Effect of photosensitizer dose on fluence rate responses to photodynamic therapy

Photodynamic therapy (PDT) regimens that conserve tumor oxygenation are typically more efficacious, but require longer treatment times. This makes them clinically unfavorable. In this report, the inverse pairing of fluence rate and photosensitizer dose is investigated as a means of controlling oxygen depletion and benefiting therapeutic response to PDT under conditions of constant treatment time. Studies were performed for Photofrin-PDT of radiation-induced fibrosarcoma tumors over fluence rate and drug dose ranges of 25-225 mW cm(-2) and 2.5-10 mg kg(-1), respectively, for 30 min of treatment. Tumor response was similar among all inverse regimens tested, and, in general, tumor hemoglobin oxygen saturation (SO2) was well conserved during PDT, although the highest fluence rate regimen (225 mWx2.5 mg) did lead to a modest but significant reduction in SO2. Regardless, significant direct tumor cell kill (>1 log) was detected during 225 mWx2.5 mg PDT, and minimal normal tissue toxicity was found. PDT effect on tumor oxygenation was highly associated with tumor response at 225 mWx2.5 mg, as well as in all other regimens tested. These data suggest that high fluence rate PDT can be carried out under oxygen-conserving, efficacious conditions at low photosensitizer dose. Clinical confirmation and application of these results will be possible through use of minimally invasive oxygen and photosensitizer monitoring technologies, which are currently under development.     

H2S‐Activable MOF Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet‐Oxygen Release

Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The search for an effective photosensitizer to realize selective cancer treatment has become one of the major foci in recent developments of PDT technology. Controllable singlet‐oxygen release based on specific cancer‐associated events, as another major layer of selectivity mode, has attracted great attention in recent years. Here, for the first time, we demonstrated that a novel mixed‐metal metal–organic framework nanoparticle (MOF NP) photosensitizer can be activated by a hydrogen sulfide (H₂S) signaling molecule in a specific tumor microenvironment for PDT against cancer with controllable singlet‐oxygen release in living cells. The effective removal of tumors in vivo further confirmed the satisfactory treatment effect of the MOF NP photosensitizer.     

Chemiluminescence as a PDT light source for microbial control

The photodynamic therapy (PDT) is a combination of using a photosensitizer agent, light and oxygen that can cause oxidative cellular damage. This technique is applied in several cases, including for microbial control. The most extensively studied light sources for this purpose are lasers and LED-based systems. Few studies treat alternative light sources based PDT. Sources which present flexibility, portability and economic advantages are of great interest. In this study, we evaluated the in vitro feasibility for the use of chemiluminescence as a PDT light source to induce Staphylococcus aureus reduction. The Photogem? concentration varied from 0 to 75 μg/ml and the illumination time varied from 60 min to 240 min.The long exposure time was necessary due to the low irradiance achieved with chemiluminescence reaction at μW/cm2 level. The results demonstrated an effective microbial reduction of around 98% for the highest photosensitizer concentration and light dose. These data suggest the potential use of chemiluminescence as a light source for PDT microbial control, with advantages in terms of flexibility, when compared with conventional sources.     

Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers

Progress in the photodynamic therapy (PDT) of cancer should benefit from a rationale to predict the most efficient of a series of photosensitizers that strongly absorb light in the phototherapeutic window (650–800 nm) and efficiently generate reactive oxygen species (ROS=singlet oxygen and oxygen‐centered radicals). We show that the ratios between the triplet photosensitizer–O₂ interaction rate constant (k_D) and the photosensitizer decomposition rate constant (k_d), k_D/k_d, determine the relative photodynamic activities of photosensitizers against various cancer cells. The same efficacy trend is observed in vivo with DBA/2 mice bearing S91 melanoma tumors. The PDT efficacy intimately depends on the dynamics of photosensitizer–oxygen interactions: charge transfer to molecular oxygen with generation of both singlet oxygen and superoxide ion (high k_D) must be tempered by photostability (low k_d). These properties depend on the oxidation potential of the photosensitizer and are suitably combined in a new fluorinated sulfonamide bacteriochlorin, motivated by the rationale.     

Modeling of a type II photofrin-mediated photodynamic therapy process in a heterogeneous tissue phantom

We present a quantitative framework to model a Type II photodynamic therapy (PDT) process in the time domain in which a set of rate equations are solved to describe molecular reactions. Calculation of steady-state light distributions using a Monte Carlo method in a heterogeneous tissue phantom model demonstrates that the photon density differs significantly in a superficial tumor of only 3 mm thickness. The time dependences of the photosensitizer, oxygen and intracellular unoxidized receptor concentrations were obtained and monotonic decreases in the concentrations of the ground-state photosensitizer and receptor were observed. By defining respective decay times, we quantitatively studied the effects of photon density, drug dose and oxygen concentration on photobleaching and cytotoxicity of a photofrin-mediated PDT process. Comparison of the dependences of the receptor decay time on photon density and drug dose at different concentrations of oxygen clearly shows an oxygen threshold under which the receptor concentration remains constant or PDT exhibits no cytotoxicity. Furthermore, the dependence of the photosensitizer and receptor decay times on the drug dose and photon density suggests the possibility of PDT improvement by maximizing cytotoxicity in a tumor with optimized light and drug doses. We also discuss the utility of this model toward the understanding of clinical PDT treatment of chest wall recurrence of breast carcinoma.     

Photosynthetic Tumor Oxygenation by Photosensitizer‐Containing Cyanobacteria for Enhanced Photodynamic Therapy

Sustained tumor oxygenation is of critical importance during type‐II photodynamic therapy (PDT), which depends on the intratumoral oxygen level for the generation of reactive oxygen species. Herein, the modification of photosynthetic cyanobacteria with the photosensitizer chlorin e6 (ce6) to form ce6‐integrated photosensitive cells, termed ceCyan, is reported. Upon 660 nm laser irradiation, sustained photosynthetic O₂ evolution by the cyanobacteria and the immediate generation of reactive singlet oxygen species (¹O₂) by the integrated photosensitizer could be almost simultaneously achieved for tumor therapy using type‐II PDT both in vitro and in vivo. This work contributes a conceptual while practical paradigm for biocompatible and effective PDT using hybrid microorganisms, displaying a bright future in clinical PDT by microbiotic nanomedicine.     

Photosynthetic Tumor Oxygenation by Photosensitizer-Containing Cyanobacteria for Enhanced Photodynamic Therapy

Sustained tumor oxygenation is of critical importance during type-II photodynamic therapy (PDT), which depends on the intratumoral oxygen level for the generation of reactive oxygen species. Herein, the modification of photosynthetic cyanobacteria with the photosensitizer chlorin e6 (ce6) to form ce6-integrated photosensitive cells, termed ceCyan, is reported. Upon 660 nm laser irradiation, sustained photosynthetic O₂ evolution by the cyanobacteria and the immediate generation of reactive singlet oxygen species (¹O₂) by the integrated photosensitizer could be almost simultaneously achieved for tumor therapy using type-II PDT both in vitro and in vivo. This work contributes a conceptual while practical paradigm for biocompatible and effective PDT using hybrid microorganisms, displaying a bright future in clinical PDT by microbiotic nanomedicine.     

Gold Nanorod–Photosensitizer Complex Obtained by Layer‐by‐Layer Method for Photodynamic/Photothermal Therapy In Vitro

Gold nanorod (GNR)–photosensitizer (PS) complex was prepared using anionic PS (sodium salt of purpurin‐18) and cationic poly(allylamine hydrochloride) by layer‐by‐layer method, and was characterized by transmission electron microscopy, UV‐vis spectroscopy, and zeta potential. The GNR–PS complex is a promising agent for synergistic (photothermal and photodynamic) therapy (PTT/PDT), in which PTT generates heat as well as operates the PS release which maximize the following PDT activity. The combined dual therapy, PTT followed by PDT, exhibits a significantly higher photocytotoxicity result based on synergistic effect of hyperthermia from PTT as well as singlet oxygen photogeneration from PDT.     

Advanced Photosensitizer Activation Strategies for Smarter Photodynamic Therapy Beacons

Photodynamic therapy (PDT) is a clinical treatment in which a light‐absorbing drug called a photosensitizer (PS) is combined with light and molecular oxygen to generate cytotoxic singlet oxygen. PDT provides additional tissue selectivity compared to conventional chemotherapy as singlet oxygen is generated only in areas in which PS accumulates and that are simultaneously illuminated by a light source with sufficient irradiance and dose. Early PDT beacons built on this concept by adding an analyte‐responsive element that simultaneously turns on PDT and fluorescence, providing both an additional layer of selectivity and real‐time feedback of the PS′s activation state. More recent PDT beacons have expanded this idea, with new methods now available for sensing analytes, generating singlet oxygen, and reporting treatment status. In this Minireview, we consider developments in advanced activation strategies implemented in therapeutic and theranostic beacons.     

An Assembled Nanocomplex for Improving both Therapeutic Efficiency and Treatment Depth in Photodynamic Therapy

Photodynamic therapy (PDT) shows unique selectivity and irreversible destruction toward treated tissues or cells, but still has several problems in clinical practice. One is limited therapeutic efficiency, which is attributed to hypoxia in tumor sites. Another is the limited treatment depth because traditional photosensitizes are excited by short wavelength light (<700 nm). An assembled nano‐complex system composed of oxygen donor, two‐photon absorption (TPA) species, and photosensitizer (PS) was synthesized to address both problems. The photosensitizer is excited indirectly by two‐photon laser through intraparticle FRET mechanism for improving treatment depth. The oxygen donor, hemoglobin, can supply extra oxygen into tumor location through targeting effect for enhanced PDT efficiency. The mechanism and PDT effect were verified through both in vitro and in vivo experiments. The simple system is promising to promote two‐photon PDT for clinical applications.     

Regulation of singlet oxygen generation using single-walled carbon nanotubes

We have designed a novel photodynamic therapy (PDT) agent using protein binding aptamer, photosensitizer, and single-walled carbon nanotube (SWNT). The PDT is based on covalently linking a photosensitizer with an aptamer then wrapping onto the surface of SWNTs, such that the photosensitizer can only be activated by light upon target binding. We have chosen the human alpha-thrombin aptamer and covalently linked it with Chlorin e6 (Ce6), which is a second generation photosensitizer. Our results showed that SWNTs are great quenchers to singlet oxygen generation (SOG). In the presence of its target, the binding of target thrombin will disturb the DNA interaction with the SWNTs and cause the DNA aptamer to fall off the SWNT surface, resulting in the restoration of SOG. This study validated the potential of our design as a novel PDT agent with regulation by target molecules, enhanced specificity, and efficacy of therapeutic function, which directs the development of photodynamic therapy to be safer and more selective.     

A Smart Photosensitizer–Manganese Dioxide Nanosystem for Enhanced Photodynamic Therapy by Reducing Glutathione Levels in Cancer Cells

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species to kill cancer cells. However, a high concentration of glutathione (GSH) is present in cancer cells and can consume reactive oxygen species. To address this problem, we report the development of a photosensitizer–MnO₂ nanosystem for highly efficient PDT. In our design, MnO₂ nanosheets adsorb photosensitizer chlorin e6 (Ce6), protect it from self‐destruction upon light irradiation, and efficiently deliver it into cells. The nanosystem also inhibits extracellular singlet oxygen generation by Ce6, leading to fewer side effects. Once endocytosed, the MnO₂ nanosheets are reduced by intracellular GSH. As a result, the nanosystem is disintegrated, simultaneously releasing Ce6 and decreasing the level of GSH for highly efficient PDT. Moreover, fluorescence recovery, accompanied by the dissolution of MnO₂ nanosheets, can provide a fluorescence signal for monitoring the efficacy of delivery.     

Reversible hydrocarbon/perfluorocarbon phase-switching of [Ru(bipy)3]2+ driven by supramolecular heteromeric fluorous carboxylate-carboxylic acid H-bond interactions

The Ru(bipy)(3) dication is efficiently and reversibly transferred into perfluorocarbons due to the formation of a highly fluorophillic hydrogen-bonded fluorous carboxylate-carboxylic acid counter-anion, whilst retaining key luminescence and photosensitizer characteristics, for example in singlet oxygen production.     

Advances in Management of Bladder Cancer—The Role of Photodynamic Therapy

Photodynamic therapy (PDT) is a non-invasive and modern form of therapy. It is used in the treatment of non-oncological diseases and more and more often in the treatment of various types of neoplasms in various locations including bladder cancer. The PDT method consists of local or systemic application of a photosensitizer, i.e., a photosensitive compound that accumulates in pathological tissue. Light of appropriate wavelength is absorbed by the photosensitizer molecules, which in turn transfers energy to oxygen or initiates radical processes that leads to selective destruction of diseased cells. The technique enables the selective destruction of malignant cells, as the photocytotoxicity reactions induced by the photosensitizer take place strictly within the pathological tissue. PDT is known to be well tolerated in a clinical setting in patients. In cited papers herein no new safety issues were identified. The development of anti-cancer PDT therapies has greatly accelerated over the last decade. There was no evidence of increased or cumulative toxic effects with each PDT treatment. Many modifications have been made to enhance the effects. Clinically, bladder cancer remains one of the deadliest urological diseases of the urinary system. The subject of this review is the anti-cancer use of PDT, its benefits and possible modifications that may lead to more effective treatments for bladder cancer. Bladder cancer, if localized, would seem to be a good candidate for PDT therapy since this does not involve the toxicity of systemic chemotherapy and can spare normal tissues from damage if properly carried out. It is clear that PDT deserves more investment in clinical research, especially for plant-based photosensitizers. Natural PS isolated from plants and other biological sources can be considered a green approach to PDT in cancer therapy. Currently, PDT is widely used in the treatment of skin cancer, but numerous studies show the advantages of related therapeutic strategies that can help eliminate various types of cancer, including bladder cancer. PDT for bladder cancer in which photosensitizer is locally activated and generates cytotoxic reactive oxygen species and causing cell death, is a modern treatment. Moreover, PDT is an innovative technique in oncologic urology.     

The impact of complement activation on tumor oxygenation during photodynamic therapy

The response to photodynamic therapy (PDT) mediated by photosensitizer Photofrin was examined with Lewis lung carcinomas growing in either complement-proficient C57BL/6 (B6) or complement-deficient complement C3 knockout (C3KO) mice. The results reveal that Photofrin-PDT was more effective in attaining cures of tumors in C3KO than in B6 hosts. Colony-forming ability of cells from tumors excised immediately after Photofrin-PDT confirmed that the direct cell killing effect was more pronounced in C3KO than in B6 hosts. In contrast, PDT mediated by photosensitizer benzoporphyrin derivative (BPD) produced higher cure rates of tumors in B6 hosts than those in C3KO hosts. Determination of tumor C3 levels by ELISA showed that Photofrin-PDT induced markedly more pronounced complement activation than BPD-PDT. Measurements of tumor oxygen tension immediately after PDT by Eppendorf pO2 histograph showed that Photofrin-PDT induced a marked decline in the oxygenation of tumors growing in B6 mice that was much less pronounced in C3KO hosts. With BPD-PDT the oxygen tensions in tumors in B6 and C3KO hosts decreased to a similar extent. This study indicates that complement activation in PDT-treated tumors that varies with different photosensitizers is an important determinant of tumor oxygen limitation effects directly associated with photodynamic action.     

肿瘤光动力治疗临床应用的光敏剂及其研究概况

光动力治疗是一种非侵蚀性并具有一定靶向性的肿瘤治疗新方法。 光动力治疗需要光敏剂、光和氧结合产生光动力反应。 光敏剂是光动力治疗的关键和物质基础。 本文概括介绍了已上市的和已被批准进入临床试验中的光敏剂,并根据其分子的骨架结构,将其分为分卟啉类、二氢卟吩（叶绿素）类和菌绿素/酞菁三类。 同时从理想光敏剂应具备特点出发,探讨了研究中的光敏剂和光动力治疗的发展前景。     

Chemiluminescence and Bioluminescence as an Excitation Source in the Photodynamic Therapy of Cancer: A Critical Review

Photodynamic therapy (PDT) of cancer is known for its limited number of side effects, and requires light, oxygen and photosensitizer. However, PDT is limited by poor penetration of light into deeply localized tissues, and the use of external light sources is required. Thus, researchers have been studying ways to improve the effectiveness of this phototherapy and expand it for the treatment of the deepest cancers, by using chemiluminescent or bioluminescent formulations to excite the photosensitizer by intracellular generation of light. The aim of this Minireview is to give a précis of the most important general chemi‐/bioluminescence mechanisms and to analyze several studies that apply them for PDT. These studies have demonstrated the potential of utilizing chemi‐/bioluminescence as excitation source in the PDT of cancer, besides combining new approaches to overcome the limitations of this mode of treatment.     

Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy

Photodynamic therapy (PDT) is a promising new treatment modality for several diseases, most notably cancer. In PDT, light, O2, and a photosensitizing drug are combined to produce a selective therapeutic effect. Lately, there has been active research on new photosensitizer candidates, because the most commonly used porphyrin photosensitizers are far from ideal with respect to PDT. Finding a suitable photosensitizer is crucial in improving the efficacy of PDT. Recent synthetic activity has created such a great number of potential photosensitizers for PDT that it is difficult to decide which ones are suitable for which pathological conditions, such as various cancer species. To facilitate the choice of photosensitizer, this review presents a thorough survey of the photophysical and chemical properties of the developed tetrapyrrolic photosensitizers. Special attention is paid to the singlet-oxygen yield (PhiDelta) of each photosensitizer, because it is one of the most important photodynamic parameters in PDT. Also, in the survey, emphasis is placed on those photosensitizers that can easily be prepared by partial syntheses starting from the abundant natural precursors, protoheme and the chlorophylls. Such emphasis is justified by economical and environmental reasons. Several of the most promising photosensitizer candidates are chlorins or bacteriochlorins. Consequently, chlorophyll-related chlorins, whose PhiDelta have been determined, are discussed in detail as potential photosensitizers for PDT. Finally, PDT is briefly discussed as a treatment modality, including its clinical aspects, light sources, targeting of the photosensitizer, and opportunities.     

PEGylated calix[4]arene as a carrier for a Bodipy-based photosensitizer

Heavy atom substituted Bodipy compounds, unlike the parent chromophore, undergo rapid intersystem crossing to generate singlet oxygen, which is the primary cytotoxic agent exploited in PDT. In this work, we show that an organic soluble calix[4]arene can be functionalized by Knoevenagel reaction and then converted into an amphiphilic photosensitizer in a few steps. In addition to generating a potentially useful photosensitizer, the sequence of reactions is the first use of a Bodipy dye as a chromophoric/fluorogenic label without the typical reactive functional groups.     

Functional organic nanoparticles for photodynamic therapy

In recent years, cancer has been one of the leading causes of death in the world. Much effort has been devoted to developing cancer treatments. Photodynamic therapy (PDT) is a noninvasive therapeutic modality by combining the light of a specific wavelength, a photosensitizer (PS) and oxygen, which has been widely applied for the treatment of cancers. However, the application of PDT in clinic is greatly limited due to lack of tumor selectivity and often causing skin photosensitivity. The use of organic nanoparticles (NPs) as an advanced technology in the field of PDT shows a great promise to overcome these shortcomings. Therefore, in this review, we summarize several functional organic NPs as PS carriers that have been developed to enhance the efficacy of PDT against cancers.