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Background: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge., Objective: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers., Design: Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics., Patients: Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease)., Methods: A single intravenous infusion of 14 mg/m(2) of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm(2) of red light (688 +/- 10 nm) from a light-emitting diode panel., Main Outcome Measures: Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months., Results: The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm(2) to 93% at 180 J/cm(2). At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm(2) to 95% at 180 J/cm(2). No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months., Conclusion: A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.

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.

Benzoporphyrin derivative (BPD) is a potent photosensitizer in biological systems. There are four structural analogues of BPD. The analogues share the same chromophor, which results in their having almost identical optical spectra, extinction coefficients, and yields of singlet oxygen. Small structural differences affect their photosensitizing potency in various biological systems, and thus make them an interesting tool to study the structure-activity relationship. The ranking of the photosensitizing potency of the analogues differed depending on the test system. The more efficient photosensitization of tumor cell lines by the highly lipophilic monoacids as compared to that by less lipophilic diacids correlated positively with the partition coefficient, and was related to the rate of diffusion into the cells. However, in the assay systems where PDT targets were located in the membrane (red blood cells hemolysis, enveloped vesicular stomatitis virus, isolated mitochondria) there was very little difference in photosensitizing potency of BPD analogues. The results indicate that the evaluation of photosensitizers is affected by the test system and thus for photosensitizers screening purposes, the choice of the test system should be made based on the intended ultimate use.

The use of transcutaneous photodynamic therapy (PDT) has been investigated in the prevention of adjuvant enhanced arthritis in MRL/lpr mice. Mice receiving adjuvant were treated with PDT at 10-day intervals starting on the day of adjuvant administration. PDT was carried out by intravenous injection of the photosensitizer, benzoporphyrin derivative-monoacid ring A, followed by its transcutaneous activation with light. Adjuvant-injected animals displayed a delayed onset and reduced incidence and severity of arthritis when compared to untreated animals. Most importantly, inflammatory structural damage to cartilage and bone tissues was prevented by PDT. PDT was found to have no adverse effects on animals as assessed by mitogen responses, hematopoiesis, and serum enzyme levels. As mitogen-activated MRL/lpr splenocytes were shown to be more susceptible to in vitro photodynamic treatment, it is postulated that the observed effects were the result of selective destruction of adjuvant-activated lymphocytes in the circulation and/or joints.

Although numerous experimental immunomodulatory 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 Freund's 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 proteinuria, 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 formation, and cartilage and bone destruction, the characteristics of adjuvant-enhanced arthritis. PDT did not affect the survival rate, lymphoproliferation, or proteinuria of the treated animals. However, indomethacin increased proteinuria, and was less effective in preventing cartilage and bone destruction. Furthermore, 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.

The photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) has been studied regarding its ability to destroy enveloped viruses in blood and blood products when activated by light. Its maximum wavelength of absorption (690 nm) has proven useful in terms of activation of the photosensitizer in materials containing red blood cells. Experiments conducted on whole blood of patients infected with the human immunodeficiency virus (HIV) demonstrated that BPD-MA and light could effectively eliminate the virus when treated materials were placed in culture and tested for viral p24, but did not appear to damage blood cells or blood components. Since HIV is largely intracellular in infected individuals, these results were investigated further. We have shown, using flow cytometry, that in HIV-infected blood, BPD-MA and light appear to selectively destroy white cells that bear the interleukin 2 receptor and the DR antigen. These markers are prevalent on activated lymphocytes, and since HIV replicates only in CD4+ T cells which are activated, this finding provides an explanation for the selective killing of HIV.

Using both the vesicular stomatitis virus (VSV) and feline leukemia virus (FeLV) as models we have shown that the photosensitizer benzoporphyrin derivative ring A (BPD), when activated with red light (600-700 nm), is effective in eliminating both free virus and virally infected cells from spiked blood products and whole blood drawn from viremic cats experimentally infected with FeLV, under conditions which appear to share red blood cells. The effect of photodynamic therapy on infected lymphocytes, as visualized by scanning electron microscopy, initially appeared as a limited area of tiny holes in the membrane. These holes were subsequently seen to increase in size until the membrane appeared completely decomposed. The red cell membranes however, seem to be undamaged by such photodynamic treatment.

We have developed procedures in which the photosensitizer benzoporphyrin derivative monoacid ring A (BPD) can be covalently linked to carrier molecules of modified polyvinyl alcohol (PVA) to produce water-soluble PVA-BPD conjugates with a molecular mass in the range of 30 kd. These carriers can subsequently be covalently linked to monoclonal antibodies (MoAbs) using heterobifunctional linking agents. We describe here such a conjugate in which the MoAb (5E8) has specificity for a glycoprotein detected on human squamous cell carcinomas of the lung. We provide evidence that the conjugates produced were covalently linked and retained both their photosensitizing and antigen-binding activities. We show further that the MoAb-PVA-BPD conjugate, in the presence of 10% fetal calf serum, exhibited highly enhanced phototoxic killing of the target cell line (A549) over that exhibited by free BPD or a control MoAb-PVA-BPD conjugate. These results demonstrate, therefore, both the selectivity and specificity of this MoAb conjugate.

A model has been developed to demonstrate the use of photodynamic treatment (PDT) to eradicate viral contaminants from donated blood and blood products. Whole blood, spiked with vesicular stomatitis virus (VSV), was treated with the photosensitizer benzoporphyrin derivative-monoacid ring A (BPD-MA). After light activation of BPD-MA, a neutral red dye uptake assay was carried out to determine virus inactivation. Various drug incubation times and light intensities were tested as well as red cell lysis and distribution of VSV in blood. At BPD-MA concentrations between 2 and 4 micrograms per mL in whole blood, up to 10(7) VSV were inactivated. Several photosensitizers were also tested with this model to determine their relative efficacy in viral inactivation.