Drug Targeting Organ-Specific Strategies

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7.3 Chronic Inflammatory Disorders 177 sequently, they proliferate and migrate towards the tumour or inflammatory site. Finally they form a capillary lumen, after which vessel maturation takes place (for a more detailed description of the molecular regulation of angiogenesis, see Chapter 9) [34]. The putative role of angiogenesis in chronic inflammatory diseases is the maintenance of the inflammatory state by allowing ongoing recruitment of inflammatory cells and by supplying nutrients and oxygen to proliferating inflamed tissue. The increased endothelial surface creates an enormous capacity for the production of cytokines, adhesion molecules, and other inflammatory stimuli [35]. In many chronic inflammatory diseases, angiogenesis can be identified in the inflamed lesions. For example, in rheumatoid arthritis extensive neovascularization is present in the inflamed synovium where it is one of the earliest histopathological findings [36]. Since in RA synoviocytes exhibit characteristics of tumour cells, including somatic mutations in key regulatory genes such as H-ras and the p53 tumour suppressor, RA can be viewed as a multicentric tumour-like mass that invades and destroys its local environment [37]. Concurrent increased endothelial cell turnover may contribute to microvascular dysfunction and thereby facilitate persistent synovitis. Although the identity of the factors that promote angiogenesis in RA specifically still remain unclear, both synovial tissue and fluid are enriched in angiogenesis-promoting factors. These include cytokines such as bFGF,VEGF, and IL-8, and soluble VCAM-1 and E-selectin [38]. In other chronic inflammatory diseases elevated levels of angiogenic factors were also found. In patients with psoriasis, skin lesions over-expressed IL-8 while the expression of one of the inhibitors of angiogenesis, thrombospondin-1, was downregulated [39]. Neovascularization in artherosclerotic lesions may be regulated by VEGF, as this factor is over-expressed by different cells in the plaque tissue [40–42]. The increased serum levels of VEGF that correlate with disease activity in patients with Crohn’s disease and ulcerative colitis, indicate a role for this cytokine in promoting inflammation. Most likely, increased vascular permeability and/or wound healing via its pro-angiogenic activity are the basis for this effect [43]. There is at present no consensus on whether inflammation and angiogenesis can exist independently from each other. This is due to the lack of suitable marker-epitopes that cover all stages of angiogenesis, resulting in an underestimation or misinterpretation of the occurrence of angiogenesis.As cells of the immune system contribute significantly to the local production of pro-inflammatory and pro-angiogenic factors, it is likely though, that inflammation and angiogenesis affect each other to a considerable extent. 7.3.3 Activation Pathways of Endothelial Cells in Chronic Inflammation Activation of endothelial cells leads to changes in endothelial cell properties such as loss of vascular integrity, expression of adhesion molecules, antithrombotic to prothrombotic phenotype changes, cytokine production and the upregulation of HLA molecules. All these diverse effects can be attributed to the activation of transcription factors [44]. Of the presently known transcription factors, NFκB is believed to be one of the most important in the regulation of endothelial cell activation. After a stimulus at the cell surface which is caused by e.g.
178 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of <strong>Drug</strong>s NFκB IκBα p50 p65 P Ub IκB degradation receptor Cytokine IκB kinases P Ub inflammatory gene Inflammatory proteins protein mRNA receptor Cytokine JAK JAK P P P P P cell membrane cytoplasm nucleus interaction between a cytokine (IL-1, TNFα) and its receptor, UV radiation, lipopolysaccharide (LPS) or oxidized low density lipoproteins (oxLDL), NFκB-inducible kinase (NIK) is activated, which in turn phosphorylates IκB-kinase-1 (IKK-1), and perhaps IKK-2. The IKK molecules phosphorylate the inhibitor of κB (IκB) at serine-residues, resulting in ubiquitination and degradation of IκB by the proteasome machinery in the cell cytoplasm. The nuclear localization sequence (NLS) of the NFκB dimer then becomes exposed, after which the transcription factor travels to the nucleus and induces transcription of many pro-inflammatory genes (Figure 7.3) [45]. Since NFκB is a key component in the inflammation process, this important transcription factor is controlled by several autoregulatory loops. The expression of the inhibitory protein IκBα to which NFκB is bound in the cytoplasm, becomes upregulated when NFκB is activated, thereby repressing the transcription of VCAM-1 and E-selectin for P P inflammatory gene P P STAT Figure 7.3. Schematic representation of some of the intracellular signal transduction pathways of cytokine receptor signalling. Interleukin (IL)-1 and TNFα, among others, induce cell activation via the NFκB pathway, although their respective signal transduction routes upstream of the NFκB system differ significantly. On interaction with their receptors, NFκB-inducible kinase (NIK) is activated resulting in IκB-kinase (IKK) phosphorylation. As a result, IκBα is phosphorylated, thereby becoming a substrate for ubiquitination and proteasome-mediated degradation. The released p50/p65 NFκB complex translocates to the nucleus, which results in the expression of inflammatory genes. The JAK/STAT route can be activated by cytokine (e.g. IL-6, IL-10 or IL-15) binding to their receptors. JAK phosphorylation is followed by phosphorylation of receptor subunits which function as a docking site for STAT molecules. Phosphorylated STAT molecules subsequently dimerize, translocate to the nucleus and modulate gene transcription.
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Drug Targeting Organ-Specific Strat
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Preface Drug Targeting Organ-Specif
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Foreword Drug Targeting Organ-Speci
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X List of Contributors Henderik W.
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XII List of Contributors Grietje Mo
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Contents Drug Targeting Organ-Speci
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Contents XVII 3 Pulmonary Drug Deli
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Contents XIX 5.2.1.6 Identification
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Contents XXI 7.5 In Vitro Technique
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Contents XXIII 9.4 Tumour Vasculatu
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Contents XXV 12.8. Tissue Slices fr
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Dexa dexamethasone DIVEMA divinyl e
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LRP lung resistance related protein
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ROS reactive oxygen species RSV res
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Index a ADEPT 217, 224, 268, 291 ad
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e E. coli expression system 292 eff
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polymers, soluble 4, 218 - dendrime
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2 1 Drug Targeting: Basic Concepts
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24 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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with monoclonal and bispecific anti
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References 117 [50] Coleman DL, Eur
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References 119 [133] Cronstein BN,
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5 Delivery of Drugs and Antisense O
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5.1 Introduction 123 convoluted tub
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Page 189 and 190: References 153 [66] Franssen EJF, M
Page 191 and 192: References 155 [145] Van Zwieten PA
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Page 235 and 236: 8.2.2 Histogenesis The traditional
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References 229 [43] Chaouchi NA, Va
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References 231 [126] Czuczman MS, G
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234 9 Tumour Vasculature Targeting
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256 10 Phage Display Technology for
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11 Development of Proteinaceous Dru
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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11.9 Recombinant Domains as Buildin
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References 305 [16] Milstein C, Wal
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References 307 [99] Verma R, Boleti
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12 Use of Human Tissue Slices in Dr
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are also extensively used in a vari
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Meanwhile many incubation systems h
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12.3 Incubation and Culture of Live
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to investigate the effect of differ
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The mechanisms of uptake and excret
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12.6 The Use of Liver Slices in Dru
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12.7 Efficacy Testing of the Drug T
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NO x µM 80 60 40 20 * * 12.7 Effic
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TNFα ng/ml 1.5 1 0.5 0 * Human (n=
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References 329 [33] Ikejima K, Enom
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References 331 [109] Dutt A, Priebe
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334 13 Pharmacokinetic/Pharmacodyna
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372 14 Drug Targeting Strategy: Scr
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374 14 Drug Targeting Strategy: Scr
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Drug Targeting Organ-Specific Strategies

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