University of Michigan

Columbia University

University of Kentucky Research Foundation

Nano Intelligent Biomedical Engineering Corporation Co. Ltd.

Victor C Yang

Mark E Meyerhoff

Donald W Landry

Chang-Guo Zhan

Shi-Xian Deng

Young Min Kwon

Roger K Sunahara

James H Woods

John J Tesmer

Diwahar L Narasimhan

Joanne MacDonald

Tien-Yi Lee

Daquan Gao

Shu-Ching Ma

Mei-Chuan Holden Ko

Bernhard O Palsson

Chong-Pyoung Chung

Yoon Jeong Park

Robert H Bartlett

Yoon-Jeong Park

Junfeng Liang

Youngro Byun

Minoo Javanmardian

Jong H Yun

Embodiments of the invention disclosed herein generally relate to anti-cocaine therapeutics. Specifically, some embodiments of the invention relate to highly efficient, thermostable, and long-lasting cocaine esterase (CocE) mutants that can protect against the toxic and reinforcing effects of cocaine in subjects. Provided herein are mutant CocE polypeptides displaying thermostable esterase activity. Also provided are methods of treating cocaine-induced conditions in a subject in need via administration of mutant CocE as well as methods for high-throughput screening of candidate esterase polypeptides.

Anti-cocaine compositions and treatment

The present invention relates to a target-activated cell/tissue-penetrating peptide for delivery of impermeable compounds (Target Activated Cell/tissue Translocation peptide for Impermeable Compound Strategy (TACTICS)), and the use thereof, and more particularly to a target-activated cell/tissue-penetrating peptide, which comprises (a) a protein transduction domain (PTD), (b) a masking domain and (c) a spacer having a cleavage site specific for a target cell/tissue enzyme and is provided with target selectivity so as to penetrate specifically into a target tissue, and to a conjugate of the peptide with a drug or drug-containing particles for imaging or therapeutic applications. Because the target-activated cell/tissue-penetrating peptide has target selectivity, the peptide-drug conjugate exhibits maximized imaging and therapeutic effects, and the non-specific distribution of the conjugate in vivo is inhibited, so that the side effects of the conjugate are minimized, the diagnostic effects of the conjugate are maximized, and the conjugate is useful for the treatment of disease.

Target-activated cell/tissue-penetrating peptide for delivery of impermeable compounds and use thereof

The present invention relates to multicomponent compositions and methods of administering these compositions, which specifically translocate therapeutic molecules (e.g., drugs or prodrugs) across biological membranes thus reducing potential toxic side effects on nontargeted cells and tissues.

Drug delivery compositions

Provided are bioactive, low-toxicity protamine fragments, compositions, combinations, kits and methods of using these components in a variety of embodiments, including neutralizing heparin and reducing post-operative bleeding. Improved protamine fragment-insulin solutions and methods for treating diabetes are also provided.

Protamine fragment compositions and methods of use

A photobioreactor system for efficient oxygen production for a closed ecological life support system (CELSS) is disclosed. Special features of this system include, e.g., the optical transmission system, uniform light distribution, continuous cycling of cells, gravity independent gas-exchange, and an ultrafiltration unit. The fiber optic based optical transmission system illuminates the reactor internally and includes a light source which is external to the reactor, preventing heat generation problems. Uniform light distribution is achieved throughout the reactor without interfering with the turbulent regime inside. The ultrafiltration unit exchanges spent with fresh media and its use results in very high cell densities, up to 10.sup.9 cells/ml for Chlorella vulgaris. The prototype photobioreactor system may be operated in a batch and continuous mode for prolonged periods of time. The photobioreactor may be used to convert CO.sub.2 to oxygen in an artificial lung.

Photobioreactors and closed ecological life support systems and

A polymeric membrane electrode gives potentiometric responses to macromolles, such as protamine, in solution or biological specimens. A protamine-responsive membrane includes a lipophilic cation-exchange material for ionic macromolecules in a specially formulated plasticized, polymeric matrix material. Potentiometric response to protamine has been observed in membranes comprising 30-70 wt. % polymeric matrix material, such as polyvinyl chloride; 1-3 wt. % salt of a tetraphenylborate, such as potassium tetrakis(4-chlorophenyl) borate or salt of an organophosph(on)ate, such as calcium bis-[4-(1,1,3,3-tetramethylbutyl)phenyl] phosphate; and 30-70 wt. % of a plasticizer, such as 2-nitrophenyl octyl ether or tris (2-ethylhexyl) phosphate. The potentiometric response of these membranes to protamine can be used to study the binding interaction of protamine with heparin (both native and low molecular fractions) or to monitor protease activity, for example, by following the rate of degradation of intact protamine or a synthetic substrate by trypsin, as well as to measure protamine concentration in biological fluids, such as blood or plasma.

Protamine-responsive polymeric membrane electrode

An anion exchange membrane for ionic macromolecules, specifically heparin, which is formed of a polymeric matrix material and an anion exchange material suitable for heparin detection can be employed in an electrochemical sensor arrangement to directly measure the concentration of heparin ions in blood or blood fluid. Potentiometric response to heparin has been observed with membranes comprising 30-70 wt. % polymeric matrix material, such as polyvinyl chloride, 0.1-12 wt. % quaternary ammonium salt, such as tridodecyl methyl ammonium chloride, and 30-70 wt. % of a plasticizer, such as dioctyl sebacate. Moreover, a solid state sensor employs tridodecyl methyl ammonium chloride (TDMAC) dissolved in a polymeric compound, such as silicone rubber, to form a membrane which is responsive to heparin concentration.

Heparin-selective polymeric membrane electrode

An anion exchange membrane for ionic macromolecules, specifically heparin, which is formed of a polymeric matrix material, an anion exchange material suitable for heparin detection, and a plasticizer can be employed in an electrochemical sensor arrangement to directly measure the concentration of heparin ions in blood or blood fluid. Potentiometric response to heparin has been observed with membranes comprising 30-70 wt. % polymeric matrix material, such as polyvinyl chloride, 0.1-12 wt. % quaternary ammonium salt, such as tridodecyl methyl ammonium chloride, and 30-70 wt. % of a plasticizer, such as dioctyl sebacate.

An arrangement for collecting blood from a source of blood employs a filter chamber having a substantially predefined volume for accumulating the collected blood, and first and second access ports for receiving the collected blood and for venting the filter chamber, respectively. A protamine filter is arranged within the filter chamber, and preferably is formed of regenerated cellulose hollow fibers which have been activated with CNBr and have protamine immobilized thereon. The amount of protamine immobilized thereon is controlled in a variety of ways, prior to installation and sealing of the filter element within the filter chamber. In a practical embodiment, the first port of the filter chamber is coupled to a conventional cannula needle for communicating transdermally with a living being or through a membrane of a blood storage container. The second port is coupled to a conventional syringe which applies a suction for facilitating withdrawal of the blood. In other embodiments, the protamine is immobilized on a biocompatible polymer substrate by covalent bonding.

Protamine-based filter device for removal of heparin from blood samples

Heparin in an extracorporeal blood flow circuit is removed from the blood flow with the use of a filter which contains immobilized protamine on a blood-compatible support. In medical procedures where blood is processed in an extracorporeal device, such as an artificial kidney, or a heart-lung machine, the blood is heparinized to prevent clotting thereof in the channels of the extracorporeal device, and the formation of thrombi. In accordance with the invention, the processed, heparinized blood is conducted to a filter arrangement wherein protamine is held immobilized on a support formed of a blood-compatible material. Such an arrangement actually removes heparin from the blood rather than merely negates the anticoagulation effects of the heparin, as is the case in conventional protamine infusion therapy. In the present invention, the extracorporeal blood which is returned to the patient is substantially free of both heparin and protamine. Various chemical mechanisms are presented for activating a polymeric support material so as to bond covalently with the protamine.

Growing community of inventors

Ann Arbor, MI, United States of America

Victor C Yang