Targeted vectors

Abstract

This invention provides therapeutic and diagnostic agent delivery vehicles, including viral vectors, that are complexed to a targeting moiety by coordinate covalent linkages mediated by a transition metal ion. The complex is typically formed with a transition metal ion that is in a kinetically labile oxidation state; after the complex is formed, the oxidation state of the transition metal ion is changed to one that renders the complex kinetically stable. The use of a coordinate covalent linkage to attach the targeting moiety to the delivery vehicle provides advantages such as the ability to readily attach a different targeting moiety to a delivery vehicle without modifying the delivery vehicle itself. This flexibility is achieved without sacrificing stability of the complex.

What is claimed is:  
     
         1 . A method of replacing a worn wear strip located between a rail and a retaining plate, the method comprising 
 (a) positioning a new wear strip adjacent the worn wear strip;    (b) securing a clamping apparatus to the rail adjacent the new wear strip opposite the worn wear strip; and,    (c) moving the rail in a direction from the clamping apparatus towards the retaining plate until the clamping apparatus abuts the retaining plate, the new wear strip pushing the worn wear strip from its position between the rail and the retaining plate.    
     
     
         2 . The method of  claim 1  wherein the clamping apparatus comprises a spacer between two flanges, with bolts inserted through the flanges and the spacer, and wherein securing the clamping apparatus comprises positioning the flanges on either side of the rail and tightening the bolts.  
     
     
         3 . The method of  claim 2  wherein the spacer comprises a plurality of plates, and wherein securing the clamping apparatus comprises selecting plates to make up the plurality of plates such that the spacer has a width slightly less than a width of the rail.  
     
     
         4 . The method of  claim 1  wherein moving the rail is accomplished by hydraulic means.  
     
     
         5 . A clamping apparatus configured to be secured to a rail, the clamping apparatus comprising first and second flanges and a spacer, the first and second flanges and spacer all having at least one bolt hole therethrough, and at least one bolt inserted through the at least one bolt hole.  
     
     
         6 . The clamping apparatus of  claim 5  wherein the at least one bolt hole through at least one of the first and second flanges is threaded to secure the at least one bolt therein.  
     
     
         7 . The clamping apparatus of  claim 5  further comprising at least one nut, wherein the at leasmethods for targeting vectors, which have significant limitations as previously discussed. First, one need not reengineer a viral genome, for example, to modify the gene that encodes the surface protein each time one wishes to use a different targeting ligand. One simply employs a different CM-targeting ligand to retarget the vector and modify its tropism. Second, coordinate covalent complexes are kinetically inert, resulting in a long-lasting targeted vector. In contrast, attachment of targeting ligands by means of non-covalent linkage, for example, antibodies that bind to viral coat proteins is not kinetically inert. 
 It is essential that one appreciate the distinction between a kinetically inert and a thermodynamically stable complex. This distinction is discussed in detail in Anderson et al. (U.S. Pat. No. 5,439,829 issued Aug. 8, 1995). Thermodynamic stability refers to the thermodynamic tendency of a species to exist under equilibrium conditions. A kinetically inert complex, on the other hand, is one that is not labile, i.e., a particular complexed ion is not able to readily engage in reactions that result in replacement of one or more ligands in its coordination sphere by others. For example, in an aqueous environment, unoccupied coordination positions on a transition metal ion are occupied by water. A chelating peptide or other chelating agent must displace the water molecules to form a complex. When such reactions occur rapidly, the reaction is termed “labile.” However, where such reactions occur very slowly or not at all, the complex is said to be kinetically “inert.” Kinetic lability or inertness, unlike thermodynamic stability or instability, is thus related to the reaction rate. A