Photodynamic therapy of the ciliary body with tin ethyl etiopurpurin and tin octaethyl benzochlorin in pigmented rabbits.

BACKGROUND AND OBJECTIVES: The authors used a pigmented rabbit model to investigate two photosensitizers, tin ethyl etiopurpurin (SnET2) and tin octaethyl benzochlorin (BNZ 203), to determine their potential for creating ciliary body injuries during photodynamic therapy (PDT). MATERIALS AND METHODS: The biodistribution of SnET2 (n = 10) and BNZ 203 (n = 9) was studied by fluorescence microscopy using a low light detection system, based on charged-coupled device photography, with digital image processing at 1 and 24 hours after injection. PDT with SnET2 (n = 8; 664 +/- 7-nm light; 75 mW/cm2; 50 or 100 J/cm2; 1-mm spot size) and BNZ 203 (n = 6; 689 nm; 75 mW/cm2; 50 or 100 J/cm2; 1-mm spot size) was performed at 24 hours post-injection. The control subjects for SnET2 (n = 5) and BNZ 203 (n = 3) were given a maximal light dose (100 J/cm2). RESULTS: Both photosensitizers demonstrated an intravascular distribution at 1 hour that shifted to a ciliary body distribution at 24 hours (SnET2 much greater than BNZ 203). In addition, the SnET2 demonstrated suborgan localization to the nonpigmented ciliary body epithelium. Both photosensitizing agents were able to produce selective injury to the rabbit ciliary body (SnET2 much greater than BNZ 203), with evidence of a small component of thermal damage (SnET2 greater than BNZ 203). CONCLUSIONS: PDT with SnET2 or BNZ 203 can produce selective injury to the pigmented rabbit ciliary body. The nonpigmented ciliary body epithelium exhibits selective retention of SnET2. This finding warrants further investigation.

Photodynamic therapy for antifibrosis in a rabbit model of filtration surgery.

BACKGROUND AND OBJECTIVE: The purpose of this pilot study was to investigate the use of photodynamic therapy (PDT) using tin ethyl etiopurpurin (SnET2) as an adjunctive antifibrotic therapy for filtering surgery in a rabbit model. MATERIALS AND METHODS: The pharmacokinetics of SnET2 were established by intravenous (1 mg/kg) and subconjunctival (25, 50, or 75 micrograms) injections and compared with controls. Intravenous and subconjunctival SnET2 injections were given prior to posterior lip sclerectomies followed by postoperative laser irradiation (664 +/- 7 nm; 100 mW/cm2; 30 J/cm2). Antifibrotic efficacy was established by clinical response and histologic examination. RESULTS: After subconjunctival injections, large areas of avascular conjunctiva were produced and filtering bleb survival was prolonged. No effect was found for intravenously administered photosensitizer followed by light irradiation. CONCLUSIONS: PDT may be an alternative antifibrotic therapy for filtration surgery that does not use chemotherapeutic agents or ionizing radiation. Multiple parameters (light, drug dose, irradiation area) may be manipulated to improve predictability of the antifibrotic effect.

Photodynamic therapy for choriocapillaris using tin ethyl etiopurpurin (SnET2).

BACKGROUND AND OBJECTIVE: To investigate the use of photodynamic therapy (PDT) using tin ethyl etiopurpurin (SnET2) for occluding the choriocapillaris in the eyes of pigmented rabbits. MATERIALS AND METHODS: Following intravenous injection of SnET2 (0.5 and 1 mg/kg) or lipid emulsion alone, the fundus of pigmented rabbits (n = 21) was irradiated starting 15 to 45 minutes after photosensitizer injection using 664-nm light at a fluence of 300 mW/cm2 and light doses of 5 to 20 J/cm2. Funduscopy, fluorescein angiography, and light and electron microscopy were performed at 1, 14, and 28 days after PDT. RESULTS: Following SnET2 and PDT, closure of the choriocapillaris was achieved with light doses as low as 5 J/cm2 (17 seconds) and a drug dose of 0.5 mg/kg of SnET2. Vascular occlusion was documented by fluorescein angiography and histology. Photodynamic damage was noted in the choriocapillary endothelial cells. Retinal pigment epithelial damage and outer retinal damage were also observed. No funduscopic, angiographic, or histologic findings were present in the eyes of pigmented control rabbits. CONCLUSIONS: PDT with SnET2 was effective in this animal model, using low levels of activating light for the occlusion of the choriocapillaris. This has clinical implications for the treatment of choroidal neovascularization and could be a more selective therapy than thermal laser photocoagulation.

Direct comparison of in-vitro and in-vivo Photofrin-II mediated photosensitization using a pulsed KTP pumped dye laser and a continuous wave argon ion pumped dye laser.

A pulsed KTP pumped dye laser (25 kHz repetition rate and 470 nsec pulse width) has been compared to a continuous wave argon ion pumped dye laser as the source of 630 nm light during in-vitro and in-vivo Photofrin-II mediated photosensitization studies. Individual experiments documented the effectiveness of each laser system on a) photosensitizer induced cytotoxicity and induction of stress protein synthesis using Chinese hamster fibroblasts; b) photobleaching of Photofrin-II in aqueous solution; c) Photofrin II mediated photosensitization of normal mouse skin; d) Photofrin II mediated photodynamic therapy of a mouse mammary carcinoma; and e) tumor temperature levels generated during laser exposure. Comparable results were obtained for both laser systems in all experiments.

Treatment of the transplantable FANFT induced bladder tumors with the purpurin SnET2 and red light emitted by a pulsed frequency doubled Nd:YAG laser.

Photodynamic therapy of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced tumors engrafted onto Fischer CDF (F-344)/CrlBR rats that had been sensitized with the photosensitizer tin (ll) etiopurpurin dichloride was performed in combination with visible light (approximately equal to 660 nm) emitted by either a continuous wave argon-dye laser or a pulsed, frequency-doubled Nd:Yag laser. Tumor control was assessed either by tumor dry-weight 12 days after treatment or by the palpatory absence of tumor at 60 days after treatment. Both laser sources were effective in creating the desired photodynamic effect. This study demonstrates the potential for the use of a solid-state pulsed laser for photodynamic therapy when used in combination with the tumor sensitizer tin (ll) etiopurpurin dichloride.

Ineffective photodynamic therapy (PDT) in a poorly vascularized xenograft model.

Haematoporphyrin derivative (HPD) photodynamic therapy (PDT) may have clinical application in the management of patients with retinoblastoma. Heterotransplantation of retinoblastoma cells into the anterior chamber of the nude mouse eye and the subsequent growth of small tumour masses has provided a model for evaluation of various therapeutic modalities. Ninety-four evaluable xenograft tumours in 54 nude mice were randomized to receive one of the following treatments: cyclophosphamide (CPM) alone, HPD-PDT alone, CPM followed by HPD-PDT, HPD-PDT followed by CPM, or saline control. Responses were demonstrated after CPM treatment in all three relevant groups. However, HPD-PDT was found to be ineffective either alone or as a contributor in the double modality treatment groups. The small tumour masses treated can be demonstrated histologically to be avascular. It is proposed that although the same retinoblastoma cells in different circumstances are responsive to HPD-PDT, no clinical response is demonstrable utilizing this model, due to the absence of tumor vascularity.

Dose measurements in photodynamic therapy of cancer.

A theory and method for prediction and measurement of the effective absorbed dose in photodynamic therapy of cancer is presented. The method depends on measuring the concentration of the photosensitizer (such as dihematorporphyrin ether), the flux density of the light, and the relative photodynamic effectiveness. Previous, less exact methods relied on specifying the drug dosage and delay after injection and or the irradiance at the surface or power from an interstitial fiber. The new formulation should permit closer control of the effective absorbed dose and better clinical results with photodynamic therapy.

Treatment of vascular lesions with a CW yellow dye laser--initial trials.

Thirteen patients with vascular lesions were treated with a CW yellow dye laser. Most of these patients were either poor candidates for argon laser treatment (ALT) or had undergone unsuccessful argon laser treatment. Twelve patients responded with a "desirable" treatment result. One patient did not respond adequately to have his result classified as "desirable," though all patients experienced fading of their lesions. None of the patients experienced scarring, epidermal thinning, or hypopigmentation. This lack of complications, associated with an incidence of desirable results in twelve of the thirteen patients, is noteworthy because all but one of the patients with portwine stain had difficult-to-treat lesions whose treatment is not attempted by many ALT centers. We believe that yellow light has certain advantages over blue-green argon laser light for the treatment of vascular lesions and think that further study is warranted.

Photodynamic therapy in otolaryngology--head and neck surgery.

Photodynamic therapy utilizes a photosensitizing drug, hematoporphyrin derivative, and laser light to diagnose and treat cancer. We used treatment and diagnostic instrumentation and techniques developed during the last seven years to treat 31 patients over the last two years. Diffuse, superficial tumors of the head and neck responded well to photodynamic therapy as did localized bulk lesions of this area. Photodynamic therapy achieved initial control in patients with early lung cancer and opened up bronchi in those with obstructive lung cancer. Widespread, bulky tumors responded inconsistently. Neck metastases responded poorly when treated for tumor control. The beneficial effects of phototherapy and its general lack of severe complications may, however, warrant its use for limited palliative goals in the patient with far-advanced head and neck cancer, especially when irradiation and surgery have failed.

Photoradiation therapy of endobronchial lung cancer. Large obstructing tumors, nonobstructing tumors, and early-stage bronchial cancer lesions.

Photoradiation (photodynamic) therapy of endobronchial primary and metastatic lung cancers uniformly results in a complete response--that is, the opening up of totally or partially obstructed bronchi to their walls. The method, employing hematoporphyrin derivative and red laser light from an argon-pumped dye laser, is safe, efficient, and effective. The safety and lack on any complications rest upon the use of light-diffusing cylinder tips, and upon clean-up bronchoscopy to remove tumor debris promptly. The trachea and main and lobar bronchi, as well as segmental and subsegmental bronchi, can be entirely freed of tumor and completely opened up.

Laser instrumentation and safety.

A review of the operation principles of lasers and the various types used in chest medicine is given. This includes CO2, Nd:YAG, argon, krypton, and dye lasers. Safety considerations in the use of lasers are also outlined.

Fluorometer for endoscopic diagnosis of tumors.

A filter fluorometer suitable for endoscopic applications has been developed for detection and characterization of superficial tumors by the fluorescence of a previously injected, tumor-specific agent, hematoporphyrin derivative. Fluorescence is excited by violet light conducted through a fiberoptic lightguide in the endoscope, and the fluorescence emission together with reflected violet are collected by another fiberoptic lightguide. The red fluorescence and violet are separated by a dichroic mirror and filter and detected in photomultiplier tubes. The ratio of the fluorescence signal to the reflected violet signal is proportional to the ratio of the fluorescence yield to the violet reflectivity but is insensitive to variations in distance, angle, and violet power. The instrument may be useful for localizing small tumors, and for quantitative measurements of the amount of hematoporphyrin derivative in the tumor, a requirement for accurate dosimetry in photoradiation therapy.

Hematoporphyrin derivative photoradiation induced damage to normal and tumor tissue of the pigmented rabbit eye.

Cytotoxicity induced by hematoporphyrin derivative (HpD) photoradiation in both normal and experimental tumor tissue of pigmented rabbit eyes has been examined. In addition, documentation of HpD induced fluorescence in ocular structures has also been obtained. Acute normal ocular tissue toxicity studies demonstrated that HpD (1-10 mg HpD/kg) followed 48 hours later by a transpupil irradiation of red light (635 nm, 36-90 J/cm2) resulted in demarcated areas of retinal damage. Long term (chronic) toxicity studies have shown that the initial damage to the retina was permanent but that no damage to the cornea, lens or vitreous could be observed during a 16 month follow-up. Visual and histological documentation have been obtained, following HpD photoradiation therapy (PRT), in rabbit eyes having heterotransplanted single nodule amelanotic melanomas. A toxic effect characterized by tumor blanching, edema and hemorrhage was observed within 24 hours of treatment. Histological examination obtained 24 hours following HpD PRT illustrated massive tumor tissue necrosis and vascular disruption. HpD PRT at clinically relevant doses was also shown to be effective in selectively curing the highly malignant amelanotic iris melanoma. It is concluded that HpD PRT may prove to be an effective modality for treating certain ocular tumors.

Photoradiation therapy of endobronchial lung cancers employing the photodynamic action of hematoporphyrin derivative.

Thirty-five patients with tumors within the tracheobronchial tree were treated with photoradiation therapy (PRT) employing the photodynamic action of hematoporphyrin derivative (HPD). An effective protocol has been developed consisting of 3.0 mg/kg HPD given intravenously 72 hours prior to the bronchoscopic illumination of the endobronchial tumor sites with red light (630 nm) from an argon pumped dye laser. Light applicators were developed that provided surface (area) and insertion (volume) illumination of tumor masses. Average light dosages of 100 J/cm2 and 200 J/cm were used for surface and insertion illumination, respectively. Delivery rates were 200 mW/cm2 and 400 mW/cm. There was no immediate visible effect such as coagulation or charring noted. All malignant endobronchial tumors responded. Tumors included primary and metastatic lesions of various histologic types. Response was complete for tumor within the bronchus after one treatment in 80% of instances. The remaining cases required two treatments to obtain a complete response due to the extensive length of bronchus involved or because multiple sites were present. A complete response, that is, the full opening up of the lumen to the bronchial wall, was accomplished in all but one instance. Atelectatic lungs or lobes were re-expanded and reaerated. Dyspnea and cough became significantly less. The follow-up achieved to date indicates improvement in symptoms, activity level, and the return to work in a significant number of cases.

Photophysics of and instrumentation for porphyrin detection and activation.

In conclusion, when considering the photophysics of porphyrin detection and activation, it must be remembered that both processes are photon absorption initiated. As such, the absorption spectrum of the porphyrin, the wavelength or spectrum of the activating light, the rate of its delivery, its mode of delivery and the optical characteristics of the tissue must all be considered. When considering instrumentation, the spectral output or spectral sensitivity of the instrumentation must be considered. It is hoped that this review will provide basic knowledge to the new and established investigators in this area and thereby help to accelerate the field.