Biolitec Pharma Marketing Ltd

Biolitec Unternehmensbeteiligungs II Ag

Biolitec Unternehmensbeteiligungs III Ag

Biolitec Ag

Universitat Duisburg-essen

Biolitec Holding Gmbh & Co Kg

Burkhard Gitter

Arno Wiehe

Volker Albrecht

Gerhard Wieland

Benjamin Florian Hohlfeld

Wolfgang Neuberger

Dorika Steen

Nikolay Nifantiev

Rainer Haag

Susanna Gräfe

Matthias Epple

Daniel Aicher

Christian B W Stark

Dmitri V Yashunsky

Susanna Graefe

Albrecht Volker

Dieter Riesenberg

Kathirvel Ganesan

Claudia S Gutsche

Karl-Heinz Völpel

Volker Schroeckh

Michael Staegemann

Janine Schwiertz

Gerhard D Wieland

Claudia Simone Gutsche

Karl-Heinz Voepel

Matthias Dr Prof Epple

Volker Dr Prof Albrecht

Ganesan Kathinvel

Biologically active compounds and their methods of preparation are provided that may be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of non-tumorous indications such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, otorhinolaryngology disorders, ophthalmological or urological disorders. As the compounds exhibit also toxicity against targets (tumor cells, bacteria, inflammation-related cells) without light these biologically active compounds may also be used for the light-independent treatment of such indications. Embodiments also include methods to synthesize boron dipyrromethene complex structures incorporating a substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyldipyrrin) unit or a substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrrin) unit. Amphiphilic compounds with increased anti-tumour and anti-bacterial efficacy are also provided. Specifically, this is achieved by substitution with bromine atoms and sugar moieties.

Application of boron dipyrromethene derivatives in anti-tumor and anti-bacterial therapy

Biologically active compounds and their methods of preparation are provided that may be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of non-tumorous indications such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, otorhinolaryngology disorders, ophthalmological or urological disorders. As the compounds exhibit also toxicity against targets (tumor cells, bacteria inflammation-related cells) without light these biologically active compounds may also be used for the light-independent treatment of such indications. Embodiments also include methods to synthesize iridium(III) complex structures incorporating a substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetratfluorophenyldipyrrin) unit or a substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrrin) unit. Amphiphilic compounds with increased anti-tumour and anti-bacterial efficacy are also provided. Specifically, this is achieved by substitution with bromine atoms and sugar moieties.

Application of dipyrrinato-iridium complexes in anti-tumor and anti-bacterial therapy

The present invention provides biologically active compounds and methods to obtain biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of non-tumorous indications such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders. As the compounds exhibit also toxicity against targets (tumor cells, bacteria, inflammation-related cells) without light these biologically active compounds may also be used for the light-independent treatment of such indications. Preferred embodiments of the present invention consist of methods to synthesize metal or half-metal complex structures incorporating one or more substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyldipyrrin) units. These dipyrromethenes (dipyrrins) can carry a variety of different substituents in the 4-position enabling a fine tuning of their biological or amphiphilic/hydrophilic properties. Another object of the present invention is to provide amphiphilic compounds with a higher membrane affinity and increased efficacy.

Application of metal complexes in anti-tumor and anti-bacterial therapy

Biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders are provided as well as providing methods to obtain them in pharmaceutical quality. In addition, conjugates are provided in which these photosensitizers are attached to water-soluble polymers via cleavable linkers that can be cleaved in the body under specific conditions. Another embodiment consists of formulating the desired tetrapyrrole photosensitizer into a pharmaceutical formulation to be injected into the body avoiding undesirable effects like solubility problems or delayed pharmacokinetics of the tetrapyrrole systems.

Conjugates of porphyrinoid photosensitizers and glycerol-based polymers for photodynamic therapy

Methods and devices to eliminate, reduce, destroy and/or inhibit undesired body fluid species, such as pathogen microbes and deteriorated or malignant cells in complex environments like blood, serum and other body fluids are provided. In preferred embodiments, an antimicrobial photodynamic therapy (PDT) treatment is given that effectively inactivates, reduces and/or destroys both Gram (&#x2212;) and Gram (+) bacteria in complex body fluids. Methods to enhance antimicrobial PDT activity include administering a photosensitizer to bacteria-contaminated fluid, after a dwell time guiding bacteria-contaminated fluid with photosensitizer through a channel, emitting radiation preferably in an intermittent manner, and restoring treated body fluids to corresponding body regions. Electromagnetic radiation is preferably delivered intermittently with pulse width based on treatment parameters. Additionally, the method/device diminishes adverse host's inflammatory responses by neutralizing the biological activity of pathogenic microorganism fragments and reducing and/or removing pathogenic microorganism fragments responsible for it.

Enhanced anti-microbial PDT

Antimicrobial molecular conjugates for the treatment and prevention of infectious diseases caused by pathogenic microorganisms in human and animals are provided. The conjugates are of the class of compounds of dihydroxychlorins or &#x3b2;-functionalized chlorins connected to carbohydrate moieties and having the general formula 

Glyco-substituted dihydroxy-chlorins and &#x3b2;-functionalized chlorins for anti-microbial photodynamic therapy

Antimicrobial molecular conjugates for the treatment and prevention of infectious diseases caused by pathogenic microorganisms in human and animals are provided. The key to these conjugates is a special spacer connecting at least one photosensitizer to a microorganism receptor (vector) which in turn binds selectively to the surface of a microorganism bringing about photo-destruction upon irradiation. Spacers having hydrophilic structure such as ethylene glycol units and amino carboxyl end capped ethylene glycol units must be used for linking the vector to the photosensitizer. In a preferred embodiment a spacer would have at least 3 ethylene glycol units and be end capped with a carboxyl group on one end and a amino group at the other end. The present invention effectively works to combat bacterial infection in the real patient-related environments where blood, serum and other body fluids are always present or at least nearby. Spacers of selected length and structure, in preferred embodiments, are used for linking the vector to the photosensitizer. These conjugate are found to be very effective in combating bacterial infection in the real patient-related environments where blood, serum and other body fluids are always present or a least nearby. A method of use is also provided.

Anti-microbial photodynamic therapy

The present invention provides pharmaceutical photosensitizer-loaded nanoparticle formulations and their methods of preparation for photodynamic therapy, comprising a hydrophobic or hydrophilic photosensitizer, nanoparticulate calcium phosphate and in certain cases auxiliary reagents such as stabilizers. The calcium phosphate-based nanoparticle formulations of the present invention provide excellent storage stability and therapeutically effective amounts of photosensitizer for intravenous or topical administration. In a preferred embodiment, tetrapyrrole derivatives such as porphyrins, chlorins and bacteriochlorins, are the preferred hydrophobic photosensitizers to be formulated in calcium phosphate nanoparticle formulations for photodynamic tumor therapy. Additionally, 5,10,15,20-tetrakis(4-phosphonooxyphenyl)porphine (pTPPP) is a preferred hydrophilic photosensitizer for photodynamic tumor therapy. In another preferred embodiment, hydrophilic cationic and anionic photosensitizers, especially those of the phenazinium, phenothiazinium and xanthenes series have been found to inactive pathogen bacteria and are the preferred photosensitizers to be formulated in calcium phosphate nanoparticle formulations for antibacterial photodynamic therapy. In another embodiment, photosensitizing nanoparticle formulations are useful to locate cells, tissues or bacteria by using fluorescence imaging methods.

Calciumphosphate-based nanoparticles as carrier-systems for photodynamic therapy

Treatment methods/devices are provided for attenuating/inactivating the pathogenic microbes found in biological fluids e.g. blood/blood products including human single-donor-fresh-frozen-plasma, platelet concentrate, red blood cells, blood clotting factors. An Antimicrobial Photodynamic Therapy method is used to eliminate multiple (resistant) bacteria, viral agents, fungi, parasites and other undetected or non-easily detected pathogenic microbes or particles in blood and blood products without affecting their biological properties. Resistant bacteria are difficult to be eliminated. This is especially true in the case forand related strains,orspecies and other bacteria found on skin. Further embodiments eliminate undetected or non-easily detected viral agents contaminating blood/blood products responsible for spreading hepatitis, Acquired ImmunoDeficiency Syndrome and other blood borne viral diseases. Human Immunodeficiency, hepatitis B and hepatitis C viruses have emerged as major blood borne infections. Numerous parasites transmitted through bloods and derived products are also eliminated by these processes/devices.

Method for microbes depletion in human blood or full serum using antimicrobial photodynamic laser therapy

A new approach for targeting chemotherapeutics to focal bacterial infections is provided. Such focal infections are characterized by high densities of different bacteria and thus high concentrations of their extracellular signal molecules sensing the cell density. In gram-negative bacteria, one of such signal molecules is acyl-homoserine lactone (acyl-HSL, member of the autoinducer family AI-1), wherein species-specificity is achieved by acyl-residues, and HSLs are common for all gram-negative bacteria. In gram-positive bacteria, oligopeptides secreted by the bacteria communicate the cell density. In addition, there are cell density signal molecules (members of the autoinducer family AI-2) which communicate between gram-positive and gram-negative bacteria. The general scheme of the present invention is molecular modules that comprise both a targeting component and a chemotherapeutical component which serves for photodynamic antimicrobial chemotherapy (PACT). One preferred embodiment of the present invention is to target photosensitizers to the extracellular signal molecules instead of on the bacteria themselves. Targeting of the photosensitizers is mediated via molecules with efficient binding to the HSL-moiety of the acyl-HSL, so that a broad spectrum of gram-negative bacteria can be knocked out. Photosensitizers used in the present invention can be packed into special liposomes with lipid chelators or multiple coupled to dendrimers, so that they are especially effective for PACT. In addition, selected molecules with high affinity to a common moiety of such signal molecules, like HSL, may be used as molecular probes for the search of yet undiscovered cell density dependent signals.

Molecular probes for targeting of cell density-indicating compounds

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Jena, Germany

Burkhard Gitter