Cel - 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. Program(-y) IC-ISC C - Activity (Euratom, EEC) on cooperation in science and technology, 1984- Temat(-y) Data not available Zaproszenie do składania wniosków Data not available System finansowania CSC - Cost-sharing contracts Koordynator LUDWIG-MAXIMILIANS UNIVERSITY OF MUNICH Wkład UE Brak danych Adres Menzingerstraße 67 80638 München Niemcy Zobacz na mapie Koszt całkowity Brak danych Uczestnicy (3) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko FORSCHUNGSVERBUND BERLIN E.V. Niemcy Wkład UE Brak danych Adres Max-Born-Strasse 2a 12489 BERLIN Zobacz na mapie Koszt całkowity Brak danych Heinrich-Heine-Universität Düsseldorf Niemcy Wkład UE Brak danych Adres Universitätstraße 1 40225 Düsseldorf Zobacz na mapie Koszt całkowity Brak danych University of Manchester Zjednoczone Królestwo Wkład UE Brak danych Adres Oxford Road M13 9PL Manchester Zobacz na mapie Koszt całkowity Brak danych
