Nuclisome: a novel concept for radionuclide therapy using targeting liposomes.
OBJECTIVE
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.


CONCLUSIONS
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.
Fondell
Amelie
A
Department of Oncology, Radiology, and Clinical Immunology, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Edwards
Katarina
K
Ickenstein
Ludger M
LM
Sjöberg
Stefan
S
Carlsson
Jörgen
J
Gedda
Lars
L
D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D008081:Liposomes / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics
D007457:Iodine Radioisotopes; D008081:Liposomes; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors