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- Fondell, Amelie, et al.
(författare)
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Nuclisome : a novel concept for radionuclide therapy using targeting liposomes
- 2010
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 37:1, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: For the treatment of cancer, the therapeutic potential of short-range, low-energy Auger-electron emitters, such as (125)I, is getting progressively wider recognition. The potency of Auger-electron emitters is strongly dependent on their location in close vicinity to DNA. We have developed a new two-step targeting strategy to transport (125)I into cancer-cell nuclei using PEG-stabilized tumour-cell targeting liposomes named "Nuclisome-particles". METHODS: In the present study, epidermal growth factor (EGF) was used as a tumour-cell-specific agent to target the EGF-receptor (EGFR) and the liposomes were loaded with (125)I-Comp1, a recently synthesized daunorubicin derivative. RESULTS: As analysed with cryo-TEM, the derivative precipitates inside liposomes at a drug-to-lipid molar ratio of 0.05:1. Receptor-specific uptake in cultured U-343MGaCl2:6 tumour cells of EGFR-targeting liposomes increased with time while non-specific and receptor-blocked uptake remained low. Nuclisome-particles were able to target single U-343MGaCl2:6 cells circulating in human blood during 4 h, with low uptake in white blood cells, as demonstrated in an ex vivo system using a Chandler loop. Autoradiography of targeted cells indicates that the grains from the radiolabelled drug are mainly co-localized with the cell nuclei. The successful targeting of the nucleus is shown to provide high-potency cell killing of cultured U-343MGaCl2:6 cells. At the concentration used, Nuclisome-particles were up to five orders of magnitude more effective in cell killing than EGFR-targeting liposomes loaded with doxorubicin. CONCLUSION: The results thus provide encouraging evidence that our two-step targeting strategy for tumour cell DNA has the potential to become an effective therapy against metastasizing cancer cells in the bloodstream.
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- Ickenstein, Ludger M., et al.
(författare)
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A novel I-125-labeled daunorubicin derivative for radionuclide-based cancer therapy
- 2006
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 33:6, s. 773-783
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Auger electron emitters, such as (125)I, are getting increasingly wider recognition as alternatives to current anticancer treatments. The effectiveness of Auger electrons is strongly dependent on their proximity to DNA and is therefore considered as harmless outside the nucleus. METHODS: (125)I or (127)I was conjugated with Comp1, Comp2 or Comp3 - three derivatives of the chemotherapeutic drug daunorubicin. Their capacity factors, DNA-binding constants and exclusion parameters, and the degree of DNA fragmentation after incubating isolated DNA with our (127)I- or (125)I-conjugated daunorubicin derivatives were determined. Human breast adenocarcinoma (SK-BR-3) cells were incubated with the derivatives; fluorescent microscopy and autoradiography images were generated; and cell growth was monitored. RESULTS AND DISCUSSION: The capacity factor of (127)I-Comp1 was similar to those of daunorubicin and doxorubicin, whereas lower capacity factors of (127)I-Comp2 and (127)I-Comp3 suggested reduced interactions with lipid membranes. DNA exclusion parameters and binding constants of (127)I-Comp1 and (127)I-Comp2, but not of (127)I-Comp3, were similar to those of doxorubicin. Fluorescent microscopy and autoradiography images of SK-BR-3 cells revealed that (127)I-Comp1 and (125)I-Comp1 accumulated in tumor cell nuclei, whereas (127)I-Comp2 and (127)I-Comp3 were present predominantly in other cell compartments. The binding of (125)I-Comp1 to isolated chromosomal DNA led to major fragmentation. Incubation of SK-BR-3 cells with (125)I-Comp1 inhibited cell growth, whereas doxorubicin or (127)I-Comp1 administered at the same concentration had no effect on cell growth. Our results thus suggest that (125)I-Comp1 has the potential to become a new tool for anticancer therapy.
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- Ickenstein, Ludger M., et al.
(författare)
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Disc formation in cholesterol-free liposomes during phase transition
- 2003
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Ingår i: Biochimica et Biophysica Acta - Biomembranes. - 0005-2736 .- 1879-2642. ; 1614:2, s. 135-138
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Tidskriftsartikel (refereegranskat)abstract
- Cryogenic transmission electron microscopy (cryo-TEM) images of lysolipid-containing thermosensitive liposomes (LTSL) revealed that open liposomes and bilayer discs appeared when liposomes were cycled through the gel (Lbeta') to liquid-crystalline (Lalpha) phase transition. The amount of bilayer discs generated was dependent on the combined presence of PEG-lipid and lysolipid in the membrane. We hypothesize that micelle-forming membrane components stabilize the rim of bilayer openings and membrane discs that form when liposomes are cycled through TC.
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