L. Molteni & C. dei F.lli Alitti Società di Esercizio SpA

A number of Zn(II)-phthalocyanines bearing peripheral substituents of cationic nature due to the presence of quaternary anilinium or ammonium groups were shown to be efficient photoantimicrobial agents: a 4-5 log decrease in the survival of both wild-type or methicillin-resistant Staphylococcus aureus was obtained upon short irradiation times in the presence of phthalocyanine concentrations as low as 0.1 μM.A careful selection of the exptl. protocol, and in particular the use of short (5 min) incubation times and mild irradiation parameters, allowed one to achieve a high selectivity of S. aureus photoinactivation as compared with important constituents of potential host tissues, such as human fibroblasts and keratinocytes.The efficiency and selectivity of the photoprocess were not affected by the presence of 5% human serum.

The synthesis of a new series of nonpeptide derivatives of interleukin-1 beta sequence is described. Compounds have been investigated for their relative activity regarding antinociception and suppression of inflammation. Several compounds with R1(R)Lys [CH2N]-Pro structure showed better efficacy in the inflamed paw pressure test than indometacin and morphine. In terms of the relative potencies the above mentioned products (i.e. compounds 2, 4, 5, 6; ED50 values of 0.002, 0.0035, 0.0032, 0.0074 mg/kg i.p. respectively) were 10-100 times more potent than indometacin and morphine (ED50 values of 0.22 and 0.75 mg/kg). Compounds 1-14 were not able to inhibit binding of labeled interleukin-1 beta to EL 4-6.1 murine cells, since they had no affinity for interleukin-1 beta receptors. The antinociceptive activity elicited by compound 4 in the rat inflamed paw pressure test was inhibited by naloxone, but the compound was inactive in the mouse hot plate and rat paw pressure tests. These results suggest that compound 4 exerts its antinociceptive activity through a mechanism which is based on the local release of endogenous opioids in injured tissue.

Antibody targeted chemotherapy is a relatively new technique which involves the specifically carrier mediated delivery of chemotherapeutic agents to tumors or other pathogens for the treatment of such diseases.Conjugation of antibodies with photosensitizers (PSs) can also lead to potential therapeutic agents which combine photodynamic cytotoxicity with specific antibody binding.The antibody mediated delivery of a photosensitizer mol. and the target destruction upon irradiation by light followed by production of singlet oxygen or other radicals, results in a higher therapeutic ratio compared to the conventional photodynamic therapy (PDT).In this study the naturally occurring PS α-terthienyl (ATT) was chem. derivatized with an amino group specific reactive side arm and to exploit its toxicity as an effector function suitable for targeted photolysis, covalently conjugated to the 225.28S monoclonal antibody (mAb) specific for the high mol. weight melanoma associated antigen (HMW-MAA).The 225-28S-ATT conjugate prepared was then tested against the melanoma cell line Colo38 in comparison with HT29 tumor cells, not recognized by 225-28S mAb, as neg. control.The selective uptake of labeled mAb 225-28S-ATT was observed and melanoma cell death following irradiation occurred.In conclusion the 225-28S-ATT conjugate, as far as one can judge from the effect on cells grown in vitro, seems a good candidate as a model to test the antibody targeted photolysis of melanoma cells for developing specific antimelanoma therapeutic agents.