Medical device with coating for capturing genetically-altered cells and methods for using same
Therapeutic and drug delivery systems are provided in the form of medical devices with coatings for capturing and immobilizing target cells such as circulating progenitor or genetically-altered mammalian cells in vivo. The genetically-altered cells are transfected with genetic material for expressing a marker gene and a therapeutic gene in a constitutively or controlled manner. The marker gene is a cell membrane antigen not found in circulating cells in the blood stream and therapeutic gene encodes a peptide for the treatment of disease, such as, vascular disease and cancer. The coating on the medical device may be a biocompatible matrix comprising at least one type of ligand, such as antibodies, antibody fragments, other peptides and small molecules, which recognize and bind the target cells. The therapeutic and/or drug delivery systems may be provided with a signal source such as activator molecules for stimulating the modified cells to express and secrete the desired marker and therapeutic gene products.
1. A method of delivering a stent into a patient, comprising the steps of:
(i) administering genetically-altered endothelial progenitor cells into the patient, said genetically-altered endothelial progenitor cells comprising exogenous nucleic acid encoding a cell membrane marker molecule not normally found in said genetically-altered endothelial progenitor cells, and at least one therapeutic gene product; said genetically-altered endothelial progenitor cells being capable of expressing said cell membrane marker molecule and said at least one therapeutic gene product, wherein said cell membrane marker molecule is selected from the group consisting of an osteogenic protein, and a prostatic cell membrane protein; and
(ii) separately administering into said patient a cell-free stent comprising a coating on the lumen surface of the stent; said coating comprising a matrix bearing a covalently attached ligand, wherein said ligand specifically recognizes and binds said cell membrane marker molecule expressed by said genetically-altered endothelial progenitor cells;
wherein the therapeutic gene product is selected from the group consisting of vascular endothelial growth factor, angiogenin, anti-angiogenic factor, and fibroblast growth factor,
and wherein said genetically altered endothelial progenitor cells bind to said ligand on said stent in vivo.
2. The method of claim 1 , wherein the ligand is selected from the group consisting of antibodies, antibody fragments, combinations of antibodies and antibody fragments thereof.
3. The method of claim 2 , wherein the antibodies and/or antibody fragments are monoclonal.
4. The method of claim 1 , wherein said exogenous nucleic acid is extrachromosomal or a plasmid.
5. The method of claim 1 , wherein said genetically altered endothelial progenitor cells comprise autologous cells.
6. The method of claim 1 , wherein said genetically altered endothelial progenitor cells comprise donor or autologous cells.
7. The method of claim 1 , wherein said genetically altered endothelial progenitor cells comprise cells harvested from blood.
8. The method of claim 1 , wherein said genetically altered endothelial progenitor cells are injected intravenously to said patient.
9. The method of claim 1 , wherein said matrix comprises at least a layer of one, or more than one, polymeric compound.
10. The method of claim 9 , wherein said one, or more than one, polymeric compound is cross-linked with a cross-linking agent that forms covalent bonds capable of being cleaved by an enzyme under in vivo conditions.
11. The method of claim 9 , wherein said one, or more than one, polymeric compound is cross-linked with a cross-linking agent that forms covalent bonds that are capable of non-enzymatic hydrolysis under in vivo conditions.
12. The method of claim 11 , wherein said cross-linking agent comprises a compound having at least two reactive functional groups selected from the group consisting of aldehydes, epoxides, acyl halides, alkyl halides, isocyanates, amines, anhydrides, acids, alcohols, haloacetals, aryl carbonates, thiols, esters, imides, vinyls, azides, nitros, peroxides, sulfones, maleimides, poly(acrylic acid), vinyl sulfone, succinyl chloride, polyanhydrides, succinimidyl succinate-polyethylene glycol, and succinimidyl succinamide-polyethylene glycol, amine reactive esters.
13. The method of claim 1 , wherein the genetically-altered endothelial progenitor cells are endothelial progenitor or endothelial stem cells derived from human origin.
14. The method of claim 1 , wherein the stent further comprises an intimal hyperplasia or restenosis inhibitory compound.
15. The method of claim 14 , wherein the compound decreases or inhibits smooth muscle cell migration, smooth muscle cell differentiation, and/or collagen deposition.
16. The method of claim 1 , wherein said stent comprises a metal stent.