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Photodynamic therapy (PDT), a treatment approach that makes use of a photosensitizer to generate a localized toxic species in diseased tissue, has recently become an approved treatment modality. So far, however, only a handful of photosensitizers have received regulatory approval and for a small number of diseases. This chapter outlines the major limitations of PDT and speculates on the possible improvements that are required in order to advance PDT to a front line therapy. Seven areas of improvements are discussed: drug selectivity, drug delivery, light delivery, combination therapies, pigmented tumors, other potential uses, and protocol optimization. For each area, current limitations are discussed, and further required studies are recommended.

Palladium octabutoxynaphthalocyanine (PdNc(OBu)8) is a potential photothermal therapy (PTT) agent, absorbing strongly in the near-infrared region with no ability to induce photodynamic-type sensitisation (unlike many related napthalocyanines). We report here on the application of high pressure liquid chromatography (HPLC) with near-infrared absorption detection for the determination of the tissue accumulation and clearance of PdNc(OBu)8 in a tumour-bearing mouse model (Balb/c mice with EMT6 carcinoma tumour). Due to its insolubility in aqueous-based solvents, the drug was delivered intraperitoneally in a Cremophor-containing vehicle. Good selective accumulation of the drug into the tumour versus muscle or skin is observed, with the best combination of selectivity and tumour concentration occurring at 24-72 h after drug administration. Clearance times are quite long. Comparison with other similar drugs as reported in the literature indicates that the Cremophor-containing vehicle is likely in large part responsible for the observed pharmacokinetic behaviour. This drug shows potential for PTT and will be investigated further for therapy in this animal model.

The method of surface-detected fluorescence has been used to monitor the emission intensity from 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in lesions and corresponding adjacent normal skin. Three types of lesions were examined: psoriatic plaques, actinic keratosis and basal cell carcinoma. This study included a total of 14 human volunteers on whom ALA-induced PpIX formation and clearance was monitored for a total of 48 h post-ALA application. Both an ALA dose-ranging study, as well as a comparison of results between normal and lesional tissue at a fixed ALA dose, were carried out. For the dose range examined (10-30%), there was no ALA dose dependency of the PpIX fluorescence for any of the lesions tested. Although all three lesions tested did show enhanced PpIX fluorescence as compared with normal skin, there was considerable lesion-to-lesion variability. Thick psoriatic plaques seem to give longer PpIX retention times than those of thin lesions. Limitations of the surface-detected fluorescence methodology are discussed.

Administration of the heme precursor 5-aminolevulinic acid (ALA) leads to the selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in certain types of normal and abnormal tissues. This phenomenon has been exploited clinically for detection and treatment of a variety of malignant and nonmalignant lesions. The present preclinical study examined the specificity of ALA-induced porphyrin fluorescence in chemically induced murine lung tumors in vivo. During the early stages of tumorigenesis, ALA-induced PpIX fluorescence developed in hyperplastic tissues in the lung and later in early lung tumor foci. In early tumor foci, maximum PpIX fluorescence occurred 2 h after the administration of ALA and returned to background levels after 4 h. There was approximately a 20-fold difference in PpIX fluorescence intensity between tumor foci and the adjacent normal tissue. The specificity of ALA-induced fluorescence for hyperplastic tissues and benign tumors in lung during tumorigenesis suggests a possible use for this fluorochrome in the detection of premalignant alterations in the lung by fluorescence endoscopy. Two non-small cell lung cancer cell lines developed ALA-induced PpIX fluorescence in vitro. These lines exhibited a light-dose-dependent phototoxic response to ALA photodynamic therapy (PDT) in vitro. Because PpIX is a clinically effective photosensitizer for a wide variety of malignancies, these results support the possible use of ALA-induced PpIX PDT for lung cancer.

Surface-detected fluorescence spectroscopy can be used to monitor the pharmacokinetics of uptake and clearance of red-absorbing fluorophores such as zinc(II) phthalocyanine (ZnPc) in vivo. When this technique is applied to mice that have been fed on a normal chlorophyll-based diet, and particularly when measurements are performed in the abdominal region, oscillations are sometimes observed superimposed on the pharmacokinetic curve of the ZnPc. An oscillatory signal has also been observed arising from the abdominal region of control mice fed a normal diet but not injected with the ZnPc photosensitizer; this oscillatory component to the signal is reduced when mice are fed a chlorophyll-free diet. The oscillatory signal component has been attributed to fluorescence arising from chlorophyll derivatives (pheophorbide/pheophytin) contained in the rodent food, whose concentration in the measured abdominal region changes substantially with time, presumably due to digestive processes. Thus it is important to be aware of the possibility of such artifactual contributions to in vivo fluorescence pharmacokinetic measurements.