12 research outputs found
Current methods for the synthesis of homogeneous antibody鈥揹rug conjugates
AbstractDevelopment of efficient and safe cancer therapy is one of the major challenges of the modern medicine. Over the last few years antibody鈥揹rug conjugates (ADCs) have become a powerful tool in cancer treatment with two of them, Adcetris庐 (brentuximab vedotin) and Kadcyla庐 (ado-trastuzumab emtansine), having recently been approved by the Food and Drug Administration (FDA). Essentially, an ADC is a bioconjugate that comprises a monoclonal antibody that specifically binds tumor surface antigen and a highly potent drug, which is attached to the antibody via either cleavable or stable linker. This approach ensures specificity and efficacy in fighting cancer cells, while healthy tissues remain largely unaffected.Conventional ADCs, that employ cysteine or lysine residues as conjugation sites, are highly heterogeneous. This means that the species contain various populations of the ADCs with different drug-to-antibody ratios (DARs) and different drug load distributions. DAR and drug-load distribution are essential parameters of ADCs as they determine their stability and efficacy. Therefore, various drug-loaded forms of ADCs (usually from zero to eight conjugated molecules per antibody) may have distinct pharmacokinetics (PK) in vivo and may differ in clinical performance. Recently, a significant progress has been made in the field of site-specific conjugation which resulted in a number of strategies for synthesis of the homogeneous ADCs. This review describes newly-developed methods that ensure homogeneity of the ADCs including use of engineered reactive cysteine residues (THIOMAB), unnatural amino acids, aldehyde tags, enzymatic transglutaminase- and glycotransferase-based approaches and novel chemical methods. Furthermore, we briefly discuss the limitation of these methods emphasizing the need for further improvement in the ADC design and development
Internal migration in Germany in 1990 and 2005
DOI: 10.2478/v10089-009-0007-0The article seeks to answer the questions concerning the possibility of
identifying regular patterns within internal migration in the towns and rural areas of the
Federal Republic of Germany as well as factors contributing to regional variations in
the process. The research involves 439 German counties (Kreise) and compares data on
internal migration in the country in the years 1991 and 2005, i.e. from its reunifi cation
until the year 2005. The 15-year period of functioning of one reunited state has been
assumed suffi cient for capturing some regularities and trends
Unique Roles of Sphingolipids in Selected Malignant and Nonmalignant Lesions of Female Reproductive System
Cancer develops as a result of the loss of self-control mechanisms by a cell; it gains the ability to induce angiogenesis, becomes immortal and resistant to cell death, stops responding to growth suppressor signals, and becomes capable of invasion and metastasis. Sphingolipids鈥攁 family of membrane lipids鈥攁re known to play important roles in the regulation of cell proliferation, the response to chemotherapeutic agents, and/or prevention of cancer. Despite the underlying functions of sphingolipids in cancer biology, their metabolism in different malignant tumors is poorly investigated. Some studies showed marked differences in ceramide content between the tumor and the respective healthy tissue. Interestingly, the level of this sphingolipid could be either low or elevated, suggesting that the alterations in ceramide metabolism in cancer tissue may depend on the biology of the tumor. These processes are indeed related to the type of cancer, its stage, and histology status. In this paper we present the unique roles of bioactive sphingolipid derivative in selected gynecologic malignant and nonmalignant lesions
FGF2 Dual Warhead Conjugate with Monomethyl Auristatin E and 伪-Amanitin Displays a Cytotoxic Effect towards Cancer Cells Overproducing FGF Receptor 1
In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs
Otrzymywanie adsorbent贸w ditlenku w臋gla na bazie polimer贸w silnie rozga艂臋zionych oraz badania ich d艂ugoterminowej stabilno艣ci
The article reports preparation and characterization of CO2 adsorbents based on hyperbranched polyamines and polyglycerols. Hyperbranched polyglycerol containing primary amine groups (A-HBPG) and polyethyleneimine (PEI) showed to be effective in CO2 capture from the ambient air. Adsorbents based on those polymers were stable for at least 17 adsorption/desorption cycles provided the desorption was performed in oxygen free atmosphere. Amine containing hyperbranched polymers are promising materials for CO2 capture.Scharakteryzowano adsorbenty CO2 otrzymane na bazie polietylenoiminy (PEI) lub hiperrozga艂臋zionego poliglicerolu zawieraj膮cego grupy aminowe (A-HBPG) osadzone na r贸偶nych pod艂o偶ach. Wykazano, 偶e A-HBPG i PEI skutecznie wychwytuj膮 CO2 z otaczaj膮cego powietrza. Badane adsorbenty wykazywa艂y stabilno艣膰 przez co najmniej 17 cykli adsorpcji/desorpcji CO2, pod warunkiem, 偶e desorpcj臋 prowadzono w atmosferze beztlenowej. Stwierdzono, 偶e hiperrozga艂臋zione polimery zawieraj膮ce grupy aminowe s膮 obiecuj膮cymi materia艂ami przeznaczonymi do wychwytywania CO2
Hyperbranched Poly(ether-siloxane)s Containing Ammonium Groups: Synthesis, Characterization and Catalytic Activity
In this article we report an easy synthetic route towards hyperbranched polyglycerols (Amm-HBPGs) containing trimethylammonium groups and siloxane or hydroxyl end-groups. Siloxane derivatives of Amm-HBPGs were synthesized in an efficient five-step procedure including an anionic ring opening copolymerization of the phthalimide-epoxy monomer with glycidol, followed by reactions with allyl bromide, hydrosililation with hydrogenheptamethyltrisiloxane, hydrazinolysis of phthalimide groups and quaternization of resulting amine groups with methyl iodide. Hydroxyl derivatives were obtained by quaternization of previously reported aminated HBPG’s with methyl iodide. Polymeric products were characterized using various NMR techniques, FTIR, and elemental analysis. Both Amm-HBPGs were shown to be effective in catalysis of addition of CO2 to oxirane. The hydrophilic catalysts showed higher efficiency but synthesis of ethylene carbonate was accompanied by formation of small amounts of ethylene glycol. The siloxane-containing catalyst was easily separable from reaction mixture showing high potential in the process of converting carbon dioxide into valuable chemical raw materials
Sugar Starvation Disrupts Lipid Breakdown by Inducing Autophagy in Embryonic Axes of Lupin (Lupinus spp.) Germinating Seeds
Under nutrient deficiency or starvation conditions, the mobilization of storage compounds during seed germination is enhanced to primarily supply respiratory substrates and hence increase the potential of cell survival. Nevertheless, we found that, under sugar starvation conditions in isolated embryonic axes of white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet) cultured in vitro for 96 h, the disruption of lipid breakdown occurs, as was reflected in the higher lipid content in the sugar-starved (-S) than in the sucrose-fed (+S) axes. We postulate that pexophagy (autophagic degradation of the peroxisome鈥攁 key organelle in lipid catabolism) is one of the reasons for the disruption in lipid breakdown under starvation conditions. Evidence of pexophagy can be: (i) the higher transcript level of genes encoding proteins of pexophagy machinery, and (ii) the lower content of the peroxisome marker Pex14p and its increase caused by an autophagy inhibitor (concanamycin A) in -S axes in comparison to the +S axes. Additionally, based on ultrastructure observation, we documented that, under sugar starvation conditions lipophagy (autophagic degradation of whole lipid droplets) may also occur but this type of selective autophagy seems to be restricted under starvation conditions. Our results also show that autophagy occurs at the very early stages of plant growth and development, including the cells of embryonic seed organs, and allows cell survival under starvation conditions
Molecular Insight into the Interaction between Epigenetics and Leptin in Metabolic Disorders
The proteomic profile is altered but not repaired after bariatric surgery in type 2 diabetes pigs
To reveal the sources of obesity and type 2 diabetes (T2D) in humans, animal models, mainly rodents, have been used. Here, we propose a pig model of T2D. Weaned piglets were fed high fat/high sugar diet suppling 150% of metabolizable energy. Measurements of weight gain, blood morphology, glucose plasma levels, cholesterol, and triglycerides, as well as glucose tolerance (oral glucose tolerance test, OGTT) were employed to observe T2D development. The histology and mass spectrometry analyses were made post mortem. Within 6 months, the high fat-high sugar (HFHS) fed pigs showed gradual and significant increase in plasma triglycerides and glucose levels in comparison to the controls. Using OGTT test, we found stable glucose intolerance in 10 out of 14 HFHS pigs. Mass spectrometry analysis indicated significant changes in 330 proteins in the intestine, liver, and pancreas of the HFHS pigs. These pigs showed also an increase in DNA base modifications and elevated level of the ALKBH proteins in the tissues. Six diabetic HFHS pigs underwent Scopinaro bariatric surgery restoring glycaemia one month after surgery. In conclusion, a high energy diet applied to piglets resulted in the development of hyperlipidaemia, hyperglycaemia, and type 2 diabetes being reversed by a bariatric procedure, excluding the proteomic profile utill one month after the surgery