The biologic effects of growth factor-toxin conjugates in models of vascular injury depend on dose, mode of delivery, and animal species.
Toxin-conjugates, complexes designed from the fusion of tissue toxins and pathology-specific ligands, offer the potential for targeted cytotoxic therapy. Some have postulated that the recurrent failure of these conjugates to exhibit benefit in animal models of vascular injury arose because the timing and frequency of conjugate delivery were insufficient to meet the demands of the arterial wall. Previous data suggest that increasingly frequent dosing would lead to superior inhibition of intimal hyperplasia. We now report on the biological effects of the controlled release of a recombinant conjugate of basic fibroblast growth factor (bFGF) and the plant toxin saporin (SAP), bFGF-SAP. Alginate/heparin-Sepharose microspheres and films were designed as drug carriers to control release the bFGF-SAP conjugate or bFGF alone in small doses. When bFGF-SAP-incorporated microspheres or films were implanted adjacent to balloon angioplastied porcine carotid arteries, the controlled release of bFGF-SAP over the four-week study stimulated rather than inhibited hyperplasia. When these same devices were used in cell culture, unexpected findings were produced. bFGF-SAP reduced in vitro bovine vascular smooth muscle cell growth at high concentrations (1-10 microgram/mL) but increased smooth muscle cell growth at lower concentrations (up to 1 microgram/mL). Microsphere controlled-released bFGF-SAP ( approximately 60 ng/mL over 4 days) stimulated the growth of smooth muscle cells more than any of the tested bolus applications of the conjugate. These data provide cause to reconsider our acceptance of controlled release technology as the answer to all forms of drug delivery problems, and to apply more rigorous means of matching the kinetics of drug delivery to the kinetics of the vascular response to injury.
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Harvard-MIT Biomedical Engineering Center, Massachusetts Institute of Technology, 16-343, Cambridge, Massachusetts 02139, Prizm Pharmaceuticals, 11035 Roselle Street, San Diego, California 92121, USA.
Cunningham
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Rogers
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Dinbergs
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Edelman
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D017130:Angioplasty; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000008:administration & dosage*; D004337:Drug Carriers; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D006965:Hyperplasia / Q000139:chemically induced; D008863:Microspheres; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010940:Plant Proteins / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013552:Swine
D003603:Cytotoxins; D004337:Drug Carriers; D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C078442:basic fibroblast growth factor-saporin mitotoxin, recombinant; D016222:Fibroblast Growth Factor 2; D000076985:Saporins