| 1. |
- 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. |
- 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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| 3. |
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| 4. |
- 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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| 5. |
- Belting, Mattias, et al.
(författare)
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Proteoglycans as endocytosis receptors for CPPs
- 2007
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Ingår i: Handbook of Cell-Penetrating Peptides, Second Edition. - 9780849350900 - 0849350905 ; , s. 219-219
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 6. |
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| 7. |
- El-Sheikh, A, et al.
(författare)
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A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment
- 2005
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Ingår i: Cancer Research. - 1538-7445. ; 65:23, s. 11109-11117
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that part of the heparin-binding domain of the vascular endothelial growth factor (VEGF), designated HBDt, localizes very selectively to surfaces of the endothelial cells of U blood vessels. Here, we have coupled the HBDt to the extracellular domain of tissue factor (TFt), to locally initiate the thrombogenic cascade. In tumor-bearing mice, infusion of this HBDt.TFt results in rapid occlusive thrombosis selective only for tumor microvasculature with resultant infarctive destruction of tumors. We now show that infusion of an optimal combination of this HBDt.TFt and its requisite cofactor (factor VIIa) in tumor models results in significant tumor eradication. Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment. The HBDt.TFt was also colocalized with the trimolecular receptor complex in endothelial sprouts from tumor tissues, and its binding inhibited the growth of such sprouts. In vitro, we show that the HBDt structure has its highest affinity for chondroitin 6 sulfate. We show the potential of this HBDt.TFt as a candidate therapeutic and elucidate its target in vivo.
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| 8. |
- Gardner, Richard Andrew, et al.
(författare)
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Synthesis and transfection efficiencies of new lipophilic polyamines
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:2, s. 308-318
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Tidskriftsartikel (refereegranskat)abstract
- A homologous series of lipophilic polyamines was synthesized and evaluated for DNA delivery and transfection efficiency. The series contained 1,4-butanediamine, 1,8-octanediamine, 2-[2-(2-amino-ethoxy)-ethoxy]-ethylamine, homospermidine, and homospermine covalently attached via their N-1 terminus to a 3,4-bis(oleyloxy)-benzyl motif. In addition, homospermidine and homospermine were also attached via amide linkers. The homospermidine derivatives (i.e., benzyl tether 25 and benzamide tether 27) showed a 3-fold and 4-fold respective enhancement in delivery of AlexaFluor-488-labeled DNA over the butanediamine analogue 22. Homospermine derivative 26 was shown to inhibit C-14-spermine uptake (IC50 similar to 10 mu M), which implied that 26 is able to compete effectively for polyamine recognition sites on the cell surface. This study demonstrated that the number and position of the positive charges along the polyamine scaffold plays a key role in DNA delivery and in determining the transfection efficiency.
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| 9. |
- Jacobsson, Mårten, et al.
(författare)
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Selective antiproliferative activity of hydroxynaphthyl-beta-D-xylosides
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:6, s. 1932-1938
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Tidskriftsartikel (refereegranskat)abstract
- The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case of transformed T24 cells, some compounds showed a clearly different behavior resulting in a selective antiproliferative effect. No such correlation was found for normal 3T3 A31 or virus transformed 3T3 SV40 cells, nor for the free aglycon. These results suggest that the antiproliferative activity shown by naphthoxylosides is diverse in different cell lines and dependent on the nature of the aglycon. The anti proliferative effect of 2- (6-hydroxynaphthyl)-beta-D-xylopyranoside, in contrast to inactive 2-naphthyl-beta-D-xylopyranoside, on T24 cells was accompanied by increased apoptosis as indicated by a TUNEL assay.
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| 10. |
- Kucharzewska, Paulina, et al.
(författare)
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The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1.
- 2009
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 380:2, s. 413-418
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-dependent angiogenesis is an inherent feature of solid tumors, and a better understanding of the molecular mechanisms of hypoxic cell-death should provide additional targets for cancer therapy. Here, we show a novel role of the polyamines in endothelial cell (EC) survival during hypoxia. Polyamine depletion by specific inhibition of ornithine decarboxylase was shown to protect ECs from hypoxia-induced apoptosis. Inhibition of the polyamines resulted in a significant induction of PI3K/AKT and its down-stream target MCL-1, i.e. an anti-apoptotic member of the BCL-2 family. Specific inhibitors of PI3K reversed the decrease of hypoxia-induced apoptosis as well as the induction of MCL-1 in polyamine-deprived cells. Moreover, siRNA-mediated down-regulation of MCL-1 was found to counter-act the protective effect of polyamine inhibition. We conclude that the polyamines regulate hypoxia-induced apoptosis in ECs through PI3K/AKT and MCL-1 dependent pathways. Our results may have important implications for the modulation of hypoxia-driven neovascularization.
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