-
Lasers in Surgery and Medicine 2002To measure the fluence at tissue surface for patients in our Phase II clinical trial of motexafin lutetium (MLu)-mediated chest wall photodynamic therapy for recurrent... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVES
To measure the fluence at tissue surface for patients in our Phase II clinical trial of motexafin lutetium (MLu)-mediated chest wall photodynamic therapy for recurrent breast carcinoma and to compare it to the calculated irradiance.
STUDY DESIGN/MATERIALS AND METHODS
The spatial and time dependence of light fluence (rate) was monitored in vivo on the chest wall surface using isotropic detectors in five patients. Patients were given MLu either 4 mg/kg with light at 18 hours or 5 mg/kg with light at 24 hours using an irradiance of 150 J/cm(2) at 730 nm, with an incident fluence rate of 75 mW/cm(2). The ratio of fluence rate to the incident fluence rate was determined at the center of the treatment field. This ratio was used to estimate the effective attenuation coefficient, mu (eff).
RESULTS
The mean and standard deviation of the ratio for all patients was 1.6 +/- 0.2. The corresponding range of mu (eff) was between 0.87 and 2.1 cm(-1), assuming reduced scattering coefficient, mu (s) = 4 cm(-1).
CONCLUSIONS
A conversion factor was determined to convert the irradiance to fluence rate on the tissue surface. However, the fluence (or the ratio) on patient surface varied by 70% due to the heterogeneity of optical properties. This supports the use of real-time in vivo dosimetry during photodynamic therapy.
Topics: Adult; Breast; Breast Neoplasms; Female; Humans; Light; Metalloporphyrins; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Radiometry; Reproducibility of Results; Scattering, Radiation; Thoracic Wall; Time Factors
PubMed: 12430147
DOI: 10.1002/lsm.10115 -
Biomaterials Research 2018Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens... (Review)
Review
BACKGROUND
Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens and induces tumour regressions. Several photodynamic treatments have been extensively studied and the photosensitizers (PS) are key to their biological efficacy, while laser and oxygen allow to appropriate and flexible delivery for treatment of diseases.
INTRODUCTION
In presence of oxygen and the specific light triggering, PS is activated from its ground state into an excited singlet state, generates reactive oxygen species (ROS) and induces apoptosis of cancer tissues. Those PS can be divided by its specific efficiency of ROS generation, absorption wavelength and chemical structure.
MAIN BODY
Up to dates, several PS were approved for clinical applications or under clinical trials. Photofrin® is the first clinically approved photosensitizer for the treatment of cancer. The second generation of PS, Porfimer sodium (Photofrin®), Temoporfin (Foscan®), Motexafin lutetium, Palladium bacteriopheophorbide, Purlytin®, Verteporfin (Visudyne®), Talaporfin (Laserphyrin®) are clinically approved or under-clinical trials. Now, third generation of PS, which can dramatically improve cancer-targeting efficiency by chemical modification, nano-delivery system or antibody conjugation, are extensively studied for clinical development.
CONCLUSION
Here, we discuss up-to-date information on FDA-approved photodynamic agents, the clinical benefits of these agents. However, PDT is still dearth for the treatment of diseases in specifically deep tissue cancer. Next generation PS will be addressed in the future for PDT. We also provide clinical unmet need for the design of new photosensitizers.
PubMed: 30275968
DOI: 10.1186/s40824-018-0140-z -
The Journal of Surgical Research Oct 2006Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates... (Comparative Study)
Comparative Study
PURPOSE
Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy.
METHODS
Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm(2) to 10 J/cm(2) three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed.
RESULTS
All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 +/- 0.18, 0.46 +/- 0.15, and 0.69 +/- 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 +/- 0.63, 0.67 +/- 0.10, and 1.1 +/- 0.80 cm for rectum, small bowel, and peritoneum, respectively.
CONCLUSION
Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.
Topics: Anastomosis, Surgical; Animals; Dogs; Evaluation Studies as Topic; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Rectal Neoplasms
PubMed: 16650871
DOI: 10.1016/j.jss.2006.01.020 -
Lasers in Surgery and Medicine Jun 2006Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed...
BACKGROUND AND OBJECTIVES
Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed.
STUDY DESIGN/MATERIALS AND METHODS
We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed.
RESULTS
We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate.
CONCLUSIONS
PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.
Topics: Adenocarcinoma; Aged; Animals; Dogs; Dose-Response Relationship, Drug; Hemoglobins; Humans; Male; Metalloporphyrins; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Oxygen; Photochemotherapy; Photosensitizing Agents; Prostate; Prostatic Neoplasms; Regional Blood Flow
PubMed: 16788929
DOI: 10.1002/lsm.20341 -
Circulation Nov 2000In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a... (Clinical Trial)
Clinical Trial
BACKGROUND
In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis.
METHODS AND RESULTS
An open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect.
CONCLUSIONS
This phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.
Topics: Humans; Peripheral Vascular Diseases; Photochemotherapy; Photosensitizing Agents; Ultrasonography
PubMed: 11067782
DOI: 10.1161/01.cir.102.19.2322 -
Transplantation Jun 2001Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex...
BACKGROUND
Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex biolocalization was examined in graft coronary artery disease (GCAD) with a rodent allograft model. After photoactivation, the effect on intimal proliferation was assessed.
METHODS
A PVG to ACI rat heterotopic heart transplantation model was used. Lu-Tex (10 mg/kg) was intravenously administered 90 days after transplantation. Photoactivation was performed 24 hr after Lu-Tex administration. A light-emitting diode, central wavelength of 742 nm, was used to illuminate the intraperitoneally placed allografts via a laparotomy (light fluence of 75 J/cm2 at a power density of 75 mW/cm2). Animals were divided into four groups according to postoperative treatments: PDT with Lu-Tex injection and light illumination (n=21), Lu-Tex injection and laparotomy (n=14), laparotomy with light only (n=14), and laparotomy only (n=16). GCAD was quantitatively assessed 14 days after treatments.
RESULTS
Lu-Tex localized in atherosclerotic plaque in vessels with GCAD. PDT significantly reduced both the percent of affected vessels and intimal proliferation compared to all other control study groups. alpha-Smooth muscle cell actin and anti-rat macrophage antibody-positive areas were significantly reduced within the neointima in allografts treated with PDT compared to all other study groups.
CONCLUSIONS
PDT significantly reduced atherosclerotic lesions of GCAD. Lu-Tex-mediated PDT may, therefore, be a potential method for treating accelerated atherosclerosis associated with transplantation.
Topics: Actins; Animals; Coronary Artery Disease; Coronary Vessels; Heart Transplantation; Male; Metalloporphyrins; Myocardium; Photochemotherapy; Photosensitizing Agents; Rats; Rats, Inbred ACI; Rats, Inbred Strains; Tissue Distribution; Tunica Intima
PubMed: 11435960
DOI: 10.1097/00007890-200106150-00008 -
Cardiovascular Research Feb 2001Motexafin lutetium (Lu-Tex, Antrin Injection) is a photosensitizer that selectively accumulates in atheromatous plaque where it can be activated by far-red light. The...
OBJECTIVE
Motexafin lutetium (Lu-Tex, Antrin Injection) is a photosensitizer that selectively accumulates in atheromatous plaque where it can be activated by far-red light. The localization and retention of intra-arterially administered Lu-Tex and its efficacy following activation by endovascularly delivered light (photoangioplasty) was evaluated.
METHODS
Bilateral iliac artery lesions were induced in 17 rabbits by balloon denudation, followed by a high cholesterol diet. Lu-Tex distribution within the atheroma was examined (n=8) following local injection. Fluorescence spectral imaging and chemical extraction techniques were used to measure Lu-Tex levels within the atheroma and adjacent normal tissue. Photoactivation was performed 15 min following Lu-Tex administration (180 J/cm fiber at 200 mW/cm fiber). Two weeks post photoangioplasty, vessels were harvested and hematoxylin and eosin (H&E) and RAM11 (macrophages) staining was performed.
RESULTS
Local delivery of Lu-Tex achieved immediate high concentrations within plaque (mean 40x control iliac atheroma). Mean percent plaque area in the treated segments was significantly lower than in the non-treated contralateral lesions (73 vs. 82%, P<0.01). No medial damage was observed. Quantitative analysis using RAM11 positive cells revealed significant reduction of macrophages in treated lesions in both the intima (5 vs. 22%, P<0.01) and in media (8 vs. 23%, P<0.01) compared to untreated contralateral segments.
CONCLUSIONS
Local delivery provides high levels of Lu-Tex selectively within atheroma. Photoactivation results in a significant decrease in macrophage and a small decrease in atheroma burden without damage to the normal vessel wall.
Topics: Angioplasty, Balloon; Angioplasty, Laser; Animals; Aorta, Abdominal; Arteriosclerosis; Iliac Artery; Infusions, Intra-Arterial; Macrophages; Male; Metalloporphyrins; Microscopy, Fluorescence; Models, Animal; Photosensitizing Agents; Postoperative Period; Rabbits; Signal Processing, Computer-Assisted
PubMed: 11164855
DOI: 10.1016/s0008-6363(00)00278-9 -
Radiation Research Sep 2010Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while...
Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug-light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/microl compared to 3.1 ng/mg in RIF tumor, and PDT-mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm(2) significantly improved long-term tumor responses over that at 75 mW/cm(2). This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm(2) PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm(2) PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm(2) PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted.
Topics: Blood Vessels; Humans; Metalloporphyrins; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents
PubMed: 20726728
DOI: 10.1667/RR2075.1 -
Journal of Clinical Oncology : Official... Apr 2001Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation... (Clinical Trial)
Clinical Trial
PURPOSE
Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival.
PATIENTS AND METHODS
Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range.
RESULTS
In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%.
CONCLUSION
Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Female; France; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Photosensitizing Agents; Prospective Studies; ROC Curve; Survival Rate; Tissue Distribution
PubMed: 11283141
DOI: 10.1200/JCO.2001.19.7.2074 -
Retina (Philadelphia, Pa.) Aug 2002To review the biophysical basis and current state of therapy for photodynamic closure of subfoveal choroidal neovascularization in the eye. (Review)
Review
PURPOSE
To review the biophysical basis and current state of therapy for photodynamic closure of subfoveal choroidal neovascularization in the eye.
METHODS
A review of the literature is included, which encompasses the chemical structure, biophysical mechanism of action, range of available agents, status of clinical trials, clinical indications, results of treatments, complications, and future directions.
RESULTS
Photodynamic therapy has been shown to be effective in closing both experimental choroidal neovascularization in animal models as well as subfoveal choroidal neovascularization in humans. The therapy results in temporary closure of choroidal new vessels for a period of approximately 1 to 4 weeks. By 12 weeks, most patients have reperfusion or reproliferation of choroidal new vessels resulting in the need for retreatment to achieve continued closure and visual stabilization. Differences exist in the quantum yield, clinical efficiency, and light and sensitizer dose requirements between different classes of agents. Further clinical trials will be required to determine the optimal form of therapy, with verteporfin (Visudyne) as the only currently approved agent. Other agents, including tin etiopurpurin (Purlytin) and motexafin lutetium (Optrin), are currently undergoing phase III, and phase II trials, respectively.
CONCLUSIONS
Photodynamic therapy is a promising treatment modality shown to be effective in achieving closure and stabilization of vision loss compared with placebo control in eyes with subfoveal choroidal neovascularization.
Topics: Choroidal Neovascularization; Clinical Trials as Topic; Humans; Macular Degeneration; Myopia; Photochemotherapy; Photosensitizing Agents
PubMed: 12172104
DOI: 10.1097/00006982-200208000-00001