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| 2. |
- Bohl Kullberg, Erika, et al.
(författare)
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Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents
- 2002
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 13:4, s. 737-743
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are of interest as drug delivery tools for therapy of cancer and infectious diseases. We investigated conjugation of epidermal growth factor, EGF, to liposomes using the micelle-transfer method. EGF was conjugated to the distal end of PEG−DSPE lipid molecules in a micellar solution and the EGF−PEG−DSPE lipids were then transferred to preformed liposomes, either empty or containing the DNA-binding compound, water soluble acridine, WSA. We found that the optimal transfer conditions were a 1-h incubation at 60 °C. The final conjugate, 125I-EGF−liposome−WSA, contained approximately 5 mol % PEG, 10−15 EGF molecules at the liposome surface, and 104 to 105 encapsulated WSA molecules could be loaded. The conjugate was shown to have EGF-receptor-specific cellular binding in cultured human glioma cells.
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| 3. |
- Bohl Kullberg, E, et al.
(författare)
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Introductory experiments on ligand liposomes as delivery agents for boronneutron capture therapy
- 2003
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Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 23:2, s. 461-467
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.
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| 5. |
- Carlsson, Jörgen, et al.
(författare)
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Conjugate chemistry and cellular processing of EGF-dextran
- 1999
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 38:3, s. 313-321
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Tidskriftsartikel (refereegranskat)abstract
- Conjugates with specific binding to the epidermal growth factor receptor, EGFR, of interest for radionuclide based imaging and therapy were prepared using mouse epidermal growth factor, mEGF, and dextran. In one type of conjugate, mEGF was coupled to dextran by reductive amination in which the free amino group on the mEGF N-terminal reacted with the aldehyde group on the reductive end of dextran. The end-end coupled conjugate could be further activated by the cyanopyridinium agent CDAP, thereby introducing tyrosines to the dextran part. In the other type of conjugate, the cyanylating procedure using CDAP was applied, first to activate dextran and then allowing for the amino terminus of mEGF to randomly attach to the dextran. In the latter case, radionuclide-labelled tyrosines or glycines could be added in the same conjugation step. All types of mEGF-dextran conjugates had EGFR-specific binding since the binding could be displaced by an excess of non-radioactive mEGF. The conjugates were to a large extent internalized in the test cells and the associated radioactivity was retained intracellularly for different times depending on both the type of cells and conjugate applied. Different intracellular 'traffic routes' for the radionuclides are discussed as well as applications for both imaging and therapy.
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| 7. |
- Carlsson, Jörgen, et al.
(författare)
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Penetration of tumor therapy interesting substances in non-vascularized metastases. : Review of studies in multicellular spheroids
- 2006
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Ingår i: Current Cancer Therapy Reviews. - : Bentham Science Publishers Ltd.. - 1573-3947. ; 27, s. 293-304
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Tidskriftsartikel (refereegranskat)abstract
- Penetration properties, studied in multicellular spheroids, of totally 23 radiolabeled or boronated substances are summarized. The spheroids were models for small non-vascularized metastases, and there is special emphasis on results obtained with a freeze-drying method. The substances were detected using autoradiography or neutron capture radiography. Certain substances, e.g. 5-FU, glucose, BSH and one antibody , penetrated efficiently, while others, e.g. vinblastine, an epidermal growth factor derivative, and two other types of antibodies only penetrated into the outer periphery of the spheroids in spite of long incubation time. The molecular weight of the substances did not relate well with the penetration properties. Instead, those substances that bound extensively had in most cases limited penetration. This was, for example, clearly shown for the drug Ara-C when applied to two different types of spheroids, one type giving low binding and good penetration and one giving extensive binding and less penetration. The penetration of an antibody and an EGF-derivative improved significantly when their binding sites were blocked. It is concluded that molecular weight is not a dominating determinant for penetration in the studied model, but that binding is. Such knowledge is valuable for the understanding of effects of chemotherapy, targeted radionuclide therapy and immunotherapy and for the development of new agents for such therapies.
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| 8. |
- Carlsson, Jörgen, et al.
(författare)
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Planning for intracavitary anti-EGFR radionuclide therapy of gliomas : Literature review and data on EGFR expression
- 2006
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 77:1, s. 33-45
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Tidskriftsartikel (refereegranskat)abstract
- Targeting with radionuclide labelled substances that bind specifically to the epidermal growth factor receptor, EGFR, is considered for intracavitary therapy of EGFR-positive glioblastoma multiforme, GBM. Relevant literature is reviewed and examples of EGFR expression in GBM are given. The therapeutical efforts made so far using intracavitary anti-tenascin radionuclide therapy of GBM have given limited effects, probably due to low radiation doses to the migrating glioma cells in the brain. Low radiation doses might be due to limited penetration of the targeting agents or heterogeneity in the expression of the target structure. In this article we focus on the possibilities to target EGFR on the tumour cells instead of an extracellular matrix component. There seems to be a lack of knowledge on the degree of intratumoral variation of EGFR expression in GBM, although the expression seemed rather homogeneous over large areas in most of the examples (n=16) presented from our laboratory. The observed homogeneity was surprising considering the genomic instability and heterogeneity that generally characterises highly malignant tumours. However, overexpression of EGFR is, at least in primary GBMs, one of the steps in the development of malignancy, and tumour cells that lose or downregulate EGFR will probably be outgrown in an expanding tumour cell population. Thus, loss of EGFR expression might not be the critical factor for successful intracavitary radionuclide therapy. Instead, it is likely that the penetration properties of the targeting agents are critical, and detailed studies on this are urgent.
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