The physics, biophysics and technology of photodynamic therapy

Photodynamic therapy (PDT) uses light-activated drugs to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections. This paper reviews the current status of PDT with an emphasis on the contributions of physics, biophysics and technology, and the challenges remaining in the optimization and adoption of this treatment modality. A theme of the review is the complexity of PDT dosimetry due to the dynamic nature of the three essential components -- light, photosensitizer and oxygen. Considerable progress has been made in understanding the problem and in developing instruments to measure all three, so that optimization of individual PDT treatments is becoming a feasible target. The final section of the review introduces some new frontiers of research including low dose rate (metronomic) PDT, two-photon PDT, activatable PDT molecular beacons and nanoparticle-based PDT.     

Clinical Application of Photodynamic Therapy

Photodynamic therapy（PDT） is a new medical technology, the study on photodynamic therapy was in full swing in the past two decade. Scientists have made great progress in it. Photosensitizer,oxygen and light source play important role in photodynamic therapy. PDT is a light activated chemotherapy. A photon is adsorbed by a photosensitizer which moves the drug into an excited state. The excited drug can then pass its energy to oxygen to create a chemical radical called “singlet oxygen”. Singlet oxygen attacks cellular structures by oxidation. Such oxidative damage might be oxidation of cell membranes or proteins. When the accumulation of oxidative damage exceeds a threshold level,the cell begins to die. Photodynamic therapy allows selective treatment of localized cancer. PDT involves administration of a photosensitizer to the patients, followed by delivery of light to the cancerous region. The light activates the agent which kills the cancer cells. Without light,the agent is harmless. As a new therapy,photodynamic Therapy has great Advantage in treating cancers. 1. PDT avoids systemic treatment. The treatment occurs only where light is delivered, hence the patient does not undergo go needless systemic treatment when treating localized disease. Side-effects are avoided, from losing hair or suffering nausea to more serious complications. 2. PDT is selective. The photosensitizing agent will selectively accumulate in cancer cells and not in surrounding normal tissues. Hence ,there is selective targeting of the cancer and sparing of surrounding tissues. 3. when surgery is not possible. PDT kills cancer cells but does not damage collagenous tissue structures,and normal cells will repopulate these structures. Hence,if a patient has cancer in a structure that cannot be removed surgicaily（eg. ,the upper bronchi of the lung） ,PDT can still treat the site. 4. PDT is repeatable. Uniike radiation therapy,PDT can be used again and again. Hence,it offers a means of longterm management of cancer even if complete cure is not attainable.     

Effects of photodynamic therapy on tumor stroma

Photodynamic therapy (PDT) is a treatment that combines a photosensitizer with light to generate oxygen-dependent photochemical destruction of diseased tissue. This modality has been approved worldwide since 1993 for the treatment of several oncological and nononcological disorders. PDT continues to be interested in both preclinical and clinical research, with more than 500 publications each year during the past 5 years. This minireview focuses on the effects of PDT on tumor stroma. A tumor consists of two fundamental elements: parenchyma (neoplastic cells) and stroma. The stroma is composed of vasculature, cellular components, and intercellular matrix and is necessary for tumor growth. All the stromal components can be targeted by PDT. Although the exact mechanism of PDT is unknown, emerging evidence has indicated that effective PDT of tumor requires destruction of both parenchyma and stroma. Further, damage to subendothelial zone of vasculature, in addition to endothelium, also appears to be a crucial factor. The PDT-generated immune response as a way of vaccination for treatment and prevention of metastatic tumors remains to be exploited.     

How tissue optics affect dosimetry of photodynamic therapy

We describe three lessons learned about how tissue optics affect the dosimetry of red to near-infrared treatment light during PDT, based on working with Dr. Tayyaba Hasan. Lesson 1-The optical fluence rate φ near the tissue surface exceeds the delivered irradiance (E). A broad beam penetrates into tissue to a depth (z) as φ=Eke(-μz), with an attenuation constant μ and a backscatter term k. In tissues, k is typically in the range 3-5, and 1∕μ equals δ, the 1∕e optical penetration depth. Lesson 2-Edge losses at the periphery of a uniform treatment beam extend about 3δ from the beam edge. If the beam diameter exceeds 6δ, then there is a central zone of uniform fluence rate in the tissue. Lesson 3-The depth of treatment is linearly proportional to δ (and the melanin content of pigmented epidermis in skin) while proportional to the logarithm of all other factors, such as irradiance, exposure time, or the photosensitizer properties (concentration, extinction coefficient, quantum yield for oxidizing species). The lessons illustrate how tissue optics play a dominant role in specifying the treatment zone during PDT.     

Effects of Photodynamic Therapy on Tumor Stroma

Photodynamic therapy (PDT) is a treatment that combines a photosensitizer with light to generate oxygen-dependent photochemical destruction of diseased tissue. This modality has been approved worldwide since 1993 for the treatment of several oncological and nononcological disorders. PDT continues to be interested in both preclinical and clinical research, with more than 500 publications each year during the past 5 years. This minireview focuses on the effects of PDT on tumor stroma. A tumor consists of two fundamental elements: parenchyma (neoplastic cells) and stroma. The stroma is composed of vasculature, cellular components, and intercellular matrix and is necessary for tumor growth. All the stromal components can be targeted by PDT. Although the exact mechanism of PDT is unknown, emerging evidence has indicated that effective PDT of tumor requires destruction of both parenchyma and stroma. Further, damage to subendothelial zone of vasculature, in addition to endothelium, also appears to be a crucial factor. The PDT-generated immune response as a way of vaccination for treatment and prevention of metastatic tumors remains to be exploited.     

Effects of Photodynamic Therapy on Tumor Stroma

Photodynamic therapy (PDT) is a treatment that combines a photosensitizer with light to generate oxygen-dependent photochemical destruction of diseased tissue. This modality has been approved worldwide since 1993 for the treatment of several oncological and nononcological disorders. PDT continues to be interested in both preclinical and clinical research, with more than 500 publications each year during the past 5 years. This minireview focuses on the effects of PDT on tumor stroma. A tumor consists of two fundamental elements: parenchyma (neoplastic cells) and stroma. The stroma is composed of vasculature, cellular components, and intercellular matrix and is necessary for tumor growth. All the stromal components can be targeted by PDT. Although the exact mechanism of PDT is unknown, emerging evidence has indicated that effective PDT of tumor requires destruction of both parenchyma and stroma. Further, damage to subendothelial zone of vasculature, in addition to endothelium, also appears to be a crucial factor. The PDT-generated immune response as a way of vaccination for treatment and prevention of metastatic tumors remains to be exploited.     

Vascular and cellular targeting for photodynamic therapy

Photodynamic therapy (PDT) involves the combination of photosensitizers (PS) with light as a treatment, and has been an established medical practice for about 10 years. Current primary applications of PDT are age-related macular degeneration (AMD) and several types of cancer and precancer. Tumor vasculature and parenchyma cells are both potential targets of PDT damage. The preference of vascular versus cellular targeting is highly dependent upon the relative distribution of photosensitizers in each compartment, which is governed by the photosensitizer pharmacokinetic properties and can be effectively manipulated by the photosensitizer drug administration and light illumination interval (drug-light interval) during PDT treatment, or by the modification of photosensitizer molecular structure. PDT using shorter PS-light intervals mainly targets tumor vasculature by confining photosensitizer localization within blood vessels, whereas if the sensitizer has a reasonably long pharmacokinetic lifetime, then PDT at longer PS-light intervals can induce more tumor cellular damage, because the photosensitizer has then distributed into the tumor cellular compartment. This passive targeting mechanism is regulated by the innate photosensitizer physicochemical properties. In addition to the passive targeting approach, active targeting of various tumor endothelial and cellular markers has been studied extensively. The tumor cellular markers that have been explored for active photodynamic targeting are mainly tumor surface markers, including growth factor receptors, low-density lipoprotein (LDL) receptors, transferrin receptors, folic acid receptors, glucose transporters, integrin receptors, and insulin receptors. In addition to tumor surface proteins, nuclear receptors are targeted, as well. A limited number of studies have been performed to actively target tumor endothelial markers (ED-B domain of fibronectin, VEGF receptor-2, and neuropilin-1). Intracellular targeting is a challenge due to the difficulty in achieving sufficient penetration into the target cell, but significant progress has been made in this area. In this review, we summarize current studies of vascular and cellular targeting of PDT after more than 30 years of intensive efforts.     

Light dosimetry for multiple cylindrical diffusing sources for use in photodynamic therapy

Since prostatic carcinoma is usually multifocal within the prostate, effective photodynamic therapy (PDT) of prostatic carcinoma is expected to require the photochemical destruction of the entire organ. Accurate light dosimetry will be essential to avoid damage to proximal sensitive tissue such as the rectum. The prostate will be illuminated using interstitial cylindrical fibreoptic light sources and, because of the limited transparency of prostate tissue, these sources will be mounted in a parallel array analogous to the source array used in brachytherapy. Both source spacing and the light delivered to each source will control light dosimetry from a parallel array of fibreoptic sources implanted into tissue. Clinical PDT will require dose planning in order to determine the position and illumination of each source prior to treatment, but unfortunately few methods of predicting light fluence from cylindrical interstitial sources currently exist. In this paper, a novel light fluence model is used to predict tissue transillumination resulting from cylindrical interstitial sources. The cylindrical source is modelled as a finite array of infinitesimal small sources using Christian Huygens' famous single-slit diffraction model. We show that this source model when combined with a robust derivation of fluence in a spherical geometry using diffusion theory, accurately predicts fluence levels from a single cylindrical source in a variety of media. This method is found to retain its accuracy near the sources. With a simple extension, this fluence model is used to predict the light fluence levels from an array of three sources and the predicted fluence is found to compare favourably with experimental data.     

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.     

光动力疗法发展近况

光动力疗法发展近况李峻亨（解放军总医院激光科北京１００８５３）ＡｂｓｔｒａｃｔＴｈｅｂａｓｉｃｐｒｉｎｃｉｐｌｅｓ，ｐｈｏｔｏｓｅｎｓｉｔｉｚｅｒｓｉｎｃｌｕｄｉｎｇａｐｐｒｏｖｅｄａｎｄｎｅｗｏｎｅｓｉｎｃｌｉｎｉｃａｌｔｒｉａｌｓｔａｇｅｓ．ｌｉ...     

Near-infrared light induced in vivo photodynamic therapy of cancer based on upconversion nanoparticles

Upconversion nanoparticles (UCNPs) that emit high-energy photons upon excitation by the low-energy near-infrared (NIR) light are emerging as new optical nano-probes useful in biomedicine. Herein, we load Chlorin e6 (Ce6), a photosensitizer, on polymer-coated UCNPs, forming a UCNP-Ce6 supramolecular complex that produces singlet oxygen to kill cancer cells under NIR light. Excellent photodynamic therapy (PDT) efficacy is achieved in tumor-bearing mice upon intratumoral injection of UCNP-Ce6 and the followed NIR light exposure. It is further uncovered that UCNPs after PDT treatment are gradually cleared out from mouse organs, without rendering appreciable toxicity to the treated animals. Moreover, we demonstrate that the NIR-induced PDT based on UCNP-Ce6 exhibits a remarkably increased tissue penetration depth compared to the traditional PDT using visible excitation light, offering significantly improved treatment efficacy for tumors blocked by thick biological tissues. Our work demonstrates NIR light-induced in vivo PDT treatment of cancer in animals, and highlights the promise of UCNPs for multifunctional in vivo cancer treatment and imaging.     

Perylenequinones in photodynamic therapy: cellular versus vascular response.

Photodynamic therapy (PDT) is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about molecular oxygen-induced cell death. We have investigated the efficacy of photosensitizers from the family perylenequinone, namely Hypericin, Hypocrellin A and B, in the treatment of cancer. These photosensitizers are known as potent second generation natural photosensitizers that have phototherapeutic advantages over the presently used porphyrins. We have studied the in vitro signaling mechanism involved in the photodynamic action following PDT in various human carcinoma cell lines. The difference of tumor cell death between two modes of action i.e., vascular- and cellular-mediated cell death, were evaluated in order to compare treatments that can efficaciously eradicate tumor in xenografts model. The antivascular effect of PDT was demonstrated in the chick chorioallantoic membrane (CAM) model. Tumor therapy based on targeting the vasculature of the tumor is indeed promising as demonstrated in the higher relative regression percentage of treated tumor compared to cellular targeted PDT. The favorable tumor response derived from short drug-light interval mediated PDT was primarily based on the differential uptake of the photosensitizer into tumor-associated vasculature as opposed to the cellular compartments of the tumor.     

Photodynamic therapy as a new treatment modality for inflammatory and infectious conditions

Photodynamic therapy (PDT) is currently used as a minimally invasive therapeutic modality for cancer. Whereas antitumor treatment regimens require lethal doses of photosensitizer and light, sublethal doses may have immunomodulatory effects, antibacterial action and/or regenerative properties. A growing body of evidence now indicates that non-lethal PDT doses can alleviate inflammation or treat established soft-tissue infections in various murine models of arthritis, experimental encephalomyelitis, inflammatory bowel disease and chronic skin ulcers. Furthermore, PDT is already used in clinical application and clinical trial for the treatment of psoriasis, chronic wounds and periodontitis in humans. Sublethal PDT should be regarded as a new viable option for the treatment of inflammatory conditions.     

Spatial distribution of liposome encapsulated tin etiopurpurin dichloride (SnET2) in the canine prostate: implications for computer simulation of photodynamic therapy

Photodynamic therapy (PDT) is a minimally invasive treatment that can be employed in many human diseases including prostate cancer. PDT for prostate cancer depends on the sequestration of a photosensitizing drug within the glandular tissue. The photosensitizer is subsequently activated by light (usually from a laser) and the active drug destroys tissue. Since prostate cancer is a multifocal disease, PDT must ablate the glandular prostate completely. This will depend on the precise placement of light sources in the prostate and delivery of a therapeutic light dose to the entire gland. Also, sources of light and their spatial distribution must be tailored to each individual patient. The uniform, therapeutic light distribution can be achieved by interstitial light irradiation. In this case, the light is delivered by diffusers placed within the substance of the prostate parallel to the urethra at a distance optimized to deliver adequate levels of light and to create the desired photodynamic effect. To help achieve the uniform light distribution throughout the prostate we have developed a computer program that can determine treatment effects. The program predicts the best set of parameters and the position of light diffusers in space, and displays them in graphical or in numerical form assuming a fixed attenuation coefficient. The two parameters of greatest importance in the computer simulation are attenuation coefficient and critical fluence. Both depend on the concentration of active drug within the prostate gland. It is necessary to know the nature of the spatial distribution of photosensitizer within the prostate to execute computer modeling of PDT with high precision. We found that the concentration of SnET2 is heterogeneous in nature, and is higher in the proximity of the glandular capsule. It is clear therefore that any future attempts of computerized modeling of this procedure must take into consideration the uneven sequestration of photosensitizer and the consequential asymmetrical necrosis of the prostate.     

Morphological changes of the dermatophyte Trichophyton rubrum after photodynamic treatment: a scanning electron microscopy study.

Treatment strategies for superficial mycosis caused by the dermatophyte Trichophyton rubrum consist of the use of topical or oral antifungal preparations. We have recently discovered that T. rubrum is susceptible to photodynamic treatment (PDT), with 5,10,15-tris(4-methylpyridinium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B) as a photosensitizer. The susceptibility appeared to depend on the fungal growth stage, with PDT efficacy higher with microconidia when compared to mycelia. The aim of this study was to investigate, with the use of scanning electron microscopy, the morphological changes caused by a lethal PDT dose to T. rubrum when grown on isolated human stratum corneum. Corresponding dark treatment and light treatment without photosensitizer were used as controls. A sub-lethal PDT dose was also included in this investigation The morphologic changes were followed at various time points after the treatment of different fungal growth stages. Normal fungal growth was characterized by a fiber-like appearance of the surface of the hyphae and microconidia with the exception of the hyphal tips in full mycelia and the microconidia shortly after attachment to the stratum corneum. Here, densely packed globular structures were observed. The light dose (108 J/cm2) in the absence of Sylsens B, or the application of the photosensitizer in the absence of light, caused reversible fungal wall deformations and bulge formation. However, after a lethal PDT, a sequence of severe disruptions and deformations of both microconidia and the mycelium were observed leading to extrusion of cell material and emptied fungal elements. In case of a non-lethal PDT, fungal re-growth started on the remnants of the treated mycelium.     

In vitro evaluation of the genotoxic and clastogenic potential of photodynamic therapy

Photodynamic therapy (PDT) was recently introduced in clinical practice for the management of cancer. As far as PDT relies on the combined action of a photosensitizer and a laser source, there is a need to evaluate the genotoxic and mutagenic potential of this treatment modality. This paper reports the effects of various photosensitizer and photo-irradiation doses on lethality to the MIA PaCa cell line using ZnPcS4 as the photosensitizer. The sister chromatid exchange (SCE) assay was used to evaluate the genotoxicity of various photosensitizer and photo-irradiation doses. Also, chromosomal aberrations at various time intervals post-irradiation were evaluated. The results showed that a combination of 3 J/cm2 irradiance with 5 microM ZnPcS4 concentration leads to the LD90 72 h post-irradiation. Eight days post-irradiation the LD90 level was achieved using a light dose of 3 J/cm2, independent of ZnPcS4 concentration. The SCE assay showed that cells treated with various light and drug doses presented no genotoxic potential, as SCE levels were not different from untreated (control) cells. Chromosomal analysis after PDT treatment at various time intervals post-irradiation showed that there was no significant chromosomal damage in cells treated photodynamically compared with untreated controls. The results show that the cell killing mechanism after PDT is not at the chromosome level, but may be at a different cellular level, such as plasma membranes, mitochondria, etc.     

Progress in the photodynamic therapy treatment of Leishmaniasis

Leishmaniasis is a serious and endemic infectious disease that has been reported in more than 90 countries and territories. The classical treatment presents a series of problems ranging from difficulty in administration, development of resistance, and a series of side effects. Photodynamic therapy (PDT) has already shown great potential for use as a treatment for leishmaniasis that is effective and non-invasive, with very minor side effects. PDT can also be inexpensive and easy to administer. In this review, we will report the most recent developments in the field, starting with the chemical diversity of photosensitizers, highlighting important mechanistic aspects, and noting information that may assist in designing and developing new and promising photosensitizer molecules.     

Immune response against angiosarcoma following lower fluence rate clinical photodynamic therapy.

Tumor response to photodynamic therapy (PDT) is dependent on treatment parameters used. In particular, the light fluence rate may be an important determinant of the treatment outcome. In this clinical case report, we describe the response of angiosarcoma to PDT carried out using different fluence rates and drug and light doses. A patient with recurrent multifocal angiosarcoma of the head and neck was recruited for PDT. A new generation chlorin-based photosensitizer, Fotolon, was administered at a dose of 2.0 to 5.7 mg/kg. The lesions were irradiated with 665 nm laser light for a light dose of 65 to 200 J/cm2 delivered at a fluence rate of 80 or 150 mW/cm2. High dose PDT carried out at a high fluence rate resulted in local control of the disease for up to a year; however, the disease recurred and PDT had to be repeated. PDT of new lesions carried out at a lower fluence rate resulted in tumor eradication. More significantly, it also resulted in spontaneous remission of neighboring and distant untreated lesions. Repeat PDT carried out on a recurrent lesion at a lower fluence rate resulted in eradication of both treated and untreated lesions despite the lower total light dose delivered. Immunohistochemical examination of biopsy samples implies that PDT could have activated a cell-mediated immune response against untreated lesions. Subsequent histopathological examination of the lesion sites showed negative for disease. Our clinical observations show that lower fluence rate PDT results in better outcome and also indicate that the fluence rate, rather than the total light dose, is a more crucial determinant of the treatment outcome. Specifically, lower fluence rate PDT appears to activate the body's immune response against untreated lesions.     

光动力学疗法和声动力学疗法

目的:通过对肿瘤治疗中光动力学疗法和声动力学疗法的研究现状及研究进展的综述,以期对临床应用或实验研究起到一定的借鉴作用。方法:本文具体阐述了光动力学疗法和声动力学疗法杀伤肿瘤细胞的分子机制以及光敏剂与声敏剂的分类,介绍了两种方法在肿瘤方面的应用及对新的治疗模式的探索,展望了光动力学疗法和声动力学疗法临床应用的巨大潜力。结果:光动力学疗法和声动力学疗法的研究已取得了一定的成果,但在组织内氧含量、新型光敏剂与声敏剂的开发、药物剂量的把握及对声动力学疗法作用机理的研究方面仍存在问题。结论:光动力学疗法和声动力学疗法作为两种新的肿瘤治疗手段,在肿瘤的防治中已展现出良好的应用前景,但在临床实际应用中光动力学疗法还未普及,而声动力学疗法起步较晚,尚处于研究阶段,未应用于临床。     

Photodynamic therapy as a potential treatment for spinal cord injury

Spinal cord injury (SCI) is a major cause of disability and largely affects the quality of life. Injured axons cannot regenerate past the lesion due to the formation of glial scar which has become an important target for regeneration research in SCI. Although significant efforts have been invested in inhibition the glial scar to promote the recovery of SCI patients, no satisfying method has been found. Photodynamic therapy (PDT) is an effective way to inhibit the growth of the target cells and tissue based on photosensitizer and light that are combined to induce cellular and tissue damages in an oxygen-dependent manner. We reasonably hypothesize that PDT might be a novel treatment for SCI.