Supramolecular agents for combination of photodynamic therapy and other treatments

Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from “always on” photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.

This review provides a summary of important research progress on supramolecular systems that can be used to combine photodynamic therapy (PDT) with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT.     

Photodynamic therapy in head and neck surgery

The results of a clinical study of photodynamic therapy (PDT) on early stage cancer in head and neck surgery are presented in this report. 30 patients with T1 malignancies of the face and oropharynx have been treated primarily with PDT. After the longest follow up of 14 months two patients revealed recurrence of the disease or residual tumor, two patients have been retreated because of residual dysplastic cells in the control biopsy, and all other patients stay histologically proven free of disease. Hence, PDT appears to be a promising cancer treatment for different histological tumors that penetrate the host tissue definitely less than a laser beam of 630 nm, which is the appropriate wavelength for PDT. Deeper-penetrating malignomas may be accessable for PDT using insertable filters when applying interstitial laser light.     

Photodynamic Therapy for Gastrointestinal Cancer

The clinical application of photodynamic therapy (PDT) for gastrointestinal (GI) neoplastic lesions has been developed with appreciation for the great efforts and kind support of Dr. Tom Dougherty and his followers’ contributions. There are several published studies on clinical PDT in the field of GI oncology. Esophageal cancer was one of the first clinical indications for PDT that was approved as an endoscopic procedure in both the United States and Japan. PDT was initially used as a palliative local treatment for patients with obstructive esophageal cancer. PDT is also indicated for eradicative therapy for dysplastic Barret’s esophagus, which is the precursor state of esophageal adenocarcinoma, with the support of level one evidence. In Japan, PDT was approved as a curative treatment for superficial esophageal carcinoma lesions, which are difficult to treat with endoscopic resection. Further, PDT using second-generation photosensitizers is approved for early local failure after radiotherapy, for which treatment with other modalities is difficult. PDT has also been assessed in other GI cancers, including gastric cancer, biliary cancer and pancreatic cancer. In this review, we overview the history and state of PDT for GI cancer.     

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.     

Rhodium Nanoparticles as a Novel Photosensitizing Agent in Photodynamic Therapy against Cancer

Photodynamic therapy (PDT) is a promising alternative treatment for different types of cancer due to its high selectivity, which prevents healthy tissues from being damaged. The use of nanomaterials in PDT has several advantages over classical photosensitizing agents, due to their unique properties and their capacity for functionalization. Especially interesting is the use of metallic nanoparticles, which are capable of absorbing electromagnetic radiation and either transferring this energy to oxygen molecules for the generation of reactive oxygen species (ROS) or dissipating it as heat. Although previous reports have demonstrated the capacity of Rh derivatives to serve as anti-tumor drugs, to the best of our knowledge there have been no studies on the potential use of small-sized Rh nanoparticles as photosensitizers in PDT. In this study, 5 nm Rh nanoparticles have been synthesized and their potential in PDT has been evaluated. The results show that treatment with Rh nanoparticles followed by NIR irradiation induces apoptosis in cancer cells through a p53-independent mechanism.     

Programming DNA Nanoassembly for Enhanced Photodynamic Therapy

Photodynamic therapy (PDT) has extraordinary promise for the treatment of many cancers. However, its clinical progress is impaired by the intrinsic hypoxic tumor microenvironment that limits PDT efficacy and the safety concern associated with biological specificity of photosensitizers or vehicles. Now it is demonstrated that rationally designed DNA nanosponges can load and delivery photosensitizer effectively, target tumor precisely, and relieve hypoxia‐associated resistance remarkably to enhance the efficacy of PDT. Specifically, the approach exhibits a facile assembly process, provides programmable and versatile nanocarriers, and enables robust in vitro and in vivo anti‐cancer efficacy with excellent biosafety. These findings represent a practical and safe approach by designer DNA nanoassemblies to combat cancer effectively and suggest a powerful strategy for broad biomedical application of PDT.     

酞菁配合物的结构与其光动力抗癌活性

光动力治疗是一种正在发展中的治疗癌症的新方法.主要是利用抗癌光敏剂可优先在 肿瘤组织中富集的特性和随后在适当波长的光照下所引发的光敏化反应来杀死癌肿瘤.自198 5年以来,酞菁配合物作为抗癌光敏剂的研究越来越引人注目. 此文在总结51篇参考文献的 基础上,提出了酞菁配合物的结构与其光动力抗癌活性的某些相关性,着重讨论了中心离子 、环取代基、轴向配体对光动力活性和相关物化性质的影响.得出的一个主要的结论是两亲 性酞菁是极具潜力的光敏剂.     

Tailoring photosensitive ROS for advanced photodynamic therapy

Photodynamic therapy (PDT) has been considered a noninvasive and cost-effective modality for tumor treatment. However, the complexity of tumor microenvironments poses challenges to the implementation of traditional PDT. Here, we review recent advances in PDT to resolve the current problems. Major breakthroughs in PDTs are enabling significant progress in molecular medicine and are interconnected with innovative strategies based on smart bio/nanomaterials or therapeutic insights. We focus on newly developed PDT strategies designed by tailoring photosensitive reactive oxygen species generation, which include the use of proteinaceous photosensitizers, self-illumination, or oxygen-independent approaches. While these updated PDT platforms are expected to enable major advances in cancer treatment, addressing future challenges related to biosafety and target specificity is discussed throughout as a necessary goal to expand the usefulness of PDT.Subject terms: Biological therapy, Biosensors     

Recent Photosensitizer Developments,Delivery Strategies and Combination-based Approaches for Photodynamic Therapy†

Photodynamic therapy of cancer (PDT) is a therapeutic technique, minimally invasive, which is currently used to treat cancerous lesions and tumors that have been in the spotlight for its potential over the recent decades. Nonetheless, PDT still needs further development to become a first-option treatment for patients. This review compiles recent progress in several aspects of the current research in the constantly growing area of PDT to overcome the main challenges as an attempt to serve as a guide and reference for newcomers into this research area. This review has been prepared to highlight the use of chemical modifications on photosensitizers to improve their solubility, photostability, selectivity and phototoxicity. Additionally, the use of liposomes and cavitands as drug delivery systems to aid in the biodistribution and bioaccumulation of photosensitizers is presented. Also, the combination of PDT with chemotherapy or immunotherapy as an option to boost and improve treatment outcomes is discussed. Finally, the inhibition of antioxidant enzymes as a strategy for a synergistic effect to ameliorate the performance of the photosensitizers in PDT is presented as an alternative for future researchers.     

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.     

Structure and Biodistribution Relationships of Photodynamic Sensitizers*

Abstract— Photodynamic therapy (PDT) has, during the last quarter century, developed into a fully fledged biomedical field with its own association, the International Photodynamic Association (IPA) and regular conferences devoted solely to this topic. Recent approval of the first PDT sensitizer, Photofrin® (porfimer sodium), by health boards in Canada, Japan, the Netherlands and United States for use against certain types of solid tumors represents, perhaps, the single most significant indicator of the progress of PDT from a laboratory research concept to clinical reality. The approval of Photofrin® will undoubtedly encourage the accelerated development of second-generation photo-sensitizers, which have recently been the subject of intense study. Many of these second-generation drugs show significant differences, when compared to Photofrin®, in terms of treatment times postinjection, light doses and drug doses required for optimal results. These differences can ultimately be attributed to variations in either the quantum efficiency of the photosensitizer in situ, which is in turn affected by aggregation state, localized concentration of endogenous quenchers and primary photophysics of the dye, or the intratumoral and intracellular localization of the photosensitizer at the time of activation with light. The purpose of this review is to bring together data relating to the biodistribution and pharmacokinetics of second-generation sensitizers and attempt to correlate this with structural and electronic features of these molecules. As this requires a clear knowledge of photosensitizer structure, only chemically well-characterized compounds are included, e.g. Photofrin® and crude sulfonated phthal-ocyanines have been excluded as they are known to be complex mixtures. Nonporphyrin-based photosensitizers, e.g. rose bengal and the hypericins, have also been omitted to allow meaningful comparisons to be made between different compounds. As the intracellular distribution of photosensitizers to organelles and other subcellular structures can have a large effect on PDT efficacy, a section will be devoted to this topic.     

Redaporfin Development for Photodynamic Therapy and its Combination with Glycolysis Inhibitors†

Photodynamic therapy (PDT) remains an underutilized treatment modality in oncology. Many efforts have been dedicated to the development of better photosensitizers, better formulations and delivery methods, rigorous planning of light dose distribution in tissues, mechanistic insight, improvement of treatment protocols and combinations with other therapeutic agents. Hopefully, progress in all these fields will eventually expand the use of PDT. Here we offer a brief review of our own contribution to the development of a photosensitizer for PDT – redaporfin – currently in Phase II clinical trials, and present data on its combination with two glycolysis inhibitors: 2-deoxyglucose and 3-bromopyruvate. We show that 3-bromopyruvate is more cytotoxic to a carcinoma cell line (CT26) than to a normal fibroblast (3T3) cell line, and that this selectivity is maintained in the in vitro combination with redaporfin-PDT. This combination was investigated in BALB/c mice with large subcutaneous CT26 tumors and it is shown that the cure rate in the combination is higher (33% cures) than in PDT (11% cures) or in 3-bromopyruvate (no cures) alone. The combination of redaporfin-PDT with 3-bromopyruvate illustrates the potential of combination therapies and how PDT benefits can be enhanced by systemic drugs with complementary targets.     

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.     

Oesophageal cancer treated by photodynamic therapy alone or followed by radiation therapy

Photodynamic therapy (PDT) with porphyrins and red light is receiving increasing attention in the management of malignant tumours. At present PDT is primarily indicated for the treatment of superficial or early-stage lesions. At the Department of Radiotherapy and the First Institute of Surgery in Padova (Italy) more than 150 cases of tumours of different types have been treated using this technique. This paper briefly describes 21 cases of superficial oesophageal cancer. A complete response was observed in 11 of 21 cases. Radiation therapy appeared to be very effective as a salvage treatment of non-response patients.     

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.     

Recent Progress in Boosted PDT Induced Immunogenic Cell Death for Tumor Immunotherapy

With the rapid development of materials science,photosensitive materials have been widely used in the field of immunogenic cell death(ICD),which was on account of the reactive oxygen species(ROS)generation by photosensitizer under light irradiation inducing cellular oxidative stress during the dying of cells.Considerable researches related to photodynamic therapy(PDT)induced ICD were conducted and exhibited brilliant performance in cancer immunotherapy.Herein,a variety of different strategies for PDT induced ICD have been summarized and discussed to provide researchers more inspiration for cancer immunotherapy.     

Influence of Intra-articular Neutrophils on the Effects of Photodynamic Therapy for Murine MRSA Arthritis

Although there have been some reports about the cytotoxic effects of photodynamic therapy (PDT) on multidrug-resistant bacteria, there have been few reports in which favorable results of PDT on a local infection site are described. This study aimed to verify the hypothesis that the low efficacy of PDT on a local infection site is due to the cytotoxic effect of PDT on leukocytes. PDT using Photofrin^® exerted significant cytotoxicity for cultured methicillin-resistant Staphylococcus aureus (MRSA). Nevertheless, this therapeutic modality was not effective for a murine MRSA arthritis model. Approximately 30% of intra-articular leukocytes, mainly neutrophils, died immediately after PDT, and a further decrease in the number of intra-articular leukocytes and atrophy of the synovial tissue were seen 24 h after PDT. Isolated peripheral neutrophils showed significant affinity for Photofrin^® and showed significant morphological damage, resulting in cell death, when they were subject to PDT using Photofrin^®. These results indicate that intra-articular neutrophils have an influence on the effects of PDT for MRSA arthritis.     

Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy

Photodynamic therapy (PDT) is now a well-recognized modality for the treatment of cancer. While PDT has developed progressively over the last century, great advances have been observed in the field in recent years. The concept of dual selectivity of PDT agents is now widely accepted due to the relative specificity and selectivity of PDT along with the absence of harmful side effects often encountered with chemotherapy or radiotherapy. Traditionally, porphyrin-based photosensitizers have dominated the PDT field but these first generation photosensitizers have several disadvantages, with poor light absorption and cutaneous photosensitivity being the predominant side effects. As a result, the requirement for new photosensitizers, including second generation porphyrins and porphyrin derivatives as well as third generation photosensitizers has arisen, with the aim of alleviating the problems encountered with first generation porphyrins and improving the efficacy of PDT. The investigation of nonporphyrin photosensitizers for the development of novel PDT agents has been considerably less extensive than porphyrin-based compounds; however, structural modification of nonporphyrin photosensitizers has allowed for manipulation of the photochemotherapeutic properties. The aim of this review is to provide an insight into PDT photosensitizers clinically approved for application in oncology, as well as those which show significant potential in ongoing preclinical studies.     

Conjugated Polymer Nanomaterials for Phototherapy of Cancer

Due to the excellent properties including high specificity,low side-effect and good biocompatibility,conjugated polymer nanomaterials have been served as efficient anticancer reagents in die past decades.According to the developed anticancer systems based on conjugated polymer nanomaterials,it could be summarized into three main cancer therapy strategies:photodynamic therapy(PDT),photothermal therapy(PTT)and combination therapy.In this mini review,we provide a brief introduction to three different cancer therapy modes,their mechanisms and potential biological applications.Furthermore,some perspectives on the further development of conjugated polymer nanomaterials are proposed in the territory of anticancer precision medicine.     

Optimization of photodynamic therapy response by survivin gene knockdown in human metastatic breast cancer T47D cells

Photodynamic therapy (PDT) leads to the generation of cytotoxic oxygen species that appears to stimulate several different signaling pathways, some of which lead to cell death, whereas others mediate cell survival. In this context, we observed that PDT mediated by methyl-5-aminolevulinic acid as the photosensitizer resulted in over-expression of survivin, a member of the inhibitor of apoptosis (IAP) family that correlates inversely with patient prognosis. The role of survivin in resistance to anti-cancer therapies has become an area of intensive investigation. In this study, we demonstrate a specific role for survivin in modulating PDT-mediated apoptotic response. In our experimental system, we use a DNA vector-based siRNA, which targets exon-1 of the human survivin mRNA (pSil_1) to silence survivin expression. Metastatic T47D cells treated with both pSil_1 and PDT exhibited increased apoptotic indexes and cytotoxicity when compared to single-agent treated cells. The treatment resulted in increased PARP and caspase-3 cleavage, a decrease in the Bcl-2/Bak ratio and no participation of heat shock proteins. In contrast, the overexpression of survivin by a survivin-expressed vector increased cell viability and reduced cell death in breast cancer cells treated with PDT. Therefore, our data suggest that combining PDT with a survivin inhibitor may attribute to a more favorable clinical outcome than the use of single-modality PDT.