Phenothiazinium Based Photosensitisers - Photodynamic Agents with a Multiplicity of Cellular Targets and Clinical Applications

F.      Harris; L.   K.   Chatfield; D.   A.   Phoenix

Abstract

Phenothiazinium based photosensitisers (PhBPs) possess planar heteroaromatic ring structures that give the parent molecules photosensitising properties. PhBPs show potential application in photodynamic therapy (PDT) as antitumour agents, and in photodynamic chemotherapy (PACT) as antimicrobial compounds. PhBPs show selectivity for tumour and microbial cells, which appears to be based on electrostatic interactions between the positive charge generally carried by these molecules and the negative charge found on the outer surface of these target cells. In some cases, a site of action for photoactivated PhBPs is the outer membrane / envelope of the target cell. Such action can involve the modification of membrane lipid and / or lipopolysaccharide, and the inactivation of essential proteins and enzymes, with these effects usually leading to cell lysis and death. However, more often, PhBPs are internalised by target cells, promoted by a variety of factors, including low pH and enzymatic reduction, and upon photoactivation, internalised, PhBPs are able to inflict damage on a number of intracellular targets. In tumour cells, PhBPs can photodamage DNA and the membranes of organelles, thereby inducing necrosis and / or apoptosis. In bacterial cells, whilst DNA is generally a primary target of PhBPs, these compounds can exhibit multiple sites of action within a given cell and show different sites of action between different bacterial species. This variable targeting makes PhBPs attractive propositions as alternatives to conventional antibiotics in that the emergence of bacterial strains with acquired resistance to these compounds appears to be highly unlikely.

Keywords: phenothiazinium-based photosensitisers, photodynamic therapy, photodynamic antimicrobial chemotherapy, antitumour, antibacterial, antiviral and antimalarial

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