Facile Direct Conjugation of Peptides, Peptide Modified Polymers and Therapeutic Agents to Tissue Surfaces. (27127)
Synthetic peptide-polymer conjugates are enzymatically coupled to cartilage under mild conditions through the formation of isopeptide bonds between the peptides and extra cellular matrix (ECM) proteins. The system provides a general means of drug delivery, tissue engineering and repair or bioadhesives administration in a biocompatible process.
ADVANTAGES: Facile enzymatic controlled tissue engineering of ECM tissues under mild physiological conditions with potential for minimally invasive therapies.
SUMMARY: A variety of strategies have been employed to chemically couple natural or synthetic molecules to biological surfaces for drug delivery, tissue repair and tissue regeneration. In contrast the present technology employs a general methodology for tissue surface modification employing biological enzyme mediated crosslinking reactions. Tissue transglutaminase (tTG), which catalyzes the crosslinking between lysine and glutamine residues, forming ε-(γ-glutaminyl) lysine isopeptide bonds, provides a vehicle to enzymatically couple synthetic molecules to tissue surfaces under physiologic conditions. Cartilage, which contains tTG and several ECM substrates of tTG, upon treatment with a variety of short synthetic peptides, containing lysine or glutamine residues conjugated with polymers, readily binds to the conjugates under the action of added tTG. Thus lysine conjugates (EO)2-FKG-NH2, (B2K); (PEG)-FKG-NH2, (B72K) and glutamine conjugates (EO)2-GQQQLG-NH2, (B2Q); (PEG)-GQQQLG-NH2, (B72Q) incubated (30 min, 37°C) with cartilage in the presence of tTG showed incorporation on the tissue surface to depths of 8-13 μM (Figure 1, 2). ECM components fibronectin, collagen II, osteonectin and osteropontin all exhibit binding to the conjugates. No surface incorporation occurs in the absence of tTG. The lysine and glutamine peptides employed were rationally designed to afford favorable tTG substrates. Peptide conjugates of hyaluronic acid (FKG-HA) and functionalized hydrocortisone (HC-GFKG) have been similarly incorporated into cartilage surfaces.
The minimally invasive administration of tTG and synthetic molecules to other tissue surfaces provides a novel means to deliver a wide range of functional polymers, biomolecules and therapeutic agents.
STATUS: Binding of a range of tissue and synthetic peptide conjugates has been demonstrated employing the technology. A patent application has been filed.
Reference: Biomaterials (2007), 28, (35), 5215-5224
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