Tumor Biology Center

Freiburg, Germany

Tumor Biology Center

Freiburg, Germany
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Hochdorffer K.,Tumor Biology Center | Abu Ajaj K.,Tumor Biology Center | Abu Ajaj K.,Leibniz Institute for Molecular Pharmacology | Schafer-Obodozie C.,ProQinase GmbH | Kratz F.,Tumor Biology Center
Journal of Medicinal Chemistry | Year: 2012

Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin. © 2012 American Chemical Society.


Lee Y.,Gwangju Institute of Science and Technology | Graeser R.,ProQinase GmbH | Kratz F.,Tumor Biology Center | Geckeler K.E.,Gwangju Institute of Science and Technology
Advanced Functional Materials | Year: 2011

Novel paclitaxel-loaded polymer nanoparticles were developed for circumventing multidrug resistance (MDR) of malignant cancerous diseases, which is an unsolved clinical problem in cancer chemotherapy. In many cases, MDR is due to the intrinsic or acquired expression of an efflux pump, the P-170 glycoprotein (P-gp). By encapsulating paclitaxel in a water-soluble and biocompatible synthetic polyampholyte using a solid-state reaction the highly water-soluble paclitaxel-loaded nanoparticles are formed. The resulting paclitaxel nanoparticles with an average diameter of 250 nm show a significant reversal of chemoresistance in the drug-resistant variants (MCF7/ADR, MT3/ADR) by a factor of 100 or more. The novel paclitaxel nanoparticles enter MDR breast cancer cells by adsorptive endocytosis bypassing the P-gp, preventing the efflux of paclitaxel and thus restoring the anti-proliferative effect of paclitaxel. Novel paclitaxel-loaded polymer nanoparticles are synthesized by supramolecular complexation in the solid state. They are highly soluble in water and taken up by wild and MDR-type breast cancer cells via adsorptive endocytosis and bypass the P-glycoprotein efflux in MDR-type cells. Their significantly enhanced cancer cell inhibition effect against MDR cells shows high potential for a new anticancer agent. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Abu Ajaj K.,Tumor Biology Center | Abu Ajaj K.,Leibniz Institute for Molecular Pharmacology | Graeser R.,ProQinase GmbH | Graeser R.,Janssen Pharmaceutical | Kratz F.,Tumor Biology Center
Breast Cancer Research and Treatment | Year: 2012

The P-glycoprotein (P-gp) is a 170-kDa protein that acts as an energy dependent, transmembrane efflux pump and is encoded by the MDR1 gene. It has been shown to be responsible for multidrug resistance (MDR) in a defined subpopulation of breast cancer patients and thus represents a molecular target for circumventing MDR in this tumor indication. MDR modulators have been developed and demonstrated high selectivity for P-gp with inhibitory activities in the low nanomolar range. Although some objective responses were achieved in clinical trials, combination therapy with these MDR modulators, such as Ca 2+ antagonists caused unacceptable toxicity. Targeting P-gp inhibitors to the tumor site is a mean to increase their therapeutic index, and in this context binding of tailor-made prodrugs to circulating albumin is an established technology to reduce the toxicity and enhance the efficacy of anticancer drugs. In this study, we consequently developed an acid-sensitive albumin-binding prodrug of the P-gp inhibitor zosuquidar (LY335979) in a two-step synthesis using a maleimide hydrazone linker system established in our laboratory that first introduces acetylbenzoic acid at the HO-group of zosuquidar followed by derivatization with 6-maleimidocaproyl hydrazide to form the acid-sensitive hydrazone bond. The maleimide group enables the prodrug to bind rapidly and selectively to the cysteine-34 position of endogenous albumin after intravenous administration. HPLC analysis demonstrated rapid albumin binding of the zosuquidar prodrug as well as the quantitative release of the acetylbenzoic ester derivative of zosuquidar at pH 5.0. Subsequently, its ability to circumvent MDR was tested in two doxorubicin-resistant breast carcinoma cell lines (MCF-7/ADR and MT-3/ADR). The MDR status of these cell lines can be reversed by zosuquidar which was confirmed in a rhodamine 123 assay using fluorescence microscopy and FACS analysis. Furthermore, zosuquidar as well its acid-sensitive albumin conjugate re-sensitized cells to doxorubicin as well as to an albumin-binding prodrug of doxorubicin, i.e., the 6-maleimidocaproyl hydrazone derivative of doxorubicin, achieving IC 50 values in the same order of magnitude as the parental cell lines. Thus, a novel formulation of zosuquidar has been developed that could have the potential to improve the toxicity issues and tumor targeting properties of the original compound. © 2012 Springer Science+Business Media, LLC.


Muller I.A.,Tumor Biology Center | Kratz F.,Tumor Biology Center | Jung M.,Albert Ludwigs University of Freiburg | Warnecke A.,Tumor Biology Center
Tetrahedron Letters | Year: 2010

A number of novel acid-sensitive Schiff bases derived from p-aminobenzyl alcohol and various benzaldehyde derivatives were synthesized and were subsequently shown to trigger benzyl elimination reactions. The kinetics of acid-catalyzed hydrolysis at pH 5.0 as well as stability at pH 7.4 were studied using fluorogenic model compounds. Two fluoro-substituted Schiff bases showed efficient hydrolysis at pH 5.0 combined with a long-term stability at pH 7.4 and are considered suitable candidates for the development of anticancer prodrugs. © 2010 Elsevier Ltd.


Kullenberg D.,Tumor Biology Center | Taylor L.A.,University of Heidelberg | Schneider M.,Lecithos Consulting | Massing U.,Tumor Biology Center
Lipids in Health and Disease | Year: 2012

Beneficial effects of dietary phospholipids (PLs) have been mentioned since the early 1900's in relation to different illnesses and symptoms, e.g. coronary heart disease, inflammation or cancer. This article gives a summary of the most common therapeutic uses of dietary PLs to provide an overview of their approved and proposed benefits; and to identify further investigational needs. From the majority of the studies it became evident that dietary PLs have a positive impact in several diseases, apparently without severe side effects. Furthermore, they were shown to reduce side effects of some drugs. Both effects can partially be explained by the fact that PL are highly effective in delivering their fatty acid (FA) residues for incorporation into the membranes of cells involved in different diseases, e.g. immune or cancer cells. The altered membrane composition is assumed to have effects on the activity of membrane proteins (e.g. receptors) by affecting the microstructure of membranes and, therefore, the characteristics of the cellular membrane, e.g. of lipid rafts, or by influencing the biosynthesis of FA derived lipid second messengers. However, since the FAs originally bound to the applied PLs are increased in the cellular membrane after their consumption or supplementation, the FA composition of the PL and thus the type of PL is crucial for its effect. Here, we have reviewed the effects of PL from soy, egg yolk, milk and marine sources. Most studies have been performed in vitro or in animals and only limited evidence is available for the benefit of PL supplementation in humans. More research is needed to understand the impact of PL supplementation and confirm its health benefits. © 2012 Küllenberg et al; licensee BioMed Central Ltd.


Arnold D.,Tumor Biology Center | Stein A.,University of Hamburg
Drugs | Year: 2013

In this review article we discuss the evolution of second-line treatment options for patients with metastatic colorectal cancer (mCRC). The benefits of second-line chemotherapy have been established for some time, but in the last decade a number of trials have evaluated combinations of irinotecan- and oxaliplatin-based chemotherapy with molecular-targeted agents; e.g., vascular endothelial growth factor (VEGF)-targeting agents (bevacizumab, aflibercept), epidermal growth factor receptor antibodies (cetuximab, panitumumab), and tyrosine kinase inhibitors (vatalanib). Recent developments include the availability of the new VEGF-targeted agent aflibercept and the new concept of continuing bevacizumab after failure of first-line bevacizumab, which is likely to become a new treatment option in the second-line setting. Choosing the most appropriate second-line treatment regimen for mCRC patients remains a complex issue. All of the currently available molecular-targeted agents seem to be active even after patients have received a bevacizumab-based first-line regimen. Overall, the selection of second-line treatment for mCRC depends on several variables and should be determined taking into account the patient's performance and disease status. © 2013 Springer International Publishing Switzerland.


Moktan S.,University of Mississippi Medical Center | Perkins E.,University of Mississippi Medical Center | Kratz F.,Tumor Biology Center | Raucher D.,University of Mississippi Medical Center
Molecular Cancer Therapeutics | Year: 2012

Elastin-like polypeptides (ELP) aggregate in response to mild hyperthermia, but remain soluble under normal physiologic conditions. ELP macromolecules can accumulate in solid tumors because of the enhanced permeability and retention effect. Tumor retention of ELPs can be further enhanced through hyperthermia-induced aggregation of ELPs by local heating of the tumor. We evaluated the therapeutic potential of ELPs in delivering doxorubicin in the E0771 syngeneic mouse breast cancer model. The ELP-Dox conjugate consisted of a cell-penetrating peptide at the N-terminus and the 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensured release of doxorubicin in the lysosomes/ endosomes after cellular uptake of the drug conjugate. ELP-Dox dosed at 5 mg doxorubicin equivalent/kg, extended the plasma half-life of doxorubicin to 5.5 hours. In addition, tumor uptake of ELP-Dox increased 2- fold when hyperthermia was applied, and was also enhanced compared to free doxorubicin. Although high levels of doxorubicin were found in the heart of animals treated with free doxorubicin, no detectable levels of doxorubicin were found in ELP-Dox-treated animals, indicating a correlation between tumor targeting and reduction of potential cardiac toxicity by ELP-Dox. At an optimal dose of 12 mg doxorubicin equivalent/kg, ELP-Dox in combination with hyperthermia induced a complete tumor growth inhibition, which was distinctly superior to free drug that only moderately inhibited tumor growth. Insummary, our findings showthat thermal targeting of ELPincreases the potency of doxorubicin underlying the potential of exploiting ELPs to enhance the therapeutic efficacy of conventional anticancer drugs. ©2012 AACR.


Kullenberg D.,Tumor Biology Center
Lipids in health and disease | Year: 2012

Beneficial effects of dietary phospholipids (PLs) have been mentioned since the early 1900's in relation to different illnesses and symptoms, e.g. coronary heart disease, inflammation or cancer. This article gives a summary of the most common therapeutic uses of dietary PLs to provide an overview of their approved and proposed benefits; and to identify further investigational needs.From the majority of the studies it became evident that dietary PLs have a positive impact in several diseases, apparently without severe side effects. Furthermore, they were shown to reduce side effects of some drugs. Both effects can partially be explained by the fact that PL are highly effective in delivering their fatty acid (FA) residues for incorporation into the membranes of cells involved in different diseases, e.g. immune or cancer cells. The altered membrane composition is assumed to have effects on the activity of membrane proteins (e.g. receptors) by affecting the microstructure of membranes and, therefore, the characteristics of the cellular membrane, e.g. of lipid rafts, or by influencing the biosynthesis of FA derived lipid second messengers. However, since the FAs originally bound to the applied PLs are increased in the cellular membrane after their consumption or supplementation, the FA composition of the PL and thus the type of PL is crucial for its effect. Here, we have reviewed the effects of PL from soy, egg yolk, milk and marine sources. Most studies have been performed in vitro or in animals and only limited evidence is available for the benefit of PL supplementation in humans. More research is needed to understand the impact of PL supplementation and confirm its health benefits.


Kratz F.,Tumor Biology Center
Journal of Controlled Release | Year: 2014

Human serum albumin (HSA) has emerged as a versatile carrier for therapeutic agents, primarily for treating diabetes and cancer, improving the pharmacokinetic profile of the drug or delivering the drug to the pathogenic site addressing diseases with unmet medical needs. Market approved products include fatty acid derivatives of human insulin or the glucagon-like-1 peptide (Levemir®, Tresiba®, and Victoza®) which bind physically to the respective binding sites of HSA thus extending their half-life. For cancer treatment, the paclitaxel albumin nanoparticle Abraxane® has been approved for treating metastatic breast cancer, non-small cell lung cancer, and advanced pancreatic cancer. Finally, the albumin-binding prodrug of doxorubicin, Aldoxorubicin, which binds covalently to the cysteine-34 position of circulating albumin, is in advanced clinical trials with a registration phase 3 trial for soft tissue sarcoma initiated in Q1 2014. © 2014 Elsevier B.V.


Ren D.,University of California at Irvine | Kratz F.,Tumor Biology Center | Wang S.-W.,University of California at Irvine
Small | Year: 2011

The E2 component of pyruvate dehydrogenase is engineered to form a caged, hollow dodecahedral protein assembly, and the feasibility of this scaffold to be used as a drug delivery system is examined by introducing cysteines to the internal cavity (D381C). The fluorescent dye Alexa Fluor 532 (AF532M) and the antitumor drug doxorubicin are coupled to this internal cavity through maleimides on the guest molecules. The viruslike particle's structure and stability remain intact after binding of the molecules within the interior of the nanocapsule. The pH-dependent hydrolysis of a hydrazone linkage to doxorubicin allows 90% drug release from the D381C scaffold within 72 h at pH 5.0. Fluorescence microscopy of MDA-MB-231 breast cancer cells indicates significant uptake of the D381C scaffold incorporating AF532M and doxorubicin, and suggests internalization of the nanoparticles through endocytosis. It is observed that the protein scaffold does not induce cell death, but doxorubicin encapsulated in D381C is indeed cytotoxic, yielding an IC50 of 1.3 ± 0.3 μM. While the majority of particulate-based drug delivery strategies encapsulates drugs within polymeric nanoparticles, these results show the potential for using macromolecular protein assemblies. This approach yields a promising new opportunity for designing highly defined nanomaterials for therapeutic delivery. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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