 Discovery Pipeline
In photodynamic therapy the powerhouse is the photosensitiser. This can be regarded as an energy transfer agent, which captures the energy of light and uses it to energise normal atmospheric oxygen into the highly cytotoxic species called singlet oxygen. This activated form of oxygen then provides the relevant therapeutic effect. A photosensitiser must at the very least have:
Photopharmica is therefore fortunate to have developed several photosensitisers which satisfy all these issues, and which are at an advanced development stage. It is true to say that no other company in the photodynamic arena has such a strong in-house drug discovery capability. However, as the number of areas where photodynamic therapy finds application continues to increase, there is a continuing need for new photosensitisers which are specific for purpose. Consequently Photopharmica maintains a strong drug discovery program, as evidenced by the breadth of the current discovery pipeline. How is a photosensitiser molecule designed? A photosensitiser molecule consists of a central chromophore to which are attached various side chains:  The chromophore is that part of the molecule that absorbs light energy and transfers it to atmospheric oxygen to produce singlet oxygen. Very careful design of this unit is required to ensure (a) that it selectively absorbs red or near-infrared light, rather than other wavelengths, (b) that it absorbs the light with very high efficiency, (c) after absorbing light it converts to a triplet state efficiently, and (d) the triplet state can interact with O2 to produce singlet oxygen. The side chains moderate such properties as solubility, uptake by different organisms, side effects and phototoxicity, and the selection of these is both critical and difficult to predict. How are new photosensitisers discovered? The photosensitiser discovery process used by Photopharmica can be summarised thus:  This requires a multidisciplinary team comprising synthetic organic chemists, biochemists, biologists and microbiologists. Screening at each stage, and continuous feedback of the results to the molecular designers enables structures to be fine-tuned, ultimately resulting in a photosensitiser with the ideal characteristics. Pipeline Compounds for Therapeutic Applications 1. New phenothiazinium photosensitisers for antimicrobial photodynamic therapy Photopharmica's most progressed antimicrobial photosensitisers are PPA904 and PPA905, which are based on the phenothiazinium cationic system:  Phenothiazinium salts of this type are blue in colour, and absorb red light strongly. The cation has its positive charge spread over several atoms and has a planar structure as shown in the following molecular model (carbon atoms are shown in blue, nitrogen in red and sulphur in yellow).  The exceptional characteristics of these two photosensitisers in antimicrobial photodynamic therapy stem from (a) the phenothiazinium chromophore, which combines strong red-light absorption with efficient singlet oxygen generation. (b) The cationic charge on the molecule, which ensures rapid uptake by microorganisms, and (c) the side chains R1 - R4 , which have been carefully selected to give optimal activity against infective microorganisms. Several new analogues of PPA904 and PPA905 have been found which are extremely effective against infection and are undergoing evaluation. Differences in specificity among these compounds will enable a wider PDT drug library to be built up, from which photosensitisers could be selected specifically for purpose. Interestingly the phenothiazinium photosensitisers have shown a moderate toxicity towards bacteria in the absence of light, additional to their powerful photocytoxicity. This has potential advantages for continuing infection control after light treatment has ceased. 2. New phenothiazinium photosensitisers for oncology. Following an investigation of structure-activity relationships in the phenothiazinium series, several compounds have now been developed which have a high PDT activity, low skin photosensitivity and show an Ames-negative response. They also show significant differences in drug-light interval profiles, which will give greater flexibility in designing optimum drug administration protocols. 3. New phenothiazinium photosensitiser modifications Photopharmica has developed a method for dramatically modifying the solubility and hydrophobic/hydrophilic properties of its phenothiazinium photosensitisers without losing their intrinsically high PDT activity. 4. Novel porphyrin-type photosensitisers Photopharmica has shown that by judicious choice of side chains, phthalocyanine photosensitisers, can be produced which are very effective against tumour cells in vivo, but which show minimal or zero skin photosensitisation side effects. These specific side chains have been patented by Photopharmica. Research has now been extended into porphyrin, chlorin and bacteriochlorin photosensitisers, with the objective of synthesising examples containing these side chains. It is hoped that in this way photosensitisers closely similar to commercial porphyrin-type photosensitisers can be produced, but without the undesirable skin photosensitisation properties that these are known to have. Synthetic expertise in these classes of compound has been acquired and examples from the porphyrin, chlorin and bacteriochlorin classes are currently under investigation. Pipeline Materials for Non-Therapeutic Applications The powerful antimicrobial properties of Photopharmica's photosensitisers can be exploited in infection prevention and control. For example, the photodynamic sterilisation of medical devices, such as prosthetics, intravenous lines and catheters provides a new and powerful way of combating acquired infections from these, and this is of increasing importance with the emergence of antibiotic resistant strains of bacteria. Photopharmica's photosensitisers can destroy such organisms as easily as normal bacteria. In the general healthcare area, photo-disinfection of surfaces which can harbour infective microorganisms (including body surfaces such as the hands) is equally important in infection control, especially if the presence of small residual amounts of a photosensitiser can maintain sterility for prolonged periods under ambient light conditions. Photopharmica has developed materials based on its photosensitiser technology for such applications. These include:
Photosensitiser-Type Molecules for Specialised Applications As a lead developer of new photosensitisers for therapy, Photopharmica is also ideally placed for developing other types of light absorbing molecules with highly specialised optical properties. These may find application in such areas as laser dyes, fluorescent imaging dyes, and near-infrared absorbing materials. Novel colourless photosensitisers have been developed which absorb strongly in the near- infrared, and which have remarkable stability towards light when applied to paper or incorporated into printing ink varnishes. Such materials can be used as invisible markers for authentification of bank notes and other high value items, and have important advantages over existing near-infared absorbers used in the security printing industry. Three lead compounds have been developed, two organic soluble, and thus suitable for adding to conventional offset inks, and one water soluble, suitable for ink jet printing formulations. There are many other specialised applications of near-infrared dyes (e.g. optical filters; laser welding) and Photopharmica has developed a completely new class of near- infrared dye which has the potential to provide a wide range of stable materials to suit the needs of these technologies. ^ top |
