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W R Potter

Publications and source records attributed to W R Potter.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1'-alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides with variable lipophilicity.

Starting from methylpheophorbide-a, a homologous series of purpurinimides containing alkyl substituents at two different positions [as 3-(1(1)-O-alkyl) and 13(2)-N-alkyl] were synthesized. These compounds with variable lipophilicity (log P 5.32-16.44) exhibit long wavelength absorption near lambda(max)700 nm (epsilon: 45 000 in dichloromethane) with singlet oxygen ((1)O2) production in the range of 57-60%. The shifts in in vivo absorptions and tumor/skin uptake of these compounds were determined in C3H mice bearing RIF tumors by in vivo reflectance spectroscopy. The results obtained from a set of photosensitizers with similar lipophilicity (log P 10.68-10.88) indicate that besides the overall lipophilicity, the presence and position of the alkyl groups (O-alkyl vs N-alkyl) in a molecule play an important role in tumor uptake, tumor selectivity, and in vivo PDT efficacy. At present, all purpurinimide analogues are being evaluated at various doses, and experiments are underway to establish a quantitative structure-activity relationship on a limited set of compounds. The 1D and 2D NMR and mass spectrometry analyses confirmed the structures of the desired purpurinimides and the byproducts formed during various reaction conditions. The mechanisms of the formation of the unexpected 12-formyl- and 12-(hydroxymethyl)purpurinimides under certain reaction conditions are also discussed.

Animals↗
PubMed2001

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy.

BACKGROUND AND OBJECTIVE: In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. RESULTS: In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. CONCLUSION: Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

Animals↗
PubMed2000

Photosensitizers related to purpurin-18-N-alkylimides: a comparative in vivo tumoricidal ability of ester versus amide functionalities.

For a comparative study, 3-(alkyloxyethyl)-3-devinylpurpurin-18-N-hexylimides with ester and amide functionalities were investigated for tumor selectivity and in vivo photosensitizing efficacy. Compared to amide analogues, the related photosensitizers with ester functionalities were found to be more effective. Among these compounds the 3-devinyl-(3-hexyloxyethyl)-purpurin-18-N-hexylimide as methyl ester 12 showed excellent tumor uptake (tumor versus muscle ratio: 8:1), and produced 100% tumor cure on day 30 at a dose of 1.0 micromol/kg. The mice were treated with light (135 J/cm2, 705 nm) at 24 h post injection of the drug.

Amides↗
PubMed2000

Comparison of photodynamic targets in a carcinoma cell line and its mitochondrial DNA-deficient derivative.

The relative contribution, to cell death, of photodynamic damage to respiratory proteins (known targets of photodynamic therapy with many photosensitizers) and other cellular sites was examined. The models were a human ovarian carcinoma cell line 2008, and its mitochondrial DNA-deficient derivative ET3, which lacks several key respiratory protein subunits. Phototoxicity was compared in the two cell lines with photosensitizers that localized to different cellular compartments. Photosensitizers included Victoria Blue BO (VBBO; mitochondria); Photofrin with a short incubation, (plasma membrane) or a long incubation (intracellular membranes including mitochondria); and Nile Blue A (NBA; lysosomes). Photosensitizer content and localization did not differ between the 2008 and ET3 cells. For sensitizers without a primary mitochondrial localization (NBA and Photofrin with a short incubation), there was no significant difference between 2008 and ET3 toxicity. Consistent with a mitochondrial localization of VBBO and independence from respiratory-chain damage, ET3 cells were less susceptible than 2008 to both dark- and light-activated VBBO-mediated damage. Statistical analysis of the data demonstrated minimal photobleaching of VBBO and a significant difference between the phototoxicity curves of ET3 and 2008. For Photofrin with a long incubation, dark- and phototoxicity effects were similar for both cell lines. Inhibition of respiratory enzymes is thus only a minor component of Photofrin-mediated (long incubation) phototoxicity in these cell lines and is overwhelmed by more significant damage elsewhere, whereas it is a major but not the exclusive element of death mediated by VBBO.

DNA, Mitochondrial↗
PubMed1999

Design and construction of a light-delivery system for photodynamic therapy.

We have developed a device to divide the output from a dye laser into as many as eight beams of equal power with negligible total power loss. In this system, 630-nm s-plane polarized laser light was split by a series of highly polarization-sensitive plate beamsplitters. Each of the beams was coupled to a 200, 400, or 600 microm diameter optical fiber. Brewster-window-type attenuators allowed the power of each beam to be individually set. It was possible to reconfigure the device to produce four, two, or one output(s). We discuss the design requirements of the beamsplitter device and describe its construction from mostly commercially available components. An apparatus for positioning and stabilizing each optical fiber relative to the skin surface of a patient is also described. The illumination from the fiberoptic supported by such an apparatus strikes a defined surface area and is independent of patient movement. Both the beamsplitter device and the optical fiber positioner are used routinely in photodynamic therapy (PDT) of malignant tumors in the clinic and in the laboratory.

Animals↗
PubMed1999

Parabolic quantitative structure-activity relationships and photodynamic therapy: application of a three-compartment model with clearance to the in vivo quantitative structure-activity relationships of a congeneric series of pyropheophorbide derivatives used as photosensitizers for photodynamic therapy.

An open three-compartment pharmacokinetic model was applied to the in vivo quantitative structure-activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0. The measured octanol-water partition coefficients, P(i) (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three-compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic-based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose-response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

Animals↗
PubMed1998

Photodynamic therapy (PDT) in the treatment of patients with resistant superficial bladder cancer: a long-term experience.

INTRODUCTION AND OBJECTIVE: Photodynamic therapy (PDT) combines a photosensitizer such as Photofrin with red laser light (630 nm) to destroy cancer cells. Investigators have reported effectiveness of PDT in the management of patients with recurrent superficial bladder cancer. We retrospectively reviewed our experience in 58 patients to assess the long-term role of PDT in the management of resistant superficial transitional cell carcinoma (TCC) including Ta, T1, and refractory carcinoma in situ (CIS) of the urinary bladder. MATERIALS AND METHODS: All 58 patients had failed at least one course of standard intravesical therapy or had contraindication for intravesical chemo- or immunotherapy. Patients with malignancy present (Ta-T1/Grade I-III, CIS) were accepted for ablative PDT. Patients undergoing prophylactic PDT after complete resection were confirmed to be tumor-free by cystoscopy and bladder was cytology before PDT. Post-PDT evaluations included weekly telephone contact to assess acute adverse reactions and assessment of efficacy and bladder toxicity at three months and quarterly thereafter. RESULTS: These 58 patients underwent a single PDT treatment with 2.0 or 1.5 mg/kg of Photofrin and 10-60 J/cm2 light (630 nm). At three months, complete response rates were 84% and 75% for residual resistant papillary TCC and refractory CIS respectively; and 90% of patients treated prophylactically had not had recurrences. At a median followup of 50 months (range 9-110), 59% (34/58) of the responders are alive, with 31/34 still disease-free. CONCLUSION: PDT using 1.5 mg/kg of Photofrin and 15 J/cm2 of light (630 nm) should be considered a safe and effective treatment for refractory CIS or recurrent papillary TCC.

Adult↗
PubMed1997

Correlation between site II-specific human serum albumin (HSA) binding affinity and murine in vivo photosensitizing efficacy of some Photofrin components.

Human serum albumin (HSA) is one of the key components in human blood that may influence drug distribution. As such, it is important to know the affinity of any drug for albumin. Previously, Photofrin, a mixture of monomeric, dimeric and oligomeric porphyrins, has been subjected to HSA binding studies. However, due to its complex nature, binding studies on Photofrin or other hematoporphyrin derivatives with HSA are inconclusive. In this report, the binding properties of some components (dimers and trimers) of Photofrin and the relationship between murine photosensitizing efficacy and those binding properties were investigated. The interaction of these porphyrins with HSA was investigated by direct ultrafiltration and fluorescent titration techniques with fluorescent probes such as dansyl-L-proline (DP), which is known to interact selectively with site II on HSA. Porphyrins also were tested for antitumor activity in a mouse model following intravenous administration and exposure to laser light. Together, the results suggest that the photosensitizers that were preferentially bound to site II of HSA were most effective at controlling murine tumor regrowth.

Animals↗
PubMed1996

Alkyl ether analogs of chlorophyll-a derivatives: Part 1. Synthesis, photophysical properties and photodynamic efficacy.

The synthesis, preliminary in vivo biological activity, singlet oxygen and fluorescence yields of a series of alkyl ether derivatives of chlorophyll-alpha analogs are described. For short-chain carbon ethers (1-7 carbon units), it was observed that the biological activity increased by increasing the length of the carbon chain, being maximum in compounds with n-hexyl and n-heptyl chains. Related sensitizers prepared by reacting 2-(1-bromoethyl)-2-devinylpyropheophorbide-alpha with (sec)alcohols were found to be less effective. Under similar treatment conditions, photosensitizers containing cis- and trans- 3-hexenyl side chains were ineffective. Thus, both stereochemical and steric factors caused differences in sensitizing activity. In general, pyropheophorbide-alpha analogs were found to be more active than related chlorin e6 derivatives, in which the isocyclic ring (ring "E") was cleaved. Related photosensitizers in the 9-deoxy- series were found to be as effective as the corresponding pyropheophorbide-alpha analogs. The photosensitizers prepared from pyropheophorbide-alpha methyl ester and chlorin e6 trimethyl ester have long wavelength absorption at 660 nm (epsilon 45 000 to 50 000). Reduction of the carbonyl group in the pyropheophorbide-alpha to methylene (ring E) resulted in a blue shift to 648 nm (epsilon 38 000).

Animals↗
PubMed1995

Photodynamic activities and skin photosensitivity of the bis(dimethylthexylsiloxy)silicon 2,3-naphthalocyanine in mice.

The photodynamic therapy (PDT) activity of the bis(dimethylthexylsiloxy)silicon 2,3-naphthalocyanine (SiNc 8) was evaluated against the EMT-6 tumor implanted intradermally in BALB/c mice. The SiNc 8 was formulated in aqueous emulsions based on Cremophor EL or Solutol HS 15. The formulation was shown to affect plasma clearance and overall pharmacokinetics. Compared to Cremophor, Solutol promoted rapid plasma clearance and high liver retention of the dye, combined with a slight increase of dye tumor concentrations. The PDT action spectrum for tumor response of SiNc 8 in Cremophor (190 mW cm-2, 200 J cm-2, 24 h postinjection [p.i.] of 1 mumol kg-1) showed a maximum at 780 nm, which corresponds to the absorption maximum of the monomeric dye as well as the in vivo maximum change in the "diffuse optical density" produced by the dye. The extent of tumor necrosis increased with augmented dye and light doses. Regardless of the formulation, at 1 h p.i. of 0.1 mumol kg-1 SiNc 8, PDT efficiency (190 mW cm-2, 400 J cm-2) was high but accompanied by severe damage to normal tissues, at 24 h p.i. PDT resulted in complete tumor regression in 80% of the animals without adverse effects to adjacent tissues, while at 72 h p.i. PDT induced no tumor response with Cremophor and only a partial response with Solutol. At the latter time point, plasma dye clearance was nearly complete while tumor tissue levels remained high, suggesting that tumor response correlates with plasma rather than tumor dye levels. Skin sensitivity of SKhI mice to solar-simulated radiation was lower with SiNc 8 as compared to Photofrin. Our data suggest the potential of SiNc 8 as a far-red absorbing photosensitizer in clinical PDT.

Animals↗
PubMed1995

Evaluation of new benzoporphyrin derivatives with enhanced PDT efficacy.

A first report on the biological evaluation of a series of isomerically pure benzoporphyrin derivatives (cis- and trans-isomers) as methyl esters is described. In preliminary in vivo studies, the n-hexyl ether analogues of both cis- and trans-isomers of benzoporphyrin derivatives were found to be more active than the industrially prepared benzoporphyrin derivative, a mixture of monocarboxylic acids (BPDMA, Quadralogic Technologies, Vancouver). Further studies with 4-de-vinyl-4- (1-hexyloxyethyl) benzoporphyrin derivative showed that, like BPDMA, it had reduced residual skin phototoxicity compared in mice with Photofrin. The uptake and clearance characteristics of BPDMA were also compared with the 4-(1-hexyloxyethyl)-derivative by in vivo reflection spectroscopy.

Animals↗
PubMed1995

The validation of a new vascular damage assay for photodynamic therapy agents.

The therapeutic effect of photodynamic therapy (PDT: photodynamic sensitizer + light) is partly due to vascular damage. This report describes a new vascular photodamage assay for PDT agents and a validation of the assay. The method described here quantitates changes in tissue blood perfusion based on the relative amount of injected fluorescein dye in treated and untreated tissues. A specially designed fluorometer uses chopped monochromatic light from an argon laser as a source for exciting fluorescein fluorescence. The fluorescent light emitted from the tissue is collected by a six element fiberoptic array, filtered and delivered to a photodiode detector coupled to a phase-locked amplifier for conversion to a voltage signal for recording. This arrangement permits a rather simple, inexpensive construction and allows for the simultaneous use of the argon laser by other investigators. The routine assay for characterizing a specific photosensitizer at a standard dose consists of the sequential allocation of eight mice to a set of different light doses designed to span the dose-response range of fluorescein fluorescence exclusion (measured 8-10 min after fluorescein injection). The assay validation experiment used an anionic photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a at a dose of 0.4 mumol/kg. The parameter estimates (n = 34 mice) from fitting the standard Hill dose-response model to the data were: median fluorescence exclusion light dose FE50 = 275 +/- 8.3 J/cm2 and Hill sigmoidicity parameter m = -3.66 +/- 0.28. Subsets of the full data set randomly selected to simulate a standard eight mice experiment yielded similar parameter estimates. The new assay provides reliable estimates of PDT vascular damage with a frugal sequential experimental design.

Animals↗
PubMed1993

Absence of rhodamine 123-photochemotoxicity in human tumor xenografts.

Rhodamine 123 (R123)-photochemotoxicity was assessed in BALB/c nude mice bearing a xenografted human squamous cell carcinoma at various power densities and wavelengths and a given incident fluence of 150 Joules/cm2. One hour before light delivery, 1 mg R123/kg was injected i.p. in 20 animals. Surface irradiance was performed on the tumor and an equal size hind leg area of 40 animals. Three groups of 10 animals were treated at 514.5 nm and 0.1 W/cm2, 1 W/cm2, and 30 W/cm2, and one at 488 nm and 30 W/cm2. In each group, five animals received R123. The R123 concentration was measured in the tumor (0.023 +/- 0.007 micrograms/g) and tumor-free tissue (0.023 +/- 0.008 micrograms/g) in three additional animals by high performance liquid chromatography 1 hour after R123-administration. Histologic assessment 72 hours after light delivery revealed no tissue damage at nonthermal power densities, either in the tumor or in the tumor-free tissue, irrespective of R123-administration. At 30 W/cm2, neither in the tumor nor in tumor-free tissues was there any significant difference in the depth of necrosis, irrespective of R123-administration and the wavelength applied. Our results question the validity of R123 as a photosensitizer, at least in this rodent tumor model.

Animals↗
PubMed1993

Murine pharmacokinetics and antitumor efficacy of the photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a.

The combination of the new photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) and laser light of wavelength 665 nm showed antitumor activity against two s.c.-implanted murine tumors. HPPH also sensitized normal mouse foot tissue to light but photosensitivity decreased rapidly with time after HPPH administration. Mechanistic studies revealed that HPPH induced little direct tumor cell toxicity but was an effective mediator of vascular photodamage. Pharmacokinetic studies following intravenous injection of 1 mg [14C]HPPH per kilogram revealed a biexponential decay with time, with plasma alpha and beta half-lives of 0.69 and 21 h respectively. Fecal excretion was the primary route of elimination. The highest levels of [14C]HPPH were found in the liver, which also showed the greatest long-term retention. The sequence of decreasing uptake levels was the liver, adrenals, lung, spleen, kidney, urinary bladder, heart, eye, skin, pancreas, muscle, testes, fat and brain. This distribution correlated with the relative blood perfusion rates in the tissues.

Animals↗
PubMed1988

Study of factors mediating effect of photodynamic therapy on bladder in canine bladder model.

The canine bladder model was employed to study the factors mediating the effect of photodynamic therapy (PDT) on the bladder. The recovery (time taken for the bladder volume to return to pre-PDT value), gross and microscopic findings, implicate both bladder high filling pressure (60 cm H2O) and high light dose as factors mediating the effect of photodynamic therapy on bladder capacity. We recommend that photodynamic therapy to the bladder be performed under a filling pressure of 30 cm H2O, which is physiologic, and whole bladder illumination at a light dose not greater than 30 J/cm2.

Animals↗