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- Belting, Mattias, et al.
(författare)
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Developments in macromolecular drug delivery.
- 2009
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Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1940-6029. ; 480, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Macromolecular drugs hold great promise as novel therapeutics of several major disorders, such as cancer and cardiovascular disease. However, their use is limited by lack of efficient, safe, and specific delivery strategies. Successful development of such strategies requires interdisciplinary collaborations involving researchers with expertise on, e.g., polymer chemistry, cell biology, nanotechnology, systems biology, advanced imaging methods, and clinical medicine. This not only poses obvious challenges to the scientific community but also provides opportunities for the unexpected at the interface between different disciplines. This introductory chapter summarizes and gives references to studies on macromolecular delivery that should be of interest to a broad scientific audience involved in macromolecular drug synthesis as well as in vitro and in vivo drug delivery studies.
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| 2. |
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| 3. |
- Belting, Mattias
(författare)
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Glycosaminoglycans in cancer treatment.
- 2014
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Ingår i: Thrombosis Research. - 1879-2472. ; 133, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- Studies aimed at the identification of biomarkers and treatment targets of cancer have focused on mRNAs, miRNAs, and proteins expressed by malignant cells, while glycoproteins mainly produced by stromal cells remain relatively unexplored. Glycans lack a given template for their biosynthesis that involves the concerted action of several, sometimes >15 different enzymes. This fact complicates the analysis at the genomic level of the role of glycoproteins in clinical oncology. The glycosaminoglycans (GAGs) stand out as highly polyanionic components at the surface of malignant and stromal tumor cells as well as their surrounding matrix. Published data thus describe a multifaceted regulatory role of GAGs and GAG-conjugated proteins, proteoglycans, in e.g. tumor associated angiogenesis, coagulation, invasion, and metastasis. Relatively small, randomized clinical trials suggest that heparin, an over-sulfated variant of the GAG heparan sulfate, may have direct, anti-tumor effects. Several ongoing trials aim at establishing whether heparin and its derivatives should be added to standard treatment of cancer patients or not, based on progression free- and overall survival end-point data. Given the potential bleeding complications with this treatment, other strategies to block GAG function should provide interesting alternatives. In the emerging era of personalized medicine, one can foresee the development of predictive biomarkers to select patients that may benefit from GAG-targeted treatments, aiming at individualized prevention of thromboembolic complications as well as inhibition of tumor development and progression. Here, the role of GAGs as targets and vehicles of cancer treatment is discussed with special emphasis on angiogenesis and coagulation associated mechanisms. © 2014 Elsevier Ltd. All rights reserved.
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| 4. |
- Belting, Mattias, et al.
(författare)
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Glypican-1 is a vehicle for polyamine uptake in mammalian cells. A pivotal role for nitrosothiol-derived nitric oxide.
- 2003
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 278:47, s. 47181-47189
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Tidskriftsartikel (refereegranskat)abstract
- Polyamines (putrescine, spermidine, and spermine) are essential for growth and survival of all cells. When polyamine biosynthesis is inhibited, there is up-regulation of import. The mammalian polyamine transport system is unknown. We have previously shown that the heparan sulfate (HS) side chains of recycling glypican-1 (Gpc-1) can sequester spermine, that intracellular polyamine depletion increases the number of NO-sensitive N-unsubstituted glucosamines in HS, and that NO-dependent cleavage of HS at these sites is required for spermine uptake. The NO is derived from S-nitroso groups in the Gpc-1 protein. Using RNA interference technology as well as biochemical and microscopic techniques applied to both normal and uptake-deficient cells, we demonstrate that inhibition of Gpc-1 expression abrogates spermine uptake and intracellular delivery. In unperturbed cells, spermine and recycling Gpc-1 carrying HS chains rich in N-unsubstituted glucosamines were co-localized. By exposing cells to ascorbate, we induced release of NO from the S-nitroso groups, resulting in HS degradation and unloading of the sequestered polyamines as well as nuclear targeting of the deglycanated Gpc-1 protein. Polyamine uptake-deficient cells appear to have a defect in the NO release mechanism. We have managed to restore spermine uptake partially in these cells by providing spermine NONOate and ascorbate. The former bound to the HS chains of recycling Gpc-1 and S-nitrosylated the core protein. Ascorbate released NO, which degraded HS and liberated the bound spermine. Recycling HS proteoglycans of the glypican-type may be plasma membrane carriers for cargo taken up by caveolar endocytosis.
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| 5. |
- Belting, Mattias
(författare)
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Heparan sulfate proteoglycan as a plasma membrane carrier
- 2003
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Ingår i: Trends in Biochemical Sciences. - 0167-7640. ; 28:3, s. 145-151
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Tidskriftsartikel (refereegranskat)abstract
- The plasma membrane defines the border of living cells and provides a barrier to extracellular components. Advances in molecular biology have resulted in the development of novel therapeutic strategies (e.g. gene therapy and cellular protein delivery) which rely on the entry of charged macromolecules into the intracellular compartment. Recent reports demonstrate an intriguing role for heparan sulfate proteoglycans in cellular internalization of viruses, basic peptides and polycation-nucleic-acid complexes and the possibility that they have important implications for gene transfer and protein delivery to mammalian cells. This review focuses on heparan sulfate proteoglycan as a plasma membrane carrier.
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| 6. |
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| 7. |
- Belting, Mattias, et al.
(författare)
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Intracellular accumulation of secreted proteoglycans inhibits cationic lipid-mediated gene transfer. Co-transfer of glycosaminoglycans to the nucleus
- 1999
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Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 274:27, s. 19375-19382
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Tidskriftsartikel (refereegranskat)abstract
- Molecules secreted by potential target cells may interfere with cationic lipid-mediated gene transfer. This has been studied using human lung fibroblasts and human epidermoid lung cancer cells. Secreted cell medium components caused a substantial decrease both in the uptake of cationic lipid-DNA complexes (2-4-fold) and in reporter gene expression (100-1000-fold). Metabolic labeling of the cell medium showed that especially [35S]sulfate-labeled macromolecules competed with DNA for binding to the cationic lipid. Release of DNA from the cationic lipid by cell medium components was demonstrated by an ethidium bromide intercalation assay. In the presence of the cationic lipid, the secreted macromolecules were internalized by the cells. By enzymatic digestions, it was shown that the competing macromolecules consist of chondroitin/dermatan sulfate and heparan sulfate proteoglycans and that the effects on transfection were mediated by the polyanionic glycosaminoglycan portion of the proteoglycan. Accordingly, pretreatment of cell medium with the polycationic peptide protamine sulfate abrogated the inhibitory effects on gene transfer. Fluorescence microscopy studies revealed that heparan sulfate, internalized as a complex with cationic lipids, accumulated in the cell nuclei. These results support the view that the lack of specificity of this type of gene transfer vehicle is a major hindrance to efficient and safe in vivo administration
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| 8. |
- Belting, Mattias, et al.
(författare)
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Macromolecular Drug Delivery: Basic Principles and Therapeutic Applications.
- 2009
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Ingår i: Molecular Biotechnology. - : Springer Science and Business Media LLC. - 1559-0305 .- 1073-6085. ; 43, s. 89-94
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Tidskriftsartikel (refereegranskat)abstract
- Macromolecular drugs hold great promise as novel therapeutics of several major disorders, such as cancer and cardiovascular disease. However, their use is limited by lack of efficient, safe, and specific delivery strategies. Successful development of such strategies requires interdisciplinary collaborations involving researchers with expertise on e.g., polymer chemistry, cell biology, nano technology, systems biology, advanced imaging methods, and clinical medicine. This poses obvious challenges to the scientific community, but also provides opportunities for the unexpected at the interface between different disciplines. This review summarizes recent studies of macromolecular delivery that should be of interest to researchers involved in macromolecular drug synthesis as well as in vitro and in vivo drug delivery studies.
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| 9. |
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| 10. |
- Belting, Mattias, et al.
(författare)
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Nuclear delivery of macromolecules: barriers and carriers.
- 2005
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X. ; 57:4, s. 505-527
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Forskningsöversikt (refereegranskat)abstract
- Recent evidence for efficient delivery of macromolecules, such as peptides and nucleic acids, from the cell exterior to the nucleus offers the interesting possibility of developing novel treatments directed at intranuclear targets. The findings should also stimulate the search for physiological ligands that utilize similar transport mechanisms to regulate pathobiological processes. Cytokines, growth factors and their receptors, as well as morphogens have all been shown to enter the nucleus to evoke biological responses in target cells. The rational design of intracellular drug delivery vehicles requires an increased understanding of the elaborate systems that mediate cellular communication and coordination with the extracellular environment without inflicting on the integrity of the cell. This review discusses some aspects of the carriers and barriers in macromolecular transport.
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