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Theresa M Busch

Publications and source records attributed to Theresa M Busch.

At least 19 recordsLinked to original sources
PubMed2006

Photofrin uptake in the tumor and normal tissues of patients receiving intraperitoneal photodynamic therapy.

PURPOSE: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues. EXPERIMENTAL DESIGN: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models. RESULTS: Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P<0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P=0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (<or=2.31). CONCLUSIONS: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.

Biopsy↗
PubMed2006

A phase II trial of intraperitoneal photodynamic therapy for patients with peritoneal carcinomatosis and sarcomatosis.

PURPOSE: A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma, Birmingham, AL)-mediated photodynamic therapy and showed encouraging efficacy. The primary objectives of this phase II study were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and sarcomatosis. EXPERIMENTAL DESIGN: Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were (a) complete response, (b) failure-free survival time, and (c) overall survival time. Photosensitizer levels in tumor and normal tissues were measured. RESULTS: One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and 11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory distress syndrome, and cardiac ischemia. CONCLUSIONS: Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.

Adult↗
PubMed2006

Fluence rate as a modulator of PDT mechanisms.

BACKGROUND AND OBJECTIVES: Molecular oxygen in the tissue to be treated by photodynamic therapy (PDT) is critical for photodynamic cell killing. The fluence rate of PDT light delivery has been identified as an important modulator of tissue oxygenation and treatment outcome. This article provides supporting evidence for the role of fluence rate in PDT and discusses the underlying mechanisms. STUDY DESIGN/MATERIALS AND METHODS: Intratumoral pO2 was measured polarographically in murine tumors before and during PDT light treatment using the Eppendorf pO2 Histograph. Tumor response as a function of fluence rate and fluence was also assessed in murine tumor models. Changes in vascular permeability as a function of fluence rate were determined in murine tumors by measuring tumor uptake of fluorescent beads (200 nm diameter). RESULTS: Severe oxygen depletion is shown to occur within seconds of illumination at a fluence rate of 75 mW/cm2 in radiation-induced fibrosarcoma (RIF) tumors photosensitized with AlPcS2. This effect was reversible and consistent with photochemical oxygen depletion, which has been shown by us and others to be fluence rate dependent. It is demonstrated that fluence rate affects the PDT tumor response in the Colon 26 tumor model, high fluence rate diminishing or even totally inhibiting tumor control, low fluence rate promoting tumor control. The influence of fluence rate is not restricted to cytocidal effects, but can also be seen in sublethal conditions such as vascular permeability. CONCLUSIONS: Fluence rate of PDT light delivery exerts far-reaching control upon treatment outcome through its oxygenation modulating properties and possibly other mechanisms yet to be identified. This has been shown to be true in the preclinical and clinical setting. Further development of in situ dosimetry will be necessary to take full advantage of these discoveries.

Animals↗
PubMed2006

Local physiological changes during photodynamic therapy.

BACKGROUND AND OBJECTIVE: Herein an overview is provided of the causes, consequences, and significance of photodynamic therapy (PDT)-mediated effects on tumor oxygenation and blood flow during illumination. STUDY DESIGN/MATERIALS AND METHODS: Techniques particularly valuable to this research have included tissue oxygen tension measurement by the Eppendorf pO2 Histograph; spatial quantification of hypoxia by EF3 and EF5; and tissue oxygenation/blood flow monitoring by diffuse reflectance/correlation spectroscopy. RESULTS: Severe hypoxia was measured in vivo during PDT and is shown to be a consequence of photochemical oxygen consumption and/or compromised vascular perfusion. Oxygen depletion can be controlled by treatment regimen, occurs in a spatially-definable pattern, and is therapy-limiting. PDT-induced changes in tumor oxygenation during illumination are correlated with outcome. In PDT-treated tissues, blood flow also is determined by treatment regimen and correlates with treatment response. CONCLUSIONS: Photodynamic therapy creates distinct, measurable changes in tumor oxygen and blood flow during illumination. These physiological changes may ultimately affect treatment efficacy.

Animals↗
PubMed2006

Updated results of a phase I trial of motexafin lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer.

Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated. Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the 732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake. Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.

Adenocarcinoma↗
PubMed2005

Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy.

PURPOSE: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. EXPERIMENTAL DESIGN: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2). RESULTS: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability. CONCLUSION: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

Animals↗
PubMed2004

Treatment-induced changes in tumor oxygenation predict photodynamic therapy outcome.

Photodynamic therapy (PDT) requires oxygen to cause tumor damage, yet therapy itself can deplete or enhance tumor oxygenation. In the present work we measured the PDT-induced change in tumor oxygenation and explored its utility for predicting long-term response to treatment. The tissue hemoglobin oxygen saturation (SO(2)) of murine tumors was noninvasively measured by broadband diffuse reflectance spectroscopy. In initial validation studies, the oxyhemoglobin dissociation curve for mouse blood was accurately recreated based on measurements during deoxygenation of a tissue phantom of mouse erythrocytes. In vivo studies exhibited excellent correlation between carbogen-induced changes in SO(2) and pO(2) of radiation-induced fibrosarcoma tumors measured by reflectance spectroscopy and the Eppendorf pO(2) histograph, respectively. In PDT studies radiation-induced fibrosarcoma tumor SO(2) was measured immediately before and after Photofrin-PDT (135 J/cm(2), 38 mW/cm(2)). Animals were subsequently followed for tumor growth to a volume of 400 mm(3) (time-to-400 mm(3)) or the presence of tumor cure (no tumor growth at 90 days after treatment). In animals that recurred, the PDT-induced change in tumor SO(2), i.e., relative-SO(2) (SO(2) after PDT/SO(2) before PDT) was positively correlated with treatment durability (time-to-400 mm(3)). The predictive value of relative-SO(2) was confirmed in a second group of animals with enhanced pre-PDT oxygenation due to carbogen breathing. Furthermore, when all of the animals were considered (those that recurred and those that were cured) a highly significant association was found between increasing relative-SO(2) and increasing probability of survival, i.e., absence of recurrence. As independent variables, the SO(2) after PDT, the pre-PDT tumor volume, and light penetration depth all failed to predict response. As an independent variable, the SO(2) before PDT demonstrated a weak negative association with treatment durability; this association was driven by a correlation between decreasing pre-PDT SO(2) and increasing relative-SO(2). These data suggest that monitoring of PDT-induced changes in tumor oxygenation may be a valuable prognostic indicator.

Animals↗
PubMed2004

Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients.

PURPOSE: Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis. EXPERIMENTAL DESIGN: Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization. RESULTS: Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as approximately 2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 +/- 0.4 to 3.9 +/- 0.5 ng/mg (mean +/- SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean +/- SE drug uptake among these patients ranged from 0.6 +/- 0.8 to 5.8 +/- 0.5 ng/mg. CONCLUSIONS: Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of approximately 10x among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.

Appendiceal Neoplasms↗
PubMed2004

Phase II trial of pleural photodynamic therapy and surgery for patients with non-small-cell lung cancer with pleural spread.

PURPOSE: Non-small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. METHODS: We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm(2). Photosensitizer levels in tumor and surrounding normal tissue were measured. RESULTS: Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. CONCLUSION: Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.

Adult↗
PubMed2004

Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors.

The rate of light delivery (fluence rate) plays a critical role in photodynamic therapy (PDT) through its control of tumor oxygenation. This study tests the hypothesis that fluence rate also influences the inflammatory responses associated with PDT. PDT regimens of two different fluences (48 and 128 J/cm(2)) were designed for the Colo 26 murine tumor that either conserved or depleted tissue oxygen during PDT using two fluence rates (14 and 112 mW/cm(2)). Tumor oxygenation, extent and regional distribution of tumor damage, and vascular damage were correlated with induction of inflammation as measured by interleukin 6, macrophage inflammatory protein 1 and 2 expression, presence of inflammatory cells, and treatment outcome. Oxygen-conserving low fluence rate PDT of 14 mW/cm(2) at a fluence of 128 J/cm(2) yielded approximately 70-80% tumor cures, whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm(2) yielded approximately 10-15% tumor cures. Low fluence rate induced higher levels of apoptosis than high fluence rate PDT as indicated by caspase-3 activity and terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. The latter revealed PDT-protected tumor regions distant from vessels in the high fluence rate conditions, confirming regional tumor hypoxia shown by 2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl) acetamide staining. High fluence at a low fluence rate led to ablation of CD31-stained endothelium, whereas the same fluence at a high fluence rate maintained vessel endothelium. The highest levels of inflammatory cytokines and chemokines and neutrophilic infiltrates were measured with 48 J/cm(2) delivered at 14 mW/cm(2) ( approximately 10-20% cures). The optimally curative PDT regimen (128 J/cm(2) at 14 mW/cm(2)) produced minimal inflammation. Depletion of neutrophils did not significantly change the high cure rates of that regimen but abolished curability in the maximally inflammatory regimen. The data show that a strong inflammatory response can contribute substantially to local tumor control when the PDT regimen is suboptimal. Local inflammation is not a critical factor for tumor control under optimal PDT treatment conditions.

Animals↗
PubMed2003

Correlation of in vivo photosensitizer fluorescence and photodynamic-therapy-induced depth of necrosis in a murine tumor model.

We compared light-induced fluorescence (LIF) to nominal injected drug dose for predicting the depth of necrosis response to photodynamic therapy (PDT) in a murine tumor model. Mice were implanted with radiation-induced fibrosarcoma (RIF) and were injected with 0, 5, or 10 mg/kg Photofrin. 630-nm light (30 J/cm(2), 75 mW/cm(2)) was delivered to the tumor after 24 hours. Fluorescence emission (lambda(excitation)=545 nm, lambda( emission)=628 nm) from the tumor was measured. The LIF data had less scatter than injected drug dose, and was found to be at least as good as an injected drug dose for predicting the depth of necrosis after PDT. Our observations provide further evidence that fluorescence spectroscopy can be used to quantify tissue photosensitizer uptake and to predict PDT tissue damage.

Animals↗
PubMed2003

Elevated serum cytokine levels in mesothelioma patients who have undergone pleurectomy or extrapleural pneumonectomy and adjuvant intraoperative photodynamic therapy.

Patients treated on a Phase-I clinical trial of photodynamic therapy (PDT) developed a systemic capillary leak syndrome that constituted the dose-limiting toxicity. We examined serum samples from patients treated at the maximally tolerated dose level for evidence of a systemic, cytokine-mediated inflammatory response. Patients underwent pleurectomy or extrapleural pneumonectomy (EPP) followed by intraoperative PDT of the thorax using Foscan at a dose of 0.1 mg/kg 6 days before surgery and 652 nm red light at a dose of 10 J/cm2. Levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12 were assayed before Foscan administration; after anesthetic induction, surgical resection and light delivery; in postoperative recovery and the day after the surgery. Of the analyzed patients, eight underwent a pleurectomy and one an EPP followed by PDT. IFN-gamma, TNF-alpha and IL-12 showed no elevation, but IL-1beta, IL-6, IL-8 and IL-10 levels were elevated after surgery and PDT. IL-1beta showed a statistically significant variation from baseline after surgery and IL-6, after PDT. The results suggest a systemically mediated inflammatory response resulting from thoracic surgery followed by PDT. Further investigation of specific mechanisms is warranted.

Adult↗
PubMed2002

Photodynamic therapy creates fluence rate-dependent gradients in the intratumoral spatial distribution of oxygen.

In photodynamic therapy (PDT), treatment efficacy may be reduced by the presence of pre-existing tumor hypoxia or by oxygen depletion during the therapy. Tumor oxygenation during PDT has been measured with needle electrodes, but the intratumoral distribution of this oxygen is not known. In the present study, the spatial distribution of hypoxia during PDT was quantified using the hypoxia-labeling marker EF3. Mice bearing radiation-induced fibrosarcoma tumors were treated with Photofrin-mediated PDT to a total dose of 135 J/cm(2), delivered at a fluence rate of either 75 mW/cm(2) or 38 mW/cm(2). PDT-created hypoxia at each fluence rate was labeled by exposing tumors to EF3 (52 mg/kg) during the period of illumination. Cryosectioning, immunohistochemistry, and fluorescence microscopy were carried out to quantify EF3 binding as a function of distance to the nearest perfused blood vessels in sections cut from within the superficial (light-adjacent) 600 micro m or the deep (light-distant) 600 micro m of tumors (5-6 mm in diameter, approximately 3 mm in depth). In both superficial and deep sections, PDT at 75 mW/cm(2) resulted in the development of significant gradients in tumor hypoxia as a function of distance to a perfused blood vessel. Furthermore, significant hypoxia was detected even in vascular-adjacent tissue. These effects were associated with a significant decrease in the percentage of perfused vessels and a significant increase in the median distance of a cell to the nearest perfused blood vessel. In contrast, during PDT at 38 mW/cm(2), sections from deep tumor levels demonstrated only insignificant increases in the rise in hypoxia as a function of distance to a perfused vessel and in the level of hypoxia in vascular-adjacent tissue. No effects on tumor perfusion were detected during PDT at 38 mW/cm(2). Overall, these results demonstrate that spatially dependent depletion of oxygen can occur during PDT as a function of the fluence rate and that PDT can create significant hypoxia in even tissue adjacent to perfused blood vessels.

Animals↗
PubMed2002

In vivo reflectance measurement of optical properties, blood oxygenation and motexafin lutetium uptake in canine large bowels, kidneys and prostates.

Motexafin lutetium (MLu) is a second-generation photosensitizer for photodynamic therapy (PDT) of cancer. We have developed and applied a diffuse optical reflectance spectrometer for in vivo measurement of MLu uptake, optical properties, haemoglobin concentration and haemoglobin oxygen saturation in normal canine large bowels, kidneys and prostates. The probe consists of a broadband fibre-optic-coupled light source and detector fibres placed at various distances from the source fibre to collect reflected light. An analysis based on the diffusion approximation of the photon transport equation was used to recover tissue optical properties from the reflectance measurements. The instrumentation and analysis methods were validated using measurements from homogeneous, highly scattering phantoms with known MLu concentrations. The same techniques were then used to estimate chromophore concentrations of normal canine large bowels, kidneys and prostates. We estimated (mean (standard deviation)) total haemoglobin concentrations of 119 (25), 340 (92) and 51 (11) microM in the large bowels, kidneys and prostates of four dogs, respectively; tissue blood oxygen saturations in these same organs were 75 (15), 76 (21) and 74 (16) per cent, respectively. Tissue MLu concentrations (mg l(-1)) were estimated from data taken 3.5 h after injection of a 2 mg kg(-1) injected dose; data from three dogs gave concentrations of 2.4 (0.4) in large bowels, 6.8 (1.3) in kidneys and 2.2 (1.1) in prostates. The reduced scattering coefficients, mu's, estimated for large bowels, kidneys and prostates at 730 nm were, respectively: 10.1 (1.3), 19.6 (4.0) and 12.7 (0.6) cm(-1). We observed significant variability in MLu uptake, tissue scattering and haemoglobin concentration between organs and even between the same organ in different dogs. This class of in situ optical property measurement may be desirable to individualize PDT drug and light delivery.

Algorithms↗
PubMedDate not supplied

Pyropheophorbide 2-deoxyglucosamide: a new photosensitizer targeting glucose transporters.

To prepare near-infrared fluorescence imaging and photodynamic therapy agents targeted at glucose transporters, pyropheophorbide 2-deoxyglucosamide (Pyro-2DG) was synthesized and evaluated in a 9L glioma rat model. Fluorescence imaging studies demonstrate that Pyro-2DG is selectively accumulated in the tumor. Upon its photoactivation, we demonstrate that this agent efficiently causes selective mitochondrial damage to the region of a tumor that was photoirradiated after administration of this agent, but does not affect tissues photoirradiated in the absence of the agent or tissues treated with the agent that are not photoirradiated. Preliminary confocal microscopy studies suggest that Pyro-2DG is delivered and trapped in tumor cells via the GLUT/hexokinase pathway and therefore is useful both as a tumor-targeted NIR fluorescence imaging probe and as a PDT agent for the destruction of cancer.

Animals↗
PubMedDate not supplied

Redox ratio of mitochondria as an indicator for the response of photodynamic therapy.

The effect of photodynamic therapy (PDT) treatment on the metabolic state of tumor mitochondria is investigated by imaging of tumor redox status. PDT is performed using the photosensitizer pyropheophorbide-2-deoxyglucosamide (Pyro-2DG), which utilizes the glucose import pathway. It is found that Pyro-2DG-induced PDT resulting in a highly oxidized state of tumor mitochondria. This is determined from the redox ratio changes derived from the intrinsic oxidized flavoprotein (Fp) and reduced pyridine nucleotide (PN) [i.e., reduced nicotinamide adenine dinucleotide (NADH)] fluorescence signals observed using a cryoimager. Thus, the redox ratio is a sensitive indicator for providing reliable and informative measurements of PDT-induced tissue damage. In the PDT treated region of the tumor, highly oxidized flavoprotein and diminishing NADH fluorescence is detected, suggesting that flavoprotein and NADH are oxidized by singlet oxygen produced in the photosensitization process.

Animals↗