Drug

Target

Target

Target

H202

Scheme 3 General scheme of photosensitization induced by drugs in biological systems.

damage. Copper acts at a lower concentration range and its activity is enhanced due to its superoxide dismutase-like activity leading to the scavenging of the superoxide anion. Thus, metal complexation (in certain cases with ligands of biological interest, such as linear and cyclic dipeptides as well as with mono- and di-functionalysed cyclodextrins) exerts an antioxidant activity and a radical blocking action protecting from drug induced photohemolysis,36'7 and lipid peroxiation.59'70'71 The particular effect of copper confirms the involvement of the superoxide anion (and of its decay product, the hydroxyl radical) in the photoinduced sensitization mechanisms. Inorganic ions also decrease drug-photoinduced DNA cleavage.72 The protective efficiency decreases with the increase of concentration of the free drug in the bulk of the solution, due probably to a scavenging action of radicals generated in the photolysis. The overall results further confirm the key role played by oxygen-mediated type I mechanism in drug photosensitization in cell membranes.

5.2 Cyclodextrins

(3-cyclodextrins can constitute an efficient photoprotective agent as regards drug photoinduced damage on biological targets.73'74 As reported above (paragraph 4), the inhibitory action detected in photosensitization processes is related to cyclodextrin ability in including the drug through a host-guest process. This process a) can modify the sensitizer photochemistry by decreasing the quantum yield of formation of the species responsible for phototoxicity; b) opposes to oxygen diffusion toward the sensitizer, and if a type II mechanism is operative, a reduction of singlet oxygen, a particularly efficient agent in inducing damages on various biological targets, occurs.64'65 On the other hand, it is to be considered that the use of this additive is valid only in a restricted range of concentrations, due to the fact high levels of cyclodextrin are toxic towards cells.73 Moreover, in some cases the cyclodextrin complexation determines an overall increase of the drug photodegradation quantum yield,65 due to an increase of the efficiency of other deactivation processes such as hydrogen abstraction from the cyclodextrin. Consequently, care has to be taken in therapeutic administration of drug-cyclodextrin associates.

5.3 Macromolecular Conjugates and Polymeric Carriers

As regards macromolecular conjugates between polyasparthamides and drugs or macrocarriers built through crosslinking by glutaraldehyde or y-rays, the design of a prodrug which can allow a gradual release of the active species and, meanwhile, decrease photosensitization damages, is taken into account. In the first case, a macromolecular conjugate between a,p-poly(N-hydroxyethyl)-DL-aspartamide and a non steroidal antiinflammatory drug, such as diflunisal, ketoprofen or naproxen leads to a strong reduction of photosensitized cell damage and this effect seems to be independent on the molecular mechanism of the photochemical reaction.75

In the second case, an anti-inflammatory drug such as suprofen is incorporated in polymer networks based on biocompatible macromolecules, such as a,(3-polyasparthydrazide (PAHy) and a,f3-poly(N-hydroxyethyl)-DL-aspaitamide (PHEA) crosslinked by glutaraldehyde or y-rays, respectively. Swelling tests and photosensitization experiments in erythrocyte membranes carried out in aqueous medium indicate that the drug is released in a sustained way both from PAHy and PHEA microparticles. Moreover, incorporation of suprofen in PAHy and PHEA networks provides a significant reduction of the drug photosensitizing activity.76 The more likely hypothesis is that the photogenerated radicals entrapped in the hydrogel are scavenged by the host organic functional groups, which can act as efficient hydrogen donors. A similar behaviour was observed in the host-guest photochemistry in the presence of cyclodextrin.65

Acknowledgments. We thank CNR and Istituto Superiore della Sanita - Progetto: "Proprieta chimico-fisiche dei medicamenti e loro sicurezza d'uso"- grants.

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A Comparison between the Photochemical and Photosensitising Properties of Different Drugs

M. Tronchin,1* F. Callegarin,1 F. Elisei,2 U. Mazzucato,2 E. Reddi1 and G. Jori1

1 Department of Biology, University of Padova via Trieste 75,1-35120 Padova, Italy

2 Department of Chemistry, University of Perugia, via Elce di Sotto 8,1-06100 Perugia, Italy

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