This proposal aims to fabricate highly selective, robust, chemical receptors for the proteins employing polymerizable mixed liposomes. Carbonic anhydrase will be used for the initial optimization studies; after the optimization studies are complete, focus will be shifted to a bio-medically relevant protein, MMP-13. Matrix metallo-proteinases (MMPs) are a class of zinc-containing endo-peptidases capable of degrading extra-cellular matrix. Over-expressions of a variety of these enzymes have been implicated in tumor invasion and metastasis. Out of this family, Collagenase-3 (MMP-13) is capable of degrading type II collagen at neutral pH. It has been found to be over-expressed in fibroblastic cells surrounding brest carcinoma. MMPs are ubiquitous and are required for normal body functions. Since over-expression of a particular class of these enzymes is associated with diseases, selective targeting to one class of these enzymes is of paramount importance in treating the disease without disrupting other body functions. The specific goals are summarized below. Synthesis of new polymerizable zwitter-ionic, cationic and hydrogen bond forming lipids; synthesis of new polymerizable lipids capable of complexing either a transition metal ion (e.g., Cu2+, Zn2+ etc.) or a luminescent lanthanide metal ion (e.g., Tb3+ or Eu3+) with high affinity (K greater than 10'5 M-1). Fabrication of stable, chemical receptors for proteins by creating a three-dimensional pattern of metal-ions, ion-pairs and hydrogen bonding sites on liposomes, complimentary to the pattern exhibited by the MMP-13. In order to achieve this objective, mixed polymerizable liposomes will be prepared with ionic lipids, metal-chelating lipids and lipids with primary amine moiety on their headgroups. Polymerizable diacyl phosphocholine (zwitter ionic) will be used as the major constituent of these liposomes. After fabrication, these liposomes (in the unpolymerized state, above the gel-transition temperature) will be allowed to interact with the protein. The metal ions on liposome surface will orient complementary to the pattern of surface-exposed histidines of MMP-13. Quaternary ammonium headgroups on the liposomes will be positioned by acidic amino acid residues (Asp, Glu) on the protein surface. Amino acid side chains of the protein capable of forming hydrogen bonds (e.g., Ser, Thr, Lys, Asn, Gln and Arg) will interact with the primary amine moieties on the liposome. The result of this equilibration step is the creation of a pattern of metal ions, charges and hydrogen bonding sites on the liposome complementary to the surface pattern exhibited by the template protein. The pattern on the liposome will then be locked by photo-polymerization. The polymerized liposomes will """"""""recognize"""""""" MMP-13 by an array of simultaneous and complementary interactions in three dimensions; thus the binding will be strong and selective. Measurement of binding affinity and selectivity by luminescence spectroscopy and micro-calorimetry; structural characterization studies by EPR spectroscopy, transmission microscopy (TEM) and atomic force microscopy (AFM). Testing of the synthetic receptors for possible applications in detection of metastatic cancer, imaging and delivery of anti- cancer drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Chin, Jean
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North Dakota State University
Schools of Arts and Sciences
United States
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