Biolitec Research GmbH

Jena, Germany

Biolitec Research GmbH

Jena, Germany
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Staegemann M.H.,Free University of Berlin | Gitter B.,Biolitec Research GmbH | Dernedde J.,Charité - Medical University of Berlin | Kuehne C.,Charité - Medical University of Berlin | And 2 more authors.
Chemistry - A European Journal | Year: 2017

The antibacterial photodynamic activity of hyperbranched polyglycerol (hPG) loaded with zinc porphyrin photosensitizers and mannose units was investigated. hPG, with a MW of 19.5kDa, was functionalized with about 15 molecules of the photosensitizer (5,10,15-tris(3-hydroxyphenyl)-20-[4-(prop-2-yn-1-ylamino)tetrafluorophenyl]porphyrinato)-zinc(II) by using copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC). These nanoparticle conjugates were functionalized systematically with increasing loadings of mannose in the range of approximately 20 to 110 groups. With higher mannose loadings (ca. 58-110 groups) the water-insoluble zinc porphyrin photosensitizer could thus be transferred into a water-soluble form. Targeting of the conjugates was proven in binding studies to the mannose-specific lectin concanavalinA (ConA) by using surface plasmon resonance (SPR). The antibacterial phototoxicity of the conjugates on Staphylococcus aureus (as a typical Gram-positive germ) was investigated in phosphate-buffered saline (PBS). It was shown that conjugates with approximately 70-110 mannose units exhibit significant antibacterial activity, whereas conjugates with approximately 20-60 units did not induce bacterial killing at all. These results give an insight into the multivalency effect in combination with photodynamic therapy (PDT). On addition of serum to the bacterial cultures, a quenching of this antibacterial phototoxicity was observed. In fluorescence studies with the conjugates in the presence of increasing bovine serum albumin (BSA) concentrations, protein-conjugate associations could be identified as a plausible cause for this quenching. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Haedicke K.,Jena University Hospital | Grafe S.,Biolitec Research GmbH | Lehmann F.,Dyomics GmbH | Hilger I.,Jena University Hospital
Biomaterials | Year: 2013

In our study we wanted to elucidate a time frame for invivo optical imaging of the therapeutic efficacy of photodynamic therapy (PDT) by using a multiplexed imaging approach for detecting apoptosis and vascularization. The internalization of the photosensitizer Foslip® into tongue-squamous epithelium carcinoma cells (CAL-27) was examined invitro and invivo. For detecting apoptosis, annexin V was covalently coupled to the near-infrared dye DY-734 and the spectroscopic properties and binding affinity to apoptotic CAL-27 cells were elucidated. CAL-27 tumor bearing mice were treated with PDT and injected 2 days and 2 weeks thereafter with DY-734-annexin V. PDT-induced changes in tumor vascularization were detected with the contrast agent IRDye® 800CW RGD up to 3 weeks after PDT. A perinuclear enrichment of Foslip® could be seen invitro which was reflected in an accumulation in CAL-27 tumors invivo. The DY-734-annexin V (coupling efficiency 30-50%) revealed a high binding affinity to apoptotic compared to non-apoptotic cells (17.2% vs. 1.2%) with a KD-value of 20nm. After PDT-treatment, the probe showed a significantly higher (p <0.05) contrast in tumors at 2 days compared to 2 weeks after therapy (2-8h post injection). A reduction of the vascularization could be detected after PDT especially in the central tumor areas. To detect the therapeutic efficacy of PDT, a multiplexed imaging approach is necessary. A detection of apoptotic cells is possible just shortly after therapy, whereas at later time points the efficacy can be verified by investigating the vascularization. © 2013 The Authors.

Haedicke K.,Friedrich - Schiller University of Jena | Graefe S.,Biolitec Research GmbH | Teichgraeber U.,Friedrich - Schiller University of Jena | Hilger I.,Friedrich - Schiller University of Jena
Biomedical Optics Express | Year: 2016

The objective of this study was to determine an optimal dose of photodynamic therapy (PDT) for inducing apoptotic tumor cells in vivo. In this context, mice bearing human tongue-squamous epithelium carcinomas were treated with various photosensitizer concentrations and fluences. Tumor apoptosis was imaged after 2 days via a self-designed DY-734-annexin V probe using near-infrared fluorescence (NIRF) optical imaging. Apoptosis was verified ex vivo via TUNEL staining. Apoptotic tumor cells were detected in vivo at a dose of 40 µg photosensitizer and a fluency of 100 J/cm2. This is the lowest photosensitizer dose reported so far. © 2016 Optical Society of America.

Haedicke K.,Friedrich - Schiller University of Jena | Kozlova D.,University of Duisburg - Essen | Grafe S.,Biolitec Research GmbH | Teichgraber U.,Friedrich - Schiller University of Jena | And 2 more authors.
Acta Biomaterialia | Year: 2015

Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye molecule DY682-NHS for enabling near-infrared fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diameter of approximately 200 nm and a zeta potential of around +22 mV. Their biodistribution at 24 h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle-PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2 days and 2 weeks after treatment to detect apoptosis. Additionally, the contrast agent IRDye® 800CW RGD was used to assess tumor vascularization (up to 4 weeks after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2 days. Decreases in tumor vascularization and tumor volume were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization. © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Moret F.,University of Padua | Scheglmann D.,Biolitec Research GmbH | Reddi E.,University of Padua
Photochemical and Photobiological Sciences | Year: 2013

The folate receptor (FR) is over-expressed in many human tumours and is being intensively studied also in the field of nanomedicine as a target to enhance the selectivity of drug delivery to cancer cells by using nanocarriers bearing folic acid (FA) on their surface. In this study we report the encapsulation of the photosensitizer (PS) meta-tetra(hydroxyphenyl)chlorin (m-THPC) in FA-targeted PEGylated liposomes used as a novel drug delivery system for photodynamic therapy (PDT) of cancer. Our in vitro investigations revealed that only a modest fraction of targeted liposomes were internalized by specific endocytosis in FR-positive KB cells. However, FA-liposomes doubled the uptake of the entrapped m-THPC with respect to un-targeted liposomes and enhanced the photo-induced cytotoxicity in KB cells. In contrast, in FR-negative A549 cells FA-targeted or un-targeted liposomes exhibited a very similar extent of internalization and as a consequence the same photo-killing efficiency. © 2013 The Royal Society of Chemistry and Owner Societies.

Beyzavi M.H.,Free University of Berlin | Beyzavi M.H.,Biolitec Research GmbH | Nietzold C.,Free University of Berlin | Nietzold C.,BAM Federal Institute of Materials Research and Testing | And 3 more authors.
Advanced Synthesis and Catalysis | Year: 2013

meso-Substituted trans-A2B2-porphyrins bearing specific patterns of substituents are crucial building blocks in porphyrin-based biomimetic systems and molecular materials and can be used for the construction of well-defined porphyrin-based architectures. A new stepwise and rational synthesis of functionalized trans-A2B2-porphyrins is reported in which for the first time donor-acceptor-substituted cyclopropane precursors (d-a cyclopropanes) are exploited. The three presented d-a cyclopropanes are readily accessible in a multi-gram scale and serve as aldehyde equivalents in the reaction with an excess of pyrrole to afford the corresponding dipyrromethanes (DPMs). The three DPMs were synthesized in yields of 60-74%. They are stable in purified form in the absence of light and air and were subsequently condensed with a wide range of aliphatic and aromatic aldehydes bearing electron-donating or electron-withdrawing substituents followed by oxidation to form the corresponding trans-A2B 2-porphyrins. Fourteen functionalized porphyrins were synthesized in yields of 14-31%, indicating the broad scope of the synthetic procedure. The possibility to introduce key functional groups is emphasized, which enables subsequent modification of these porphyrins with moieties inducing biological activity. Modification of the tetrapyrroles may occur by addition to one of the porphyrin peripheral double bonds, the use of substituents of the aryl groups or via the methoxycarbonyl group at two of the meso-substituents. Three examples of porphyrins were converted into the corresponding 7,8-dihydroxychlorins by osmium-mediated dihydroxylation and one of the resulting chlorins was subjected to saponification to give a highly polar chlorin dicarboxylic acid. A 4-bromophenyl-substituted d-a cyclopropane was prepared by rhodium-catalyzed cyclopropanation and then transformed into a DPM which was subsequently condensed to a porphyrin. Its Zn complex allowed a Heck reaction to afford the functionalized bis(alkenyl)-substituted trans-A2B2-Zn- porphyrin. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hamed B.,Free University of Berlin | Haimberger T.V.,Free University of Berlin | Kozich V.,Free University of Berlin | Wiehe A.,Biolitec Research GmbH | Heyne K.,Free University of Berlin
Journal of Photochemistry and Photobiology A: Chemistry | Year: 2014

The two-photon absorption of the photosensitizers 5,10,15,20-tetrakis(m-hydroxyphenyl) porphyrin and the corresponding chlorin has been studied in the near infrared (IR) range using open-aperture z-scan technique. We found cross sections of 10-40 GM in the Q-band region, comparable to values in the Soret-band. Both photosensitizers are promising candidates for IR two-photon photodynamic therapy given the better penetration of IR light into tissue. © 2014 Elsevier B.V. All rights reserved.

Golf H.R.A.,Free University of Berlin | Golf H.R.A.,Biolitec Research GmbH | Reissig H.-U.,Free University of Berlin | Wiehe A.,Free University of Berlin | Wiehe A.,Biolitec Research GmbH
Organic Letters | Year: 2015

The reaction of alcohols with (pentafluorophenyl)dipyrromethane (PFP-DPM) under basic conditions has been studied, giving access to the corresponding alkoxy-substituted DPMs. This method represents the first high-yielding substitution of PFP-DPM carried out with oxygen nucleophiles. Condensation of these prefunctionalized DPMs with aldehydes led to the respective trans-A2B2 porphyrins. This pathway allows a simple synthesis of multifunctionalized tetrapyrroles. Oxidation and boron complexation of these DPMs, on the other hand, led to meso-functionalized difluoroboraindacenes (BODIPYs). In addition, nucleophilic substitution of PFP-BODIPY with sodium azide led to a 4-azidophenyl derivative, thus further enhancing the scope of reactive sites suitable for subsequent transformations. © 2015 American Chemical Society.

Beyzavi M.H.,Free University of Berlin | Beyzavi M.H.,Biolitec Research GmbH | Lentz D.,Free University of Berlin | Reissig H.-U.,Free University of Berlin | And 2 more authors.
European Journal of Organic Chemistry | Year: 2013

Calix[4]phyrins are an important class of hybrid macrocyclic systems at the interface between porphyrins and calixpyrroles (porphyrinogens). A new stepwise synthesis of oxidation-resistant meso-hydrogenated calix[4]phyrins is reported, which allows variable substitution in the residues of their sp 2-meso-centers without the need for a porphyrin intermediate. It relies on the acid-catalyzed condensation of a sterically hindered donor-acceptor-substituted cyclopropane precursor with pyrrole to form a sterically congested dipyrromethane. This was subsequently condensed with a wide range of alkyl and aryl aldehydes bearing electron-donating or electron-withdrawing substituents followed by an oxidation step to form stable calix[4]phyrin( with bridging meso-CH hydrogen atoms through an acid-promoted dehydrative condensation. The methodology avoids any need for premetallation of the macrocycle and/or the use of organometallic catalysts or reagents and allows the incorporation of the bulky cyclopropane-derived substituents specifically into the 5,15-meso-like positions. The resulting regioisomerically pure products display conformational features that reflect their mixed nature between porphyrins and calixpyrroles and they were assessed by X-ray diffraction analysis, NMR techniques and UV/Vis spectroscopy. The possibility to introduce key functional groups enables subsequent modification of these calix[4]phyrins and allows their connection to other groups such as biologically active moieties. Of special interest is an unprecedented example of an acid-driven lactonization that results in the incorporation of a mono-meso-spirolactone into a calix[4]phyrin( Moreover, it is demonstrated that this approach to calix[4]phyrins is also applicable to other sterically congested dipyrromethanes. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Beyzavi M.H.,Free University of Berlin | Beyzavi M.H.,Biolitec Research GmbH | Lentz D.,Free University of Berlin | Reissig H.-U.,Free University of Berlin | And 2 more authors.
Chemistry - A European Journal | Year: 2013

The article describes the synthesis of new functionalized calyx(n)phyrin macrocycles with varied ring sizes by using a sterically congested dipyrromethane. Lewis acids that are common for the synthesis of porphyrinoids: boron trifluoride diethyl etherate, candiumACHTUNGTRENUNG(III) ACHTUNGTRENUNGtriflate, p-toluenesulfonic acid (p-TSA) and polyphosphoric acid (PPA). The results reveal that each of the products can be obtained as the dominant product under certain conditions, for example, compound 5 was obtained in a maximum yield of 26% by using 75 mol% of TFA after 18 h. To the best of the knowledge, the published syntheses are limited to the preparation of calixphyrins as final products. No functionalizations at their peripheries have been studied. The introduction of suitable functional groups, however, would enable these macrocycles to be connected with other interesting compounds and to initiate new applications.

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