Objective
- Modification of natural Chlorophylls and Bacteriochlorophylls with improved phototoxicity;
- Characterisation and engineering of their excited states photophysics and photochemistry;
- Uptake of photosensitising porphyrins into melanoma cells in cell culture. Choosing an adequate photosensitise and adequate irradiation conditions to kill melanoma cells;
- Site selective substitution of porphyrins to form stable inclusin complexes with dimeric cyclodextrins in order to enhance tumour selectivity;
- Conjugation of (bacterio) chlorophyll derivatives to amino acid and targeting peptides or proteins;
- Proof of selectivity in tumour models (microspheres in cell culture, microtumours on growing chicken embryos, heterotransplants of human tumours in nude mice).
- Uptake studies showed concentration of the applied drugs up to 10{8} to 10{0} molecules of the photosensitises per tumour cell during 2-5 minutes of incubation in cell suspension. These numbers are extremely high in melanotic melanomas in comparison to non-melanotic tumours and point to a special uptake mechanism now under investigation.
- Just very low fluence rates lead to cell death (LD 90 values below 1 J/cm2 at the absorption maxima of the applied drugs). Laser diode arrays are constructed suitable for clinical application of the drugs.
- Chemical modification of the drugs to stabilise inclusion into dimeric cyclodextrins yielded a 9000 fold better stability as compared with the complexes obtained with monomeric methyl beta-cyclodextrin.
- Spacer structure holding together the beta-cyclodextrin moieties of beta-cyclodextrin dimmers in 6,6' or 2,2' positions was veered in length to adapt the dimmers to the drugs to be complexed. The stability constants amount up to 10{7} (l/mol).
- These complexes are stable enough to separate the drugs from the lipoprotein system in human plasma. The attachment of biotin and hydroxypropyl groups is now under investigation.
- First animal experiments showed high yield of recovery from solid tumours after topical treatment. Phamacokinetics were determined and treatment followed by magnetic resonance imaging.
- The work is done in close co-operation between three groups in Germany, one group in the UK and two groups in Israel;
- Melanoma cells used in these studies are M2R mouse melanoma. A 375 amelanotic human melanoma and SKMEC 25 melanotic human melanoma;
- Uptake studies concentrate on two chlorophyll derived photosensitises : Pd-bacteriopheophorbide ethyl ester and bacteriochlorophyll serine;
- Introduction of tert.butylphenoxy- and tert. butyl benzoic acid groups at position 31 of the photosensitising pigments and conjugation to aminoacid derivatives;
- Construction of dimeric beta-cyclodextrins including biotinyl side groups and hydroxypropylation in order to enhance solubility in human blood plasma;
- Determination of stability constants of the drug-dicyclodextrin complexes;
- Proof of selectivity on tumour models using the biotin-aviding accumulation systems;
- Topical treatment of human tumours in nude mice.
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Programme(s)
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Coordinator
80638 München
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.