The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

Photodynamic Therapy

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

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Photodynamic therapy of cancer: An update†‡

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Principles Of Fluorescence Spectroscopy

A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues.

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Optical properties of biological tissues: a review.

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.

https://cancerres.aacrjournals.org/content/canres/64/6/2120.full.pdf

Choice of Oxygen-Conserving Treatment Regimen Determines the Inflammatory Response and Outcome of Photodynamic Therapy of Tumors

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/cm 2 ,1 35 J/cm 2 ). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was corre- lated with treatment durability, defined as the time of tumor growth to a volume of 400 mm 3 . 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 F SE: 168.1 F 39.5%) and subsequent decrease (59.2 F 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,r 2 = 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P =0 .016,r 2 = 0.50) association between interval time and time-to-400 mm 3 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 V 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.

https://clincancerres.aacrjournals.org/content/clincanres/11/9/3543.full.pdf

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

We report the synthesis, calibration, and examples of application of two new phosphorescent probes, Oxyphor R4 and Oxyphor G4, optimized specifically for in vivo oxygen imaging by phosphorescence quenching. These “protected” dendritic probes can operate in either albumin-rich (blood plasma) or albumin-free (interstitial space) environments at all physiological oxygen concentrations, from normoxic to deep hypoxic conditions. Oxyphors R4 and G4 are derived from phosphorescent Pd-meso-tetra-(3,5-dicarboxyphenyl)-porphyrin (PdP) or Pd-meso-tetra-(3,5-dicarboxyphenyl)-tetrabenzoporphyrin (PdTBP), respectively, and possess features common for protected dendritic probes, i.e., hydrophobic dendritic encapsulation of phosphorescent metalloporphyrins and hydrophilic PEGylated periphery. The new Oxyphors are highly soluble in aqueous environments and do not permeate biological membranes. The probes were calibrated under physiological conditions (pH 6.4–7.8) and temperatures (22–38 °C), showing high stability, reprod...

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Two New “Protected” Oxyphors for Biological Oximetry: Properties and Application in Tumor Imaging

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. Lasers Surg. Med. © 2006 Wiley-Liss, Inc.

Fluence rate as a modulator of PDT mechanisms.

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 (SO2) 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 SO2 and pO2 of radiation-induced fibrosarcoma tumors measured by reflectance spectroscopy and the Eppendorf pO2 histograph, respectively. In PDT studies radiation-induced fibrosarcoma tumor SO2 was measured immediately before and after Photofrin-PDT (135 J/cm2, 38 mW/cm2). Animals were subsequently followed for tumor growth to a volume of 400 mm3 (time-to-400 mm3) or the presence of tumor cure (no tumor growth at 90 days after treatment). In animals that recurred, the PDT-induced change in tumor SO2, i.e. , relative-SO2 (SO2 after PDT/SO2 before PDT) was positively correlated with treatment durability (time-to-400 mm3). The predictive value of relative-SO2 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-SO2 and increasing probability of survival, i.e. , absence of recurrence. As independent variables, the SO2 after PDT, the pre-PDT tumor volume, and light penetration depth all failed to predict response. As an independent variable, the SO2 before PDT demonstrated a weak negative association with treatment durability; this association was driven by a correlation between decreasing pre-PDT SO2 and increasing relative-SO2. These data suggest that monitoring of PDT-induced changes in tumor oxygenation may be a valuable prognostic indicator.

https://cancerres.aacrjournals.org/content/canres/64/20/7553.full.pdf

Theresa M. Busch

Papers

Choice of Oxygen-Conserving Treatment Regimen Determines the Inflammatory Response and Outcome of Photodynamic Therapy of Tumors

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

Two New “Protected” Oxyphors for Biological Oximetry: Properties and Application in Tumor Imaging

Fluence rate as a modulator of PDT mechanisms.

Treatment-Induced Changes in Tumor Oxygenation Predict Photodynamic Therapy Outcome