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Allan R Oseroff

Publications and source records attributed to Allan R Oseroff.

At least 19 recordsLinked to original sources
PubMed2007

Aminolevulinic acid photodynamic therapy for skin cancers.

Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and noninvasive therapy for superficial basal cell carcinoma (BCC) and Bowen's disease. It also may have a role in the treatment of nodular BCC and other cutaneous malignancies, including localized cutaneous lymphomas. ALA-PDT offers multiple advantages over traditional treatments, including little to no scarring, excellent cosmetic results, and the ability to treat multiple lesions simultaneously. It is not an effective therapy for aggressive subtypes of BCC or for invasive squamous cell carcinoma. Finally, ALA-PDT may be a useful way to prevent new skin cancers in certain high-risk patients.

Aminolevulinic Acid↗
PubMed2006

Clinical pharmacokinetics of the PDT photosensitizers porfimer sodium (Photofrin), 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-induced protoporphyrin IX.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. STUDY DESIGN/MATERIALS AND METHODS: Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. RESULTS: Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. CONCLUSION: We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted.

Administration, Topical↗
PubMed2006

A dose ranging study of photodynamic therapy with porfimer sodium (Photofrin) for treatment of basal cell carcinoma.

BACKGROUND AND OBJECTIVES: While basal cell carcinoma (BCC) is effectively treated by several methods, many patients with numerous or frequently occurring lesions seek alternatives that can treat multiple cancers, with improved cosmetic outcome. PDT for esophageal and lung carcinomas is approved at a porfimer sodium (Photofrin) dose of 2 mg/kg, but lower doses increase selectivity and decrease both cutaneous phototoxicity and cost. We evaluated low doses of porfimer sodium PDT for treatment of multiple BCC. MATERIALS AND METHODS: Seventy-seven patients with 2,041 BCC were injected with 0.75, 0.875, or 1.0 mg/kg porfimer sodium and treated 2 days later with 630-nm light. Clinical responses were determined at 6 months, then periodically to 5 years. RESULTS: Increasing porfimer sodium dose increased complete responses (CR), with initial CR rates of 72.7% (66-78%, 95% CI), 79.9% (73-86%, 95% CI), and 92.2% (91-93%, 95% CI), albeit with some lower selectivity at the highest dose. At 1 mg/kg, 5-year recurrence rates were 28% (21-35%, 95% CI) and 15% (11-18%, 95% CI) for sporadic and nevoid basal cell carcinoma syndrome (NBCCS) lesions, respectively. CONCLUSIONS: This is the largest dose-ranging study of porfimer sodium, and the largest number of lesions treated in a single study. We found that with 1 mg/kg porfimer sodium, PDT can be a selective and durable treatment for sporadic and NBCCS-associated BCC.

Adult↗
PubMed2005

Mild skin photosensitivity in cancer patients following injection of Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; HPPH) for photodynamic therapy.

PURPOSE: To measure skin photosensitivity in cancer patients infused with the new second-generation photodynamic sensitizer Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a). A major disadvantage of using the clinically approved photosensitizer Photofrin is potentially prolonged and sometimes severe cutaneous phototoxicity. PATIENTS AND METHODS: Forty-eight patients enrolled in Phases 1 and 2 clinical trials underwent two or more exposures to four graded doses (44.4, 66.6, 88.8 or 133.2 J/cm2) of artificial solar-spectrum light (SSL) before and after administration of Photochlor at a dose of 2.5, 3, 4, 5 or 6 mg/m2 . RESULTS: The most severe skin response, experienced by only six of the subjects, was limited to erythema without edema and could only be elicited by exposure to the highest light dose. Conversely, eight subjects had no discernible reaction to SSL at any light dose. For nearly all the patients, the peak skin response was obtained when the interval between sensitizer injection and exposure to SSL was 1 day and, generally, their sensitivity to SSL decreased with increasing sensitizer-light interval. For example, a 2-day sensitizer-SSL interval resulted in less severe reactions than those obtained with the 1-day interval in 79% of the subjects, while 90% of the subjects exposed to SSL 3 days after Photochlor infusion had responses that were less severe than those obtained with either the 1- or 2-day sensitizer-SSL interval. CONCLUSIONS: Photochlor, at clinically effective antitumor doses, causes only mild skin photosensitivity that declines rapidly over a few days.

Dihematoporphyrin Ether↗
PubMed2005

Tumor vascular response to photodynamic therapy and the antivascular agent 5,6-dimethylxanthenone-4-acetic acid: implications for combination therapy.

PURPOSE: Photodynamic therapy (PDT) is a clinically approved treatment for a variety of solid malignancies. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a potent vascular targeting agent that has been shown to be effective against a variety of experimental rodent tumors and xenografts and is currently undergoing clinical evaluation. We have previously reported that the activity of PDT against transplanted mouse tumors is selectively enhanced by DMXAA. In the present study, we investigated the in vivo tumor vascular responses to the two treatments given alone and in combination. EXPERIMENTAL DESIGN: Vascular responses to (i) four different PDT regimens using the photosensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) at two different fluences (128 and 48 J/cm(2)) and fluence rates (112 and 14 mW/cm(2)), (ii) 5-aminolevulinic acid (ALA)-sensitized PDT (135 J/cm(2) at 75 mW/cm(2)), (iii) DMXAA at a high (30 mg/kg) and low dose (25 mg/kg), and (iv) the combination of HPPH-PDT (48 J/cm(2) at 112 mW/cm(2)) and low-dose DMXAA were studied in BALB/c mice bearing Colon-26 tumors. RESULTS: PDT-induced changes in vascular permeability, determined using noninvasive magnetic resonance imaging with a macromolecular contrast agent, were regimen dependent and did not predict tumor curability. However, a pattern of increasing (4 hours after treatment) and then decreasing (24 hours after) contrast agent concentrations in tumors, seen after high-dose DMXAA or the combination of PDT and low-dose DMXAA, was associated with long-term cure rates of >70%. This pattern was attributed to an initial increase in vessel permeability followed by substantial endothelial cell damage (CD31 immunohistochemistry) and loss of blood flow (fluorescein exclusion assay). Low dose-rate PDT, regardless of the delivered dose, increased the level of magnetic resonance contrast agent in peritumoral tissue, whereas treatment with either DMXAA alone, or PDT and DMXAA in combination resulted in a more selective tumor vascular response. CONCLUSIONS: The observed temporal and spatial differences in the response of tumor vessels to PDT and DMXAA treatments could provide valuable assistance in the optimization of scheduling when combining these therapies. The combination of PDT and DMXAA provides therapeutically synergistic and selective antitumor activity. Clinical evaluation of this combination is warranted.

Aminolevulinic Acid↗
PubMed2005

Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy.

OBJECTIVE: To report the use of wide-area 5-aminolevulinic acid photodynamic therapy to treat numerous basal cell carcinomas (BCCs) and basaloid follicular hamartomas (BFHs). DESIGN: Report of cases. SETTING: Roswell Park Cancer Institute. Patients Three children with BCCs and BFHs involving 12% to 25% of their body surface areas. Interventions Twenty percent 5-aminolevulinic acid was applied to up to 22% of the body surface for 24 hours under occlusion. A dye laser and a lamp illuminated fields up to 7 cm and 16 cm in diameter, respectively; up to 36 fields were treated per session. MAIN OUTCOME MEASURES: Morbidity, patient response, and light dose-photodynamic therapy response relationship and durability. RESULTS: Morbidity was minimal, with selective phototoxicity and rapid healing. After 4 to 7 sessions, with individual areas receiving 1 to 3 treatments, the patients had 85% to 98% overall clearance and excellent cosmetic outcomes without scarring. For laser treatments, a sigmoidal light dose-response relationship predicted more than 85% initial response rates for light doses 150 J/cm(2) or more. Responses were durable up to 6 years. Conclusion 5-Aminolevulinic acid photodynamic therapy is safe, well tolerated, and effective for extensive areas of diffuse BCCs and BFHs and appears to be the treatment of choice in children.

Adolescent↗
PubMed2004

Photodynamic therapy causes cross-linking of signal transducer and activator of transcription proteins and attenuation of interleukin-6 cytokine responsiveness in epithelial cells.

Photodynamic therapy (PDT) is a local treatment of cancers. The principle of PDT is the production of reactive oxygen species, in particular singlet oxygen, by light activation of a photosensitizer introduced into the target cells. The direct photochemical and subsequent redox reactions can lead to cell death. This study sought to identify effects occurring during PDT and some of their consequences in surviving cells. Using epithelial cells in tissue culture and in tumors, several distinct PDT-mediated reactions were found, including global dephosphorylation of proteins, induced phosphorylation of a 71-kDa protein, initiation of cellular stress responses, structural modification and loss of epidermal growth factor receptor, and cross-linking of proteins. Specific covalent cross-linking of nonactivated signal transducer and activator of transcription (STAT)-3, and to a lesser extent of STAT1 and STAT4, correlated with PDT dose. Cross-linked STAT3 was primarily localized to the cytoplasm and failed to bind to DNA. The combination of STAT cross-linking and inactivation of receptor functions rendered PDT-treated cells refractory for at least 24 hours to interleukin-6 and oncostatin M, cytokines known to be elevated at site of tissue damage and inflammation. It is suggested that the loss of responsiveness to these inflammatory cytokines in the PDT-treated field assists tumor cells in evading the growth-suppressive activity of these mediators expected to be present at tissue sites after PDT.

Animals↗
PubMed2003

Water soluble, core-modified porphyrins. 3. Synthesis, photophysical properties, and in vitro studies of photosensitization, uptake, and localization with carboxylic acid-substituted derivatives.

Water soluble, core-modified porphyrins 1-5 bearing 1-4 carboxylic acid groups were prepared and evaluated in vitro as photosensitizers for photodynamic therapy. The 21,23-core-modified porphyrins 1-5 gave band I absorption maxima with lambda(max) of 695-701 nm. The number of carboxylic acid groups in the dithiaporphyrins 1-4 had little effect on either absorption maxima (lambda(max) of 696-701 nm for band I) or quantum yields of singlet oxygen generation [phi((1)O(2)) of 0.74-0.80]. Substituting two Se atoms for S gave a shorter band I absorption maximum (lambda(max) of 695 nm) and a smaller value for the quantum yield for generation of singlet oxygen [phi((1)O(2)) of 0.30]. The phototoxicity of 1-5 was evaluated against R3230AC cells. The phototoxicities of dithiaporphyrin 2, sulfonated thiaporphyrin 30, HPPH, and Photofrin were also evaluated against Colo-26 cells in culture using 4 J cm(-2) of 570-800 nm light. Compound 2 was significantly more phototoxic than sulfonated dithiaporphyrin 30, HPPH, or Photofrin. Cellular uptake was much greater for compounds 1, 2, and 5 relative to compounds 3 and 4. Confocal scanning laser microscopy and double labeling experiments with rhodamine 123 suggested that the mitochondria were an important target for dithiaporphyrins 1 and 2. Inhibition of mitochondrial cytochrome c oxidase activity in whole R3230AC cells was observed in the dark with compounds 1 and 30 and both in the dark and in the light with core-modified porphyrin 2.

Animals↗
PubMed2003

Ceramic-based nanoparticles entrapping water-insoluble photosensitizing anticancer drugs: a novel drug-carrier system for photodynamic therapy.

A novel nanoparticle-based drug carrier for photodynamic therapy is reported which can provide stable aqueous dispersion of hydrophobic photosensitizers, yet preserve the key step of photogeneration of singlet oxygen, necessary for photodynamic action. A multidisciplinary approach is utilized which involves (i) nanochemistry in micellar cavity to produce these carriers, (ii) spectroscopy to confirm singlet oxygen production, and (iii) in vitro studies using tumor cells to investigate drug-carrier uptake and destruction of cancer cells by photodynamic action. Ultrafine organically modified silica-based nanoparticles (diameter approximately 30 nm), entrapping water-insoluble photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide, have been synthesized in the nonpolar core of micelles by hydrolysis of triethoxyvinylsilane. The resulting drug-doped nanoparticles are spherical, highly monodispersed, and stable in aqueous system. The entrapped drug is more fluorescent in aqueous medium than the free drug, permitting use of fluorescence bioimaging studies. Irradiation of the photosensitizing drug entrapped in nanoparticles with light of suitable wavelength results in efficient generation of singlet oxygen, which is made possible by the inherent porosity of the nanoparticles. In vitro studies have demonstrated the active uptake of drug-doped nanoparticles into the cytosol of tumor cells. Significant damage to such impregnated tumor cells was observed upon irradiation with light of wavelength 650 nm. Thus, the potential of using ceramic-based nanoparticles as drug carriers for photodynamic therapy has been demonstrated.

Antineoplastic Agents↗
PubMed2003

Photodynamic therapy mediates immediate loss of cellular responsiveness to cytokines and growth factors.

Photodynamic therapy (PDT) is a minimally invasive procedure with increasing promise in treatment of malignant and nonmalignant diseases. Most PDT studies have focused on issues of how to enhance the photocytotoxic reaction leading to apoptosis and/or necrosis of targeted tumor cells. However, the reactions of surviving cancer cells, as well as normal host cells, are important elements that contribute to the outcome. Little is known about how these cells at sites of treatment react to inflammatory cytokines and growth factors that are elicited by PDT. To answer this question, we treated several epithelial cancer cell lines and normal epithelial and stromal cells with membrane- and mitochondria-damaging PDT. At different time points after PDT, cells were stimulated with interleukin 6 class cytokines or epidermal growth factor (EGF). Cellular responsiveness was determined by the activation of signaling proteins. We found that within the time period of PDT reaction, both normal and malignant cells lost their responsiveness to the cytokines and growth factor in a PDT dose-dependent manner. Photosensitizers targeted to the plasma membrane or mitochondria had similar effects. The recovery of responsiveness required 48-72 h and was accompanied by resumption of cell proliferation. Although the loss of EGF response could be explained by the immediate degradation of EGF receptor, the loss of cytokine response was only, in part, correlated with a reduction in cytokine receptor proteins. A PDT-mediated reduction of Janus protein tyrosine kinase-1 was also observed in HeLa cells. Our results demonstrate that PDT alters the regulatory capability of normal and tumor cells by lowering the responsiveness to factors that are known to assist in tissue repair and immune response. This effect of PDT has to be considered when predicting outcome of PDT.

Aminolevulinic Acid↗
PubMed2003

Population pharmacokinetics of the photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a in cancer patients.

Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal carcinoma, high-grade dysplasia associated with Barrett's esophagus, carcinoma of the lung, or multiple basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous phototoxicity responses were determined, as a function of time after HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating HPPH metabolites, and in vitro incubation of HPPH with human liver microsomal preparations resulted in no metabolite or glucuronic acid-HPPH conjugate production. A minimal skin response to the solar simulator was observed, mostly in patients treated with the highest dose of HPPH, 6 mg/m(2). All of the HPPH pharmacokinetic parameters were consistent with a highly lipophilic agent that is concentrated in plasma and is nearly 100% bound to plasma proteins; this was verified by plasma protein binding studies. Whereas low concentrations of HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general, HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer photodynamic therapy agent.

Adult↗
PubMed2003

Photodynamic therapy for nonmelanoma skin cancers. Current review and update.

Photodynamic therapy (PDT) is a therapeutic modality involving the use of a photosensitizing agent activated by light to destroy tumor cells. Over the past 25 years, PDT has been shown useful in the treatment of actinic keratoses and certain nonmelanoma skin cancers, such as Bowen's disease and basal cell carcinoma. We review the current data available for PDT with systemic photofrin and topical 5-aminolevulinic acid (ALA). PDT offers many advantages including its non-invasiveness and its ability to treat multiple lesions simultaneously and is, therefore, an interesting alternative for treating certain skin malignancies.

Aminolevulinic Acid↗
PubMed2003

Successful treatment of extramammary Paget's disease with imiquimod.

Extramammary Paget's Disease (EMPD) is an uncommon neoplasm found in the genital, anorectal, or axillary area. Surgical excision is considered the standard treatment, although possible loss of tissue function and disease recurrence are seen. Other treatment modalities such as radiotherapy, topical chemotherapy, and photodynamic therapy are associated with varying degrees of effectiveness, but the search for an effective, safe treatment with minimal side effects proves to be challenging. We report a case where complete clinical and histological resolution of non-invasive EMPD of the penis was achieved with minimal adverse effects after six weeks of imiquimod (Aldara) application. As an immune system modifier that stimulates cytokine and interferon production, imiquimod may be a useful alternative or adjuvant in the treatment of EMPD.

Aged↗
PubMed2002

In vitro photodynamic properties of chalcogenopyrylium analogues of the thiopyrylium antitumor agent AA1.

Several series of chalcogenopyrylium dyes were prepared with one or two 4-anilino substituents at the 2- and 6-positions and with phenyl, 4-N,N-dimethylanilino, or 4-(N-morphilino)phenyl substituents at 2- and/or 4-positions. The dye series are all related in structure to AA1, a thiopyrylium dye that targets mitochondria. The chalcogenopyrylium nuclei included sulfur, selenium, and tellurium at the 1-position. Key intermediates in the dye synthesis were the corresponding Delta-4H-chalcogenopyran-4-ones. All of the dyes of this study were evaluated for dark and phototoxicity toward Colo-26 cells in vitro. There was no correlation of dark toxicity with either the reduction potential of the chalcogenopyrylium dye or the n-octanol/water partition coefficient, log P. Several of the dyes of this study (thiopyrylium dyes 1-S and 13-S, selenopyrylium dyes 1-Se, 2-Se, 3-Se, 4-Se, 13-Se, 14-Se, and 27-Se, and telluropyrylium dye 13-Te) showed added phototoxicity upon irradiation. Dyes with the highest therapeutic ratio as measured by dark toxicity/phototoxicity (15 J cm(-2) of 360-800-nm light) had values of log P of 1.0-1.2. Studies of cytochrome c oxidase activity in whole R3230AC cells suggested that dyes 1-S and 3-Se, with values of log P of 2.2 and 1.7, respectively, were localized in the mitochondria. Cytocrome c oxidase activity in whole cells was inhibited by 1-S and 3-Se in the dark. Chalcogenopyrylium dyes 2-Se, 4-Se, 13-Te, and 14-Se inhibited whole-cell cytochrome c oxidase activity only following irradiation, which suggests that these dyes relocalized to mitochondria following irradiation.

Aniline Compounds↗
PubMed2002

Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy. II. Effects of core heteroatoms and meso-substituents on biological activity.

Water-soluble, core-modified porphyrins were prepared and evaluated as sensitizers for photodynamic therapy (PDT). The addition of an aromatic aldehyde to 2,5-dilithiothiophene or -selenophene gave diol 3 as a nearly equimolar mixture of meso and d,l diastereomers, which gave a single diastereomer following careful recrystallization. The condensation of pyrrole with a diol 3 using catalytic BF(3)-etherate gave bispyrrolochalcogenophenes (4). Condensation of a diol 3 with 4 in the presence BF(3)-etherate gave 21,23-dichalcogenaporphyrins (5). 21-Thiaporphyrins (6) were prepared by condensation of a diol 3 with excess pyrrole and benzaldehyde in the presence of tetrachlorobenzoquinone and catalytic BF(3)-etherate. Sulfonation of 5 and 6 with concentrated sulfuric acid at 100 degrees C gave sulfonated derivatives 7-15. Bis-4-methoxy-21,23-dithiaporphyrins 5h and 5l were demethylated with BBr(3), and the resulting phenols were alkylated with ethyl bromoacetate. Saponification gave 21,23-dithiaporphyrin dicarboxylate salts 16 and 17. The 21,23-core-modified porphyrins gave band I absorption maxima (lambda(max) of 689-717 nm) at longer wavelengths than band I for the corresponding 21-core-modified porphyrins, but both classes had band I maxima at longer wavelengths than either TPPS(4) or Photofrin (lambda(max) of 630 nm for both). The core heteroatoms had little effect on either absorption maxima or quantum yields of singlet oxygen generation in 7-17. The meso substituents had a greater impact on absorption maxima. Compounds 7-17 were evaluated for phototoxicity against Colo-26 cells in culture using 4 J cm(-2) of 570-800 nm light. Compounds 8-12, 14, 16, and 17 gave a 50% cell kill in vitro at a lower concentration than Photofrin [5.7 mg (9 micromol)/kg]. Compounds 14, 16, and 17 gave a 50% cell kill with 4 J cm(-2) of light and submicromolar concentrations of sensitizer. Sensitizers 8 and 11 showed no toxicity or side effects in BALB/c mice observed for 90 days following a single intravenous injection of 10 mg/kg of sensitizer. Distribution studies show that sensitizer 8 accumulates in the tumors of BALB/c mice. PDT with 8 at 0.125 mg (0.13 micromol)/kg or 11 at 2.5 mg (2.5 micromol)/kg and 135 J cm(-2) of 694 nm light was comparable to PDT with Photofrin at 2.5 mg (4 micromol)/kg and 135 J cm(-2) of 630 nm light against Colo-26 tumors in BALB/c mice.

Animals↗
PubMed2002

Electrically enhanced percutaneous delivery of delta-aminolevulinic acid using electric pulses and a DC potential.

Selectivity of photodynamic therapy can be improved with localized photosensitizer delivery, but topical administration is restricted by poor diffusion across the stratum corneum. We used electric pulses to increase transdermal transport of delta-aminolevulinic acid (ALA), a precursor to the photosensitizer protoporphyrin IX (PpIX). ALA-filled electrodes were attached to the surface of excised porcine skin or the dorsal surface of mice. Pulses were administered and, in some in vivo cases, a continuous DC potential (6 V) was concomitantly applied. For in vitro 14C ALA penetration, 10 microm layers parallel to the stratum corneum were assayed by liquid scintillation analysis, and 10 microm cross sections were examined autoradiographically. As the electrical dose (voltage x frequency x pulse width x treatment duration) increased, there was an increase in penetration depth. In vivo delivery was assayed by measuring the fluorescence of PpIX in skin samples. A greater than two-fold enhancement of PpIX production with electroporative delivery was seen versus that obtained with passive delivery. Superimposition of a DC potential resulted in a nearly three-fold enhancement of PpIX production versus passive delivery. Levels were higher than the sum of PpIX detected after pulse-alone and DC-alone delivery. Electroporation and electrophoresis are likely factors in electrically enhanced delivery.

Administration, Cutaneous↗
PubMed2002

A beam-splitting device for use with fiber-coupled laser light sources for photodynamic therapy.

A device that divides light into eight, four or two beams of equivalent power with only minor total power loss was designed, built and tested. The apparatus accepts light from a 200 microm diameter, 0.16 numerical aperture, silica-silica multimode optical fiber connected to one of several laser light sources for photodynamic therapy (PDT) of cancer. The incorporation of a variable iris diaphragm into the optical couplers allows the power of the beams to be independently set. Each of the beams can be coupled to a 400 or 600 microm diameter optical fiber to deliver the therapeutic light to the patient. This device is used in our institute for PDT of patients with either numerous small malignant tumors or single tumors with large surface area.

Equipment Design↗