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1. Cross-boundary Evolution of Urban Planning and Urban Drainage Towards the Water Sensitive 'Sponge City'

Author

Zhou, Meiyue, Köster, Stephan, Zuo, Jian’e, Che, Wu, Wang, Xianping, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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2. Maintenance and Safety of Sponge City Infrastructure

Author

Köster, Stephan, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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3. Bodenschutz

Author

Förstner, Ulrich, Köster, Stephan, Förstner, Ulrich, and Köster, Stephan

Published
2018
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4. Trinkwasser

Author

Förstner, Ulrich, Köster, Stephan, Förstner, Ulrich, and Köster, Stephan

Published
2018
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5. Abfall

Author

Förstner, Ulrich, Köster, Stephan, Förstner, Ulrich, and Köster, Stephan

Published
2018
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6. Schadstoffe

Author

Förstner, Ulrich, Köster, Stephan, Förstner, Ulrich, and Köster, Stephan

Published
2018
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14. Correction to: Urban Water Management for Future Cities

Author

Köster, Stephan, Reese, Moritz, Zuo, Jian’e, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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15. Since 2015 the SinoGerman research project SIGN supports water quality improvement in the Taihu region, China

Author

Schmidt, Kathrin Rachel, der Beek, Tim aus, Dai, Xiaohu, Dong, Bingzhi, Dopp, Elke, Eichinger, Florian, Hammers-Wirtz, Monika, Haußmann, Regina, Holbach, Andreas, Hollert, Henner, Illgen, Marc, Jiang, Xia, Koehler, Jan, Koester, Stephan, Korth, Andreas, Kueppers, Stephan, Li, Aili, Lohmann, Matthias, Moldaenke, Christian, Norra, Stefan, Qin, Boqiang, Qin, Yanwen, Reese, Moritz, Riehle, Edmund, Santiago-Schuebel, Beatrix, Schaefer, Charlotte, Simon, Anne, Song, Yonghui, Staaks, Christian, Steinhardt, Joerg, Subklew, Guenter, Tao, Tao, Wu, Tingfeng, Yin, Daqiang, Zhao, Fangfang, Zheng, Binghui, Zhou, Meiyue, Zou, Hua, Zuo, Jiane, and Tiehm, Andreas

Published
2016
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18. Development of a Novel Imaging Agent for Determining Albumin Uptake in Solid Tumors

Author

K Abu Ajaj, Friederike I. Nollmann, P Perez Galan, S Chercheja, J Garcia Fernandez, Magnusson Johannes Pall, Steffen Daum, Koester Stephan David, Felix Kratz, Anna Warnecke, Lara Pes, and Federico Medda

Subjects
Pathology, medicine.medical_specialty, Biodistribution, medicine.diagnostic_test, business.industry, Albumin, Spleen, Imaging agent, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Pharmacokinetics, 030220 oncology & carcinogenesis, medicine, Original Article, Radiology, Nuclear Medicine and imaging, Drug carrier, business, Emission computed tomography, Conjugate
Abstract

PURPOSE: The purpose of this study was to investigate the albumin-binding compound (111)In-C4-DTPA as an imaging agent for the detection of endogenous albumin accumulation in tumors. METHODS: (111)In-C4-DTPA was injected in healthy nude mice for pharmacokinetic and biodistribution studies (10 min, 1, 6, 24, and 48 h, n = 4) and subsequently in tumor-bearing mice for single-photon emission computed tomography/X-ray-computed tomography (SPECT/CT) imaging studies. Four different human tumor xenograft models (LXFL529, OVXF899, MAXFTN401, and CXF2081) were implanted subcutaneously unilaterally or bilaterally (n = 4–8). After intravenous administration of (111)In-C4-DTPA, SPECT/CT images were collected over 72 h at 4–6 time points. Additionally, gamma counting was performed for the blood, plasma, lungs, heart, liver, spleen, kidneys, muscle, and tumors at 72 h post-injection. RESULTS: (111)In-C4-DTPA bound rapidly to circulating albumin upon injection, and the radiolabeled albumin conjugate thus formed was stable in murine and human serum. SPECT/CT images demonstrated a time-dependent uptake with a maximum of 2.7–3.8% ID/cm(3) in the tumors at approximately 24 h post-injection and mean tumor/muscle ratios in the range of 3.2–6.2 between 24 and 72 h post-injection. The kidneys and bladder were the predominant elimination organs. Gamma counting at 72 h post-injection showed 1.3–2.5% ID/g in the tumors and mean tumor/muscle ratios in the range of 4.9–9.4. CONCLUSION: (111)In-C4-DTPA bound rapidly to circulating albumin upon injection and showed time-dependent uptake in the tumors demonstrating a potential for clinical application as a companion imaging diagnostic for albumin-binding anticancer drugs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13139-019-00587-w) contains supplementary material, which is available to authorized users.

Published
2019

19. Novel auristatin E-based albumin-binding prodrugs with superior anticancer efficacy in vivo compared to the parent compound

Author

Javier Garcia Fernandez, Anna Warnecke, Serghei Chercheja, Heidi-Kristin Walter, Lara Pes, Felix Kratz, Federico Medda, Friederike I. Nollmann, Didier Rognan, Steffen Daum, Khalid Abu Ajaj, Patricia Perez Galan, Magnusson Johannes Pall, and Koester Stephan David

Subjects
Models, Molecular, Drug, media_common.quotation_subject, Serum albumin, Mice, Nude, Pharmaceutical Science, Antineoplastic Agents, 02 engineering and technology, Pharmacology, Rats, Sprague-Dawley, 03 medical and health sciences, In vivo, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Aminobenzoates, Prodrugs, Serum Albumin, 030304 developmental biology, media_common, 0303 health sciences, biology, Chemistry, Melanoma, Albumin, Hydrogen-Ion Concentration, Prodrug, 021001 nanoscience & nanotechnology, medicine.disease, Xenograft Model Antitumor Assays, Drug Liberation, Drug delivery, biology.protein, Female, 0210 nano-technology, Drug carrier, Oligopeptides
Abstract

Auristatins are a class of highly cytotoxic tubulin-disrupting peptides, which have shown limited therapeutic effect as free agents in clinical trials. In our continuing effort to develop acid-sensitive albumin-binding anticancer drugs exploiting circulating serum albumin as the drug carrier, we investigated the highly toxic drug payload auristatin E to assess whether the corresponding albumin-binding prodrugs were a viable option for achieving significant and concomitant tolerable antitumor activity. To achieve our goal, we developed a new aromatic maleimide-bearing linker (Sulf07) which enhanced both water solubility and stability of the prodrugs. In this study, we describe two auristatin E-based albumin-binding drugs, AE-Keto-Sulf07 and AE-Ester-Sulf07, which were designed to release the active compound at the tumor site in a pH-dependent manner. These prodrugs incorporate an acid-sensitive hydrazone bond, formed by the reaction of a carbonyl-containing auristatin E derivative with the hydrazide group of the water-solubilizing maleimide-bearing linker Sulf07. A panel of patient- and cell-derived human tumor xenograft models (melanoma A375, ovarian carcinoma A2780, non-small-cell lung cancer LXFA737 and LXFE937, and head and neck squamous cell carcinomas) were screened with starting tumor volumes in the range of either 130–150 mm3 (small tumors) or 270–380 mm3 (large tumors). Both albumin-binding prodrugs showed compelling anticancer efficacy compared to the parent drug auristatin E, inducing statistically significant long-term partial and/or complete tumor regressions. AE-Keto-Sulf07 displayed very good antitumor response over a wide dose range, 3.0–6.5 mg/kg (5–8 injections, biweekly). AE-Ester-Sulf07 was highly efficacious between 1.9 and 2.4 mg/kg (8 injections, biweekly) or at 3.8 mg/kg (4 injections, weekly), but caused cumulative skin irritation due to scratching and biting. In contrast at its MTD, auristatin E (0.3 mg/kg, 8 injections, biweekly) was only marginally active. In summary, AE-Keto-Sulf07 and AE-Ester-Sulf07 are novel acid-sensitive albumin-binding prodrugs demonstrating tumor regressions in all of the evaluated human tumor xenograft models thus supporting the stratagem that albumin can be used as an effective drug carrier for the highly potent class of auristatins.

Published
2019

20. Abstract 2661: Novel albumin-binding maytansinoids inducing long-term partial and complete tumor regressions in several human cancer xenograft models in nude mice

Author

Nollmann, Friederike I., primary, Galan, Patricia Perez, additional, Fernandez, Javier Garcia, additional, Walter, Heidi K., additional, Magnusson, Johannes P., additional, Medda, Federico, additional, Kratz, Felix, additional, Koester, Stephan D., additional, Ajaj, Khalid Abu, additional, Pes, Lara, additional, Chercheja, Serghei, additional, and Warnecke, Anna, additional

Published
2018
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21. Abstract 1657: Structure-activity relationship studies and biological evaluation of novel maytansinoids, a class of highly selective tubulin inhibitors

Author

Nollmann, Friederike I., primary, Galan, Patricia Perez, additional, Fernandez, Javier Garcia, additional, Walter, Heidi K., additional, Magnusson, Johannes P., additional, Medda, Federico, additional, Kratz, Felix, additional, Koester, Stephan D., additional, Ajaj, Khalid Abu, additional, Pes, Lara, additional, Chercheja, Serghei, additional, and Warnecke, Anna, additional

Published
2018
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22. Abstract 3703: Superior efficacy of novel albumin-binding auristatin E-based prodrugs compared to auristatin E in a panel of human xenograft models in mice

Author

Koester, Stephan D., primary, Pes, Lara, additional, Magnusson, Johannes P., additional, Chercheja, Serghei, additional, Medda, Federico, additional, Nollmann, Friederike I., additional, Galan, Patricia Perez, additional, Fernandez, Javier Garcia, additional, Walter, Heidi-Kristin, additional, Ajaj, Khalid Abu, additional, Warnecke, Anna, additional, and Kratz, Felix, additional

Published
2018
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23. Abstract 3703: Superior efficacy of novel albumin-binding auristatin E-based prodrugs compared to auristatin E in a panel of human xenograft models in mice

Author

Felix Kratz, Federico Medda, Javier Garcia Fernandez, Heidi-Kristin Walter, Serghei Chercheja, Anna Warnecke, Lara Pes, Patricia Perez Galan, Magnusson Johannes Pall, Friederike I. Nollmann, Khalid Abu Ajaj, and Koester Stephan David

Subjects
Cancer Research, Antibody-drug conjugate, biology, business.industry, Albumin, Serum albumin, Pharmacology, Prodrug, chemistry.chemical_compound, Oncology, Monomethyl auristatin E, chemistry, Drug delivery, biology.protein, Cytotoxic T cell, Medicine, Cytotoxicity, business
Abstract

Auristatins are highly cytotoxic antimitotic tubulin-binding peptides. Of this family, only Adcetris®, an antibody drug conjugate (ADC) derived from monomethyl auristatin E (MMAE), is approved and marketed. Other auristatins such as dolastatin 10, dolastatin 15, and auristatin PE reached phase 1 and 2 clinical trials, but due to systemic toxicity and low antitumor activity they were discontinued.1 Because of the high cytotoxicity, it is important to deliver these drugs selectively to the tumor avoiding premature release in the blood circulation. We developed an acid-sensitive drug delivery system that uses circulating endogenous serum albumin as a macromolecular carrier. The drug is rapidly bound covalently to albumin upon i.v. injection and, following accumulation in the tumor due to enhanced uptake and retention mechanisms, the highly cytotoxic agent is released in a pH-dependent manner.2 Herein we present in-vivo data of the considerably improved efficacy of two auristatin E derived prodrugs, AE-Keto-Sulf07 and AE-Ester-Sulf07, compared to the parent compound auristatin E. The acid-sensitive hydrazone prodrugs were prepared from the respective carbonyl-containing auristatin E derivatives and the water-solubilizing maleimide-bearing linker Sulf07. Female NMRI nu/nu mice were inoculated subcutaneously with patient- or cell-derived human tumor xenografts (A375, A2780, RXF631, LXFA737) and randomized (n=7-8 per group) with starting tumor volumes in the range of 140-350 mm3. AE-Keto-Sulf07 showed excellent antitumor response over a wide dose range (3.0-6.5 mg/kg twice per week over 3-4 weeks), with optimal dosage at 4.5 mg/kg twice per week over 4 weeks. AE-Ester-Sulf07 was highly efficacious between 1.9 and 2.4 mg/kg dosed twice per week over 3-4 weeks or at 3.8 mg/kg dosed once per week over 4 weeks, but caused cumulative skin lesions due to scratching and biting. In contrast, auristatin E was dosed at 0.3 mg/kg twice per week over 3-4 weeks and was only marginally active. In summary, we have shown for the first time that auristatin E derivatives, namely AE-Keto-Sulf07 and AE-Ester-Sulf07, bound to circulating albumin demonstrate promising antitumor efficacy and induce statistically significant long-term partial or complete remission in a panel of human xenograft models in mice. Citation Format: Stephan D. Koester, Lara Pes, Johannes P. Magnusson, Serghei Chercheja, Federico Medda, Friederike I. Nollmann, Patricia Perez Galan, Javier Garcia Fernandez, Heidi-Kristin Walter, Khalid Abu Ajaj, Anna Warnecke, Felix Kratz. Superior efficacy of novel albumin-binding auristatin E-based prodrugs compared to auristatin E in a panel of human xenograft models in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3703.

Published
2018

24. Abstract 1657: Structure-activity relationship studies and biological evaluation of novel maytansinoids, a class of highly selective tubulin inhibitors

Author

Felix Kratz, Federico Medda, Javier Garcia Fernandez, Heidi K. Walter, Friederike I. Nollmann, Lara Pes, Magnusson Johannes Pall, Koester Stephan David, Patricia Perez Galan, Khalid Abu Ajaj, Serghei Chercheja, and Anna Warnecke

Subjects
chemistry.chemical_classification, Cancer Research, Stereochemistry, Prodrug, Maytansinoid, In vitro, Amino acid, chemistry.chemical_compound, Oncology, chemistry, In vivo, Structure–activity relationship, Cytotoxicity, Linker
Abstract

Introduction and objectives: Maytansine and its analogs (DM1 and DM4) are potent microtubule-targeting compounds that inhibit proliferation of cells during mitosis.1 Unfortunately, their narrow therapeutic window prevents a clinical application of these molecules. So far only T-DM1, an antibody-maytansinoid conjugate targeting the HER2 receptor, has been approved for the treatment of resistant breast cancer. Previous work on maytansinoids showed that their potent cytotoxic activity is related to the nature of the substituent at the C3 acyloxy side chain. In order to harness the potential of compounds of the maytansinoid family while diminishing dose-limiting side effects, we synthesized a library of novel analogs which can be attached to serum albumin in vivo through an acid-sensitive linker ensuring release of the active maytansinoid at the tumor site. All novel maytansine analogs contain a keto moiety as an attachment point for the linker and differ in their substitution pattern at C3. The analogs we studied can be classified into those containing an amino acid spacer between C3 and the keto group (maytansine-type) and those obtained through direct esterification at the C3-OH-position with various carboxylic acids (ansamitocin-type). Methods: All the newly synthesized molecules were screened for their in vitro cytotoxicity against 11 cancer cell lines. In order to explore the influence of the maytansine functional groups at C3, we designed novel analogs with different amino acid spacers at this position. We evaluated the influence of the chain length, the degree of steric hindrance, the need of the chiral center and the influence of the N-methyl on the cytotoxicity as well as stability in murine and human blood plasma. Moreover, we studied the structure-activity relationship of the ansamitocin-type of analogs including the influence of the chain length, the degree of steric hindrance and the effect of introducing different heteroatoms in the alkyl chain. Result and conclusion: A total of 32 new maytansinoid analogs were synthesized, and seven of them were found to be more potent than the parent drug maytansine in inhibiting the growth of human cancer cells in vitro. Clear SARs were identified for both classes of compounds. Based on these studies, lead compounds have been selected for creating albumin-binding derivatives and their further in vivo evaluation.2 1) W. C. Widdison et al, J. Med. Chem., 49: 4392-4408 (2006); K. A. Poon et al, Toxicology and Applied Pharmacology, 273: 298-313 (2013); H. L. Perez et al, Drug Discovery Today, 19:869-881 (2014) 2) Abstract "In vivo efficacy of novel acid-sensitive albumin-binding Maytansinoid-based prodrugs in human cancer xenograft models in nude mice" Citation Format: Friederike I. Nollmann, Patricia Perez Galan, Javier Garcia Fernandez, Heidi K. Walter, Johannes P. Magnusson, Federico Medda, Felix Kratz, Stephan D. Koester, Khalid Abu Ajaj, Lara Pes, Serghei Chercheja, Anna Warnecke. Structure-activity relationship studies and biological evaluation of novel maytansinoids, a class of highly selective tubulin inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1657.

Published
2018

25. Abstract 2661: Novel albumin-binding maytansinoids inducing long-term partial and complete tumor regressions in several human cancer xenograft models in nude mice

Author

Javier Garcia Fernandez, Lara Pes, Heidi K. Walter, Friederike I. Nollmann, Federico Medda, Magnusson Johannes Pall, Felix Kratz, Anna Warnecke, Koester Stephan David, Serghei Chercheja, Patricia Perez Galan, and Khalid Abu Ajaj

Subjects
Drug, Cancer Research, Chemistry, media_common.quotation_subject, Cell, Albumin, Cancer, Pharmacology, medicine.disease, Human serum albumin, In vitro, medicine.anatomical_structure, Oncology, In vivo, Drug delivery, medicine, media_common, medicine.drug
Abstract

Introduction and objectives: Maytansine and its analogs (DM1 and DM4) are potent microtubule-targeting compounds that inhibit proliferation of cells during mitosis. Their potent anticancer activity made them attractive for drug development.1 Unfortunately, their narrow therapeutic window prevents the clinical application of these molecules. So far only T-DM1, an antibody-maytansinoid conjugate targeting the HER2 receptor, has been approved for the treatment of Herceptin®-resistant breast cancer. Previous work2 showed that by direct esterification at the C3-OH-position of maytansinol, in vitro cytotoxicity may be enhanced compared to the parent drug maytansine. To make these highly potent compounds available for cancer treatment, novel maytansinoids were attached to a water-solubilizing hydrazone linker which selectively binds to the Cys-34 position of human serum albumin upon i.v. injection. The active drug is designed to be liberated in the acidic environment of the tumor as well as in acidic cellular compartments of tumor cells.3 Based on stability and release data in vitro, albumin-binding maytansinoids were selected for further in vivo evaluation. Herein, we present the data from a head-to-head comparison of novel albumin-binding maytansinoids with their parent maytansine in different cell- and patient-derived human tumor xenograft models. Methods: Patient-derived human tumor xenografts (LXFE937 etc.) or tumor cells (A2780, MDA-MB 231, MDA-MB 468 etc.) were transplanted subcutaneously to female NMRI nu/nu mice (n=7-8 per group). Therapy with maytansine (0.4 or 0.5 mg/kg) and albumin-binding maytansinoids (2-3 mg/kg maytansine eq) was initiated after tumors reached a mean volume of 80-380 mm3. Animals were treated by i.v. injection once per week over 4 weeks. Result and conclusion: Treatment with novel albumin-binding maytansinoids was better tolerated than with maytansine and MTDs were 4-7 times higher showing no significant body weight loss (< 5%). The albumin-binding maytansinoids demonstrated a significantly higher antitumor activity compared to both the control group and the group treated with maytansine and induced long-term partial and complete tumor regressions in all experiments. 1) W. C. Widdison et al, J. Med. Chem., 49: 4392-4408 (2006); K. A. Poon et al, Toxicology and Applied Pharmacology, 273: 298-313 (2013); H. L. Perez et al, Drug Discovery Today, 19:869-881 (2014) 2) Abstract XXX (Structure-activity relationship studies and biological evaluation of novel maytansinoids, a class of highly selective tubulin inhibitors) 3) F. Kratz et al., ChemMedChem, 3:20-53 (2008); US 7, 387, 771; F. Kratz, J. Control. Release, 132:171-183 (2008), F. Kratz, U. Beyer, Drug Delivery, 5: 281-299 (1998). Citation Format: Friederike I. Nollmann, Patricia Perez Galan, Javier Garcia Fernandez, Heidi K. Walter, Johannes P. Magnusson, Federico Medda, Felix Kratz, Stephan D. Koester, Khalid Abu Ajaj, Lara Pes, Serghei Chercheja, Anna Warnecke. Novel albumin-binding maytansinoids inducing long-term partial and complete tumor regressions in several human cancer xenograft models in nude mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2661.

Published
2018

27. Abstract 4858: LADR™: A novel linker activated drug release technology for drug delivery

Author

Felix Kratz, Friederike I. Nollmann, Olga Fuchs, Koester Stephan David, Simon Waltzer, André Warnecke, and Khalid Abu Ajaj

Subjects
0301 basic medicine, Drug, Cancer Research, Nemorubicin, Chemistry, media_common.quotation_subject, Aldoxorubicin, 02 engineering and technology, Pharmacology, 021001 nanoscience & nanotechnology, Galenic formulation, 03 medical and health sciences, 030104 developmental biology, Oncology, Drug delivery, medicine, Doxorubicin, 0210 nano-technology, Drug carrier, Linker, medicine.drug, media_common
Abstract

Drug delivery systems in oncology for treating cancer are based on different drug release mechanisms at the tumor site including primarily hydrolytic, reductive, enzymatic and/or acid-sensitive cleavage. Drug carrier conjugates that incorporate an acid-sensitive breaking-point exploit the extra- and intracellular acidic environment of the tumor. Important requirements for acid-sensitive bonds are high stability of the carrier-bound drug in the blood circulation and an effective or sustained release of the active drug in the acidic tumor interstitium and acidic endosomes/lysosomes of tumor cells. In addition, sufficient stability of the acid-sensitive bond is a prerequisite for galenic formulation and reconstitution. As a continuation of our development of aldoxorubicin, an acid-sensitive albumin-binding drug of doxorubicin, which is being clinically assessed in advanced clinical trials (www.cytrx.com), we have set out to design a novel acid-sensitive drug release platform that is applicable to carriers such as serum proteins and antibodies. The key components of this specific drug delivery system are linkers containing a thiol-binding maleimide group and a substituted aromatic hydrazine to form an acid-cleavable hydrazone bond with suitable carbonyl-containing drugs. For establishing and fine-tuning the pH-dependent release profiles, the aromatic moiety of the linker was substituted with a spectrum of electron-withdrawing groups, and reacted with the anthracyclines doxorubicin and nemorubicin. The resulting hydrazone derivatives were conjugated to the cysteine-34 position of albumin as a model protein. Subsequently, the drug release was determined at physiological and acidic conditions as well as in human plasma. It was discovered that by variation of the electron-withdrawing groups, the pH dependent release of the drug could be substantially varied between 1-50 h in the pH range of 4-5. The technology using these linkers was coined LADR™ (Linker Activated Drug Release) and has the additional advantage that the galenic formulation and reconstitution of LADR™-based drugs is facilitated. We have applied the LADR™ technology to several anticancer drugs such as vinblastine and gemcitabine. In summary, LADR™ is an innovative and versatile linker technology creating a platform for developing acid-sensitive drug carrier conjugates that allow the carrier-bound drug to be released in a controlled manner resulting in sustained exposure to cancer cells. Citation Format: Khalid Abu Ajaj, Stephan David Koester, Friederike Inga Nollmann, Simon Waltzer, Olga Fuchs, André Warnecke, Felix Kratz. LADR™: A novel linker activated drug release technology for drug delivery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4858.

Published
2016

29. China’s National Governance Framework for Urban Water Resource Management

Author

Lv, Zhongmei, You, Mingqing, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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30. Urban Water Governance in Europe and in China: Key Challenges, Benchmarks and Approaches

Author

Reese, Moritz, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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31. Economic Requirements and Instruments for Sustainable Urban Water Management – Comparative Review

Author

Gawel, Erik, Bedtke, Norman, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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32. The Economics and Management of Flood Risk in Germany

Author

Meyer, Volker, Schwarze, Reimund, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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33. The Eco-Compensation Mechanism in Tai Lake Watershed

Author

Dai, Liping, Qin, Tianbao, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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34. Full Cost Accounting of Urban Water-Use

Author

Song, Guo-jun, Gao, Wen-cheng, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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35. Economic Policies of Water Pollution Control in the Taihu Lake Basin, China

Author

Zhou, Yuanchun, Bi, Jun, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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36. Regional Water Policy in China – Problems and Approaches in the Taihu und Wuhan Regions

Author

Dai, Liping, Qin, Tianbao, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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37. Information, Participation and Public Control in Water Management & Water Infrastructure Development: the European and German Perspective

Author

Laskowski, Silke R., Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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38. German Water Protection Law with a Particular Focus on Waste Water Management

Author

Köck, Wolfgang, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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39. Wetland Ecological Restoration Using Near-Natural Method

Author

Ye, Chun, Li, Chun-Hua, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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40. Sustainable Water Resource Management in China – Reflections from a Comparative Governance Perspective

Author

Grambow, Martin, Disse, Markus, Chen, Ke, Patalong, Hannah, Uhl, Hans-Dietrich, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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41. Special Issues of Wastewater Management in China

Author

Dohmann, Max, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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42. Implementing Real Time Control Systems to Minimize Emissions from the Sewer System

Author

Pabst, Michael, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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43. Urban Flood Prevention

Author

Illgen, Marc, Ackermann, Holger, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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44. Preventive and Customized Maintenance of Underground Water Infrastructure

Author

Zhao, Fangfang, Haußmann, Regina, Pinnekamp, Johannes, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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45. Urban Pipe Assessment Method and Its Application in Two Chinese Cities

Author

Zuo, Jian’e, Ye, Xiangyang, Hu, Xiaoqing, Yu, Zhonghan, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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46. Fostering Water Treatment in Eutrophic Areas: Innovative Water Quality Monitoring, and Technologies Mitigating Taste & Odor Problems Demonstrated at Tai Hu

Author

Küppers, Stephan, der Beek, Tim aus, Chu, Wenhai, Dong, Bingzhi, Dahlhaus, Anna, Hollert, Henner, Hua, Jianliang, Hua, Wei, Jia, Yunlu, Li, Lei, Lutze, Holger, Moldaenke, Christian, Qin, Yanwen, Schmidt, Wido, Staaks, Christian, Stange, Claudia, Yin, Daqiang, Zhao, Ji, Zheng, Binghui, Zhu, Linyan, Zou, Hua, Tiehm, Andreas, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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47. Urban Drinking Water Challenges and Solutions: Energy Nexus

Author

Smith, Kate, Liu, Ying, Liu, Shuming, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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48. Future-oriented Strategic Planning of Wastewater Treatment Plants

Author

Manig, Nina, Beier, Maike, Rosenwinkel, Karl-Heinz, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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49. Urban Stormwater Management and Sponge City Concept in China

Author

Che, Wu, Zhang, Wei, Ahern, Jack, Editorial Board Member, Bolte, John, Editorial Board Member, Dawson, Richard J., Editorial Board Member, Devine-Wright, Patrick, Editorial Board Member, Farina, Almo, Editorial Board Member, Green, Raymond James, Editorial Board Member, Guntenspergen, Glenn R., Editorial Board Member, Haase, Dagmar, Editorial Board Member, Jenks, Mike, Editorial Board Member, Konijnendijk, Cecil C., Series Editor, Nassauer, Joan, Editorial Board Member, Pauleit, Stephan, Editorial Board Member, Pickett, Steward, Editorial Board Member, Vale, Robert, Editorial Board Member, Yeang, Ken, Editorial Board Member, Yokohari, Makoto, Editorial Board Member, Köster, Stephan, editor, Reese, Moritz, editor, and Zuo, Jian'e, editor

Published
2019
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