R. K. Chowdhary

Drug delivery systems for photodynamic therapy

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitizing drug and visible light causes destruction of selected cells. Over the past two decades, photodynamic therapy has enjoyed a period of intense investigation, both in the laboratory and in the clinic. Although still widely considered to be an experimental technique, its status and value within modern clinical practice continues to grow. The PDT field has, to date, been dominated by a small number of pharmaceutical companies and inhabited almost exclusively by clinicians and those involved in fundamental scientific research. True pharmaceutical formulation development has been limited, to some extent, by financial constraints. If PDT is to realise its undoubted potential in clinical practice it is important that awareness of the need for appropriate photosensitizer delivery systems is raised. Accordingly, this article deals with the innovations pertaining to drug delivery systems for photodynamic therapy as disclosed in recent patent literature.

Amelioration of antigen‐induced arthritis in rabbits by induction of apoptosis of inflammatory‐cells with local application of transdermal photodynamic therapy

OBJECTIVE To study the efficacy and mechanism of local transdermal photodynamic therapy (tPDT) in rabbits with antigen-induced arthritis (AIA). METHODS AIA in rabbits on day 14 postinduction was treated with an intravenous injection of benzoporphyrin-derivative monoacid ring A (BPD; Verteporfin) and subsequent transdermal exposure of the knee joint to light. BPD uptake and PDT-induced apoptosis of the synovium was studied applying fluorescence confocal microscopy and immunohistochemistry. The (histo)pathology of the joints was assessed at day 28. RESULTS Treatment with tPDT resulted in significant amelioration of synovial inflammation and an almost complete prevention of pannus formation and bone and cartilage destruction. BPD uptake was detectable in activated T cells and macrophages, and there was significant PDT-induced increase in the number of apoptotic cells in the synovium. CONCLUSION Because photodynamic therapy is both specific and noninvasive, our findings suggest that it could be used for treating arthritic joints in humans.

Photodynamic therapy ; a comparison with other immunomodulatory treatments of adjuvant-enhanced arthritis in MRL-lpr mice

Although numerous experimentat immunomodulalory regimens have been reported to be effective in the treatment of rheumatoid arthritis, they also produce undesirable side effects. An alternative specific modality of localized treatment is photodynamic therapy (PDT). In this study we treated 13‐week‐old MRL‐lpr mice whose spontaneous arthritis was enhanced by intradermal injection of Freunds complete adjuvant (FCA). One group received transcutaneous photodynamic therapy at days 0, 10, and 20, following the FCA injection. The other groups were injected with 1 mg/kg per day indomethacin, 40 mg/kg per day cyclosporin A (CsA), or treated with 3 Gy sublethal whole body irradiation (WBI). The development of swelling was monitored for 1 month, at which time proteinurca, lymphadenopathy and the histopathology of the joints and kidneys were assessed. The results demonstrated that PDT and the conventional treatments significantly ameliorated swelling of the hindlimbs from 70%in the untreated FCA‐injected animals to below the 19% level characteristic of the unmanipulated control. Histological examination showed a reduction in pannus fornamtion, and cartilage and bone destruetion, the characteristics of adjuvant‐enhanced arthritis. PDT did not affect the survival rate, lymphoproliferation, or proteinuria of the treated animals. However, indomethacin increased proteinurea, and was less effective in preventing cartilage and bone destruction, furhtermore, lower doses of CsA and WBI exacerbated arthritis activity. These results indicate that photodynamic therapy can inhibit the development of adjuvant‐enhanced arthritis in MRL‐lpr mice with similar effectiveness to the conventional treatments, but without their negative side effects.

Uptake of verteporfin by articular tissues following systemic and intra-articular administration.

Photodynamic therapy (PDT) using the photosensitizer BPD‐Verteporfin (liposomal benzoporphyrin derivative‐monoacid ring A) has been shown in previous studies to be effective in the amelioration of inflammatory arthritis in both the MRL‐lpr mouse and the New Zealand White (NZW) rabbit models, and could potentially offer alleviation of certain inflammation‐related symptoms of rheumatoid arthritis. Time and dose dependency of BPD‐MA tissue uptake was carried out in the inflamed synovium and other articular and peri‐articular tissues following intravenous and intra‐articular administration in the NZW rabbit model. As some articular and peri‐articular tissues are difficult to extract, this study uses a rapid fluorimetric sampling of tissues following dissolution in Soluene 350. Our results showed that i.v. injected BPD‐MA preferentially distributed in the inflamed synovium, and in tissues with a high degree of vascularization. Little or no association was found with avascular tissues such as cartilage and tendons. Clearance from the synovium was rapid, supporting earlier rather than late light treatment. Much higher association of BPD‐MA with the synovium was achieved using intra‐articular injection, and BPD‐MA concentrations were maintained at relatively steady levels for several hours. These observations support the possibility that PDT could offer a safe, highly versatile clinical option for the management of inflamed joints in autoimmune disorders.

Formulation of Benzoporphyrin Derivatives in Pluronics

This study investigates the potential of Pluronics for the formulation of tetrapyrrole‐based photosensitizers, with a particular focus on B‐ring benzoporphyrin derivatives. TheB‐ring derivatives have a high tendency to aggregate in aqueous solutions, and this poses a significant formulation problem. Pluronics are ABA‐type triblock copolymers composed of a central hydrophobic polypropylene oxide section with two hydrophilic polyethylene oxide sections of equal length at either end. Out of a range of different commercially available block copolymers studied, it was found that the longer the hydrophobic block, the better the stabilization of tetrapyrrolic drugs in monomeric form in aqueous suspensions. Of these the best performance was observed in the micelle‐forming Pluronic P123. Micelle size determination by laser light scattering confirmed that particle size in stable Pluronic formulations was around 20 nm. Pluronics such as L122 formed emulsions spontaneously without the need for emulsion stabilizers; emulsions were highly stable at ambient temperatures over several days and also highly effective as potential drug delivery agents.

Treatment of experimental murine arthritis with transdermal photodynamic therapy

Photodynamic therapy (PDT) using benzoporphyrin derivative, monoacid ring A (BPD), and transdermal light was able to significantly treat symptoms of adjuvant-enhanced arthritis in MRL-lpr mice. Clinical and histological evaluation showed that PDT was able to modify the progression of adjuvant-enhanced arthritis up to 10 days after induction. When PDT was used on arthritic joints displaying swelling, it prevented further deterioration of clinical symptoms (76%, 16/21). However, it did not significantly effect the histopathologic parameters. As we have previously reported that mitogen activated MRL-lpr splenocytes were shown to be more susceptible to in vitro PDT we postulate that our findings reflect a selective destruction of adjuvant activated lymphocytes in the circulation and/or joints. The application of PDT to eliminate activated cells responsible for the inflammatory reaction at the arthritic site may have significant clinical implications for the treatment of rheumatoid arthritis.

Immune modulation using transdermal photodynamic therapy

The photosensitizer benzoporphyrin derivative monoacid ring A (VerteporfinR or BPD) has maximum absorption characteristics (690 nm) and biodistribution characteristics which permit activation of the drug in capillaries of the skin without causing skin photosensitivity (transdermal PDT). This permits targeting of cells in the circulation for selective ablation. Since BPD has been shown to accumulate preferentially in activated lymphocytes and monocytes, studies have been undertaken to determine the effect of transdermal PDT on murine models for rheumatoid arthritis (the MRL/lpr adjuvant enhanced model) and multiple sclerosis (the experimental allergic encephalomyelitis (EAE) model in PL mice). Localized transdermal PDT with BPD was found to be completely successful in preventing the development of adjuvant enhanced arthritis in the MRL/lpr mouse as well as improving the underlying arthritic condition of these animals. In the EAE model, in which an adoptive transfer system was used, it was found that transdermal PDT of recipients was effective in preventing EAE if treatments were implemented up to 24 hours after cell transfer but was not effective if given later, indicating the requirement for circulating T cells for effective treatment.