion binding site to form the metal active site. The outermost surface of the dendrimer construct is sufficiently densely packed to restrict the movement of larger molecules from the milieu into the dendritic construct Smaller molecules such as the superoxide anion (O
2
·−
) move freely from the milieu into the dendrimer construct and to the metal active site, where the dismutation of superoxide to hydrogen peroxide is effected; and smaller molecules such as hydrogen peroxide move freely out from the dendrimer construct to the milieu.
In some embodiments the metal ion in the complex is an ion of a transition metal such as copper, manganese, or iron; in particular embodiments the metal ion is an ion of copper, particularly copper(II); or is an ion of iron, particularly iron(III).
In some embodiments the dendrimer construct results from sequential monomer addition in a divergent synthesis, beginning from a core and constructing the branched arms by proceeding outwardly through successive generations (the core being the zeros
th
generation). One mode of such divergent synthesis proceeds by sequential addition of monomers
Asinovsky Olga
DendriMolecular, Inc.
Haynes Beffel & Wolfeld LLP
Kennedy Bill
Seidleck James J.
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