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Non-Porphyrin Dyes Used as Photosensitizers in Photodynamic Therapy
Abstract
Photodynamic therapy (PDT) is the process of applying a light source onto a photosensitive chemical in order to produce reactive oxygen species. This process has gained prevalence within the oncology space as a potential treatment strategy, as PDT allows for accumulation of the photosensitive chemical at the site of the malignancy; therefore, when the reactive oxygen species are formed, they can to be cytotoxic towards the malignant cells. This treatment is especially appealing as an oncologic therapy since physicians are able to localize the light source in the area of the cancer cells. Without the light source, the photosensitizer will not enter its excited state to form reactive oxygen species, thus reducing the incidence of systemic adverse effects. This review article highlights the in vitro and in vivo results of second-generation non-porphyrin agents such as the squaraine, xanthene, cyanine, anthraquinone, phenothiazine, borondipyrromethene (BODIPY) and aza-BODIPY dyes. Second-generation photosensitizers have demonstrated promise in PDT as a result of their ability to have enhanced localization at the site of action due to tissue stability, absence of dark toxicity, and have the ability to be rapidly cleared from the body, among other advantages; however, literature has demonstrated both benefits and obstacles within each of the second-generation non-porphyrin dye treatment families. This article will also discuss some of the emerging therapies within this treatment strategy referred to as the third-generation PDT agents, following in particular the advancements made on the second-generation photosensitizers, and how advanced delivery systems influence the efficacy of the aforementioned second-generation non-porphyrin PDT dyes.
... It exhibited promising outcomes in individuals diagnosed with high-grade dysplasia linked to Barrett's esophagus, as well as esophageal and endobronchial cancer. 13 Despite being a novel therapeutic option in the field, the hematoporphyrin medication exhibited various drawbacks, such as chemical heterogeneity and limited penetration. 13 The specification of certain features for PSs suitable for PDT has evolved as advancements have been made from first-generation to modern PSs used in the treatment of various diseases. ...
... 13 Despite being a novel therapeutic option in the field, the hematoporphyrin medication exhibited various drawbacks, such as chemical heterogeneity and limited penetration. 13 The specification of certain features for PSs suitable for PDT has evolved as advancements have been made from first-generation to modern PSs used in the treatment of various diseases. 14 In this regard, the intricate natural amalgamation of oligomeric hematoporphyrin derivatives (HpDs), commonly referred to as HpD, is recognized as a constituent of the initial generation of PSs. 15 The utilization of PDT using HpD was implemented during the 1970s for the purpose of treating bladder cancer. ...
... In addition, third-generation PDT utilizes carriers such as liposomes, micelles, and nanoparticles to enhance the accumulation of PS at specific targeted sites. 13 The rapid advancement of nanotechnology has led to the emergence of several nanomaterials that can serve as nano-PSs or PS carriers. 16 At present, there exist several clinically approved PSs that are commonly utilized. ...
Light is an efficient technique that has a significant influence on contemporary medicine. Photodynamic therapy (PDT), which involves the combined action of photosensitizers (PSs) , oxygen and light, has emerged as a therapeutically promising method for treating a broad variety of solid tumors and infectious diseases. PDT is minimally invasive, has few side effects, lightens scars, and reduces tissue loss while preserving organ structure and function. In particular, PDT has a high healing potential for wounds (PDT stimulates wound healing by enhancing re-epithelialization, promoting angiogenesis as well as modulating skin homeostasis). Wound healing involves interactions between many different processes, including coagulation, inflammation, angiogenesis, cellular migration and proliferation. Poor wound healing with diabetes or extensive burns remains a difficult challenge. This review emphasizes PDT as a potential research field and summarizes PDT's role in wound healing, including normal wounds, chronic wounds, aging wounds.
... Non-porphyrin-based PSs belong to the second generation of PSs. When compared with porphyrin-based PSs, their application in cancer treatment is considerably behind Squaraines, cyanines, xanthenes, anthraquinones, phenothiazines, curcuminoids, or bo ron-dipyrromethene (BODIPY) are examples of dyes or natural compounds used in can cer PDT [154]. Some of these chemical structures are shown in Figure 10. ...
... When compared with porphyrin-based PSs, their application in cancer treatment is considerably behind. Squaraines, cyanines, xanthenes, anthraquinones, phenothiazines, curcuminoids, or borondipyrromethene (BODIPY) are examples of dyes or natural compounds used in cancer PDT [154]. Some of these chemical structures are shown in Figure 10. ...
... BODIPY is photochemically stable and has good absorption properties in the NIR spectral range. Furthermore, recent research has investigated the integration of metals into the BODIPY core, providing further options for exploration and improvement of its properties [154]. BODIPY derivatives and their NP complexes have gained significant attention owing to such properties as ease of structural synthesis, high photostability, rapid clearing in normal tissues, and good photo-dark toxicity ratio [184]. ...
Malignant melanoma poses a significant global health burden. It is the most aggressive and lethal form of skin cancer, attributed to various risk factors such as UV radiation exposure, genetic modifications, chemical carcinogens, immunosuppression, and fair complexion. Photodynamic therapy is a promising minimally invasive treatment that uses light to activate a photosensitizer, resulting in the formation of reactive oxygen species, which ultimately promote cell death. When selecting photosensitizers for melanoma photodynamic therapy, the presence of melanin should be considered. Melanin absorbs visible radiation similar to most photosensitizers and has antioxidant properties, which undermines the reactive species generated in photodynamic therapy processes. These characteristics have led to further research for new photosensitizing platforms to ensure better treatment results. The development of photosensitizers has advanced with the use of nanotechnology, which plays a crucial role in enhancing solubility, optical absorption, and tumour targeting. This paper reviews the current approaches (that use the synergistic effect of different photosensitizers, nanocarriers, chemotherapeutic agents) in the photodynamic therapy of melanoma.
... Generally, light with a long wavelength is chosen, because it will have enough energy to start the formation of singlet oxygen [13]. The first PDT sensitizer to receive FDA (Federal Drug Administration) approval, Photofrin™, was introduced to the market in 1995 and demonstrated encouraging results in patients with high-grade dysplasia associated with Barrett's esophagus, esophageal, and endobronchial cancer [15]. Although new at the time in this therapeutic field, this hematoporphyrin medication had several shortcomings, including chemical heterogeneity and limited penetration [15]. ...
... The first PDT sensitizer to receive FDA (Federal Drug Administration) approval, Photofrin™, was introduced to the market in 1995 and demonstrated encouraging results in patients with high-grade dysplasia associated with Barrett's esophagus, esophageal, and endobronchial cancer [15]. Although new at the time in this therapeutic field, this hematoporphyrin medication had several shortcomings, including chemical heterogeneity and limited penetration [15]. ...
... Second-generation PS have a number of advantages over first-generation, including longer absorption wavelengths, the ability to be activated by near-infrared (NIR) light, greater depth of effect, high singlet oxygen quantum yield, an better tissue selectivity, as well as the ability to be quickly metabolized, which reduces the side effects [18]. Third-generation PS is distinguished by the combination of second-generation PS with specific components such as antibodies, carbohydrates, amino acids, or peptides or by encapsulating into carriers such as liposomes, micelles, and nanoparticles to increase PS accumulation at the specific targeted sites [15]. Multiple nanomaterials that can function as nano-PSs or PS carriers have emerged as a result of the rapid ongoing development of nanotechnology [18]. ...
Photodynamic therapy (PDT) is a noninvasive therapeutic approach that has been applied in
studies for the treatment of various diseases. In this context, PDT has been suggested as a new therapy
or adjuvant therapy to traditional cancer therapy. The mode of action of PDT consists of the generation
of singlet oxygen (1O2) and reactive oxygen species (ROS) through the administration of a compound
called photosensitizer (PS), a light source, and molecular oxygen (3O2). This combination generates
controlled photochemical reactions (photodynamic mechanisms) that produce ROS, such as singlet
oxygen (1O2), which can induce apoptosis and/or cell death induced by necrosis, degeneration of the
tumor vasculature, stimulation of the antitumor immune response, and induction of inflammatory
reactions in the illuminated region. However, the traditional compounds used in PDT limit its
application. In this context, compounds of biotechnological origin with photosensitizing activity in
association with nanotechnology are being used in PDT, aiming at its application in several types
of cancer but with less toxicity toward neighboring tissues and better absorption of light for more
aggressive types of cancer. In this review, we present studies involving innovatively developed PS
that aimed to improve the efficiency of PDT in cancer treatment. Specifically, we focused on the
clinical translation and application of PS of natural origin on cancer.
... They display valuable photophysical and optoelectronic properties, such as high quantum yields of fluorescence, small absorption and emission bandwidths, high stability at physiological pH values, and chemical inertness along with ample opportunities to modify a structure of the chromophoric BODIPY ligand and thus impart new properties to the system [6]. The BODIPY fluorescent dyes, being structural analogs of porphyrins, are widely used in biochemistry, biophysics, and biotechnology as fluorescent markers, and in medicine for imaging living cells and animals in preclinical research [7,8]. A number of reports are devoted to the structural modification of the BODIPY compounds aiming at improving and extending their application scope [9]. ...
... BNCT is a binary method for the treatment of cancer that is based on the selective absorption of the non-radioactive 10 B isotope in the tumor tissue followed by irradiation with low energy thermal neutrons. The 10 B(n,α) 7 Li reaction produces the energetic α particles and residual 7 Li nuclei (with the energies of 200 and 350 keV μm -1 , respectively) that have a cell killing effect within a 10 µm range (about one cell diameter) causing the lethal damage of the 10 B enriched tumor cells. Therefore, BNCT selectively destroys cancer cells without damaging the surrounding healthy tissue. ...
... BNCT is a binary method for the treatment of cancer that is based on the selective absorption of the non-radioactive 10 B isotope in the tumor tissue followed by irradiation with low energy thermal neutrons. The 10 B(n,α) 7 Li reaction produces the energetic α particles and residual 7 Li nuclei (with the energies of 200 and 350 keV μm -1 , respectively) that have a cell killing effect within a 10 µm range (about one cell diameter) causing the lethal damage of the 10 B enriched tumor cells. Therefore, BNCT selectively destroys cancer cells without damaging the surrounding healthy tissue. ...
A series of new carborane–BODIPY conjugates bearing succinimide–triazole or maleimide functional groups are prepared from synthetically available amino-substituted BODIPYs. The resulting compounds are characterized by UV–vis, IR, and NMR spectroscopy as well as mass spectrometry.
... Merocyanines raised hope for low-invasive lymphoma [98], leukemia [99] and neuroblastoma [100] treatments as they exhibited high specificity for cancer cells. The compounds are currently undergoing preclinical studies as a treatment for leukemia [99]. ...
... Merocyanines raised hope for low-invasive lymphoma [98], leukemia [99] and neuroblastoma [100] treatments as they exhibited high specificity for cancer cells. The compounds are currently undergoing preclinical studies as a treatment for leukemia [99]. The exceptional permeability of the MC540 dye to leukemic leukocytes and immature hemopoietic precursors led to its extensive analysis. ...
... Moreover, merocyanines, are especially worth mentioning for their unique immunoregulatory properties, namely, the ability to interact with lymphocytes [105]. Currently, merocyanines are in preclinical studies focused on treating leukemia [99]. ...
Photodynamic therapy (PDT) is a method of cancer treatment that leads to the disintegration of cancer cells and has developed significantly in recent years. The clinically used photosensitizers are primarily porphyrin, which absorbs light in the red spectrum and their absorbance maxima are relatively short. This review presents group of compounds and their derivatives that are considered to be potential photosensitizers in PDT. Cyanine dyes are compounds that typically absorb light in the visible to near-infrared-I (NIR-I) spectrum range (750–900 nm). This meta-analysis comprises the current studies on cyanine dye derivatives, such as indocyanine green (so far used solely as a diagnostic agent), heptamethine and pentamethine dyes, squaraine dyes, merocyanines and phthalocyanines. The wide array of the cyanine derivatives arises from their structural modifications (e.g., halogenation, incorporation of metal atoms or organic structures, or synthesis of lactosomes, emulsions or conjugation). All the following modifications aim to increase solubility in aqueous media, enhance phototoxicity, and decrease photobleaching. In addition, the changes introduce new features like pH-sensitivity. The cyanine dyes involved in photodynamic reactions could be incorporated into sets of PDT agents.
... Nonporphyrin PS such as distyryl boron dipyrromethene (BODIPY), methylene blue, toluidine blue, cyanine, fluorescein and rhodamine, among others, have also been derivatized (48). A wide range of BODIPYs have been reported in the literature for PDT applications. ...
... Chemical structures of Nonporphyrin derivatives. Summarized for references(28,29,34,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). ...
Photodynamic therapy of cancer (PDT) is a therapeutic technique, minimally invasive, which is currently used to treat cancerous lesions and tumors that has 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 are presented. Also, the combination of PDT with chemotherapy or immunotherapy as an option to boost and improve treatment outcomes are discussed. Finally, the inhibition of antioxidant enzymes as a strategy for a synergistic effect to ameliorate the performance of the photosensitizers in PDT are presented as an alternative for future researchers.
... PDT consists of the annihilation of several cancers, through an incident visible light (VL), which sensitizes a drug called photosensitizer (PS), causing damage to living tissue (cancer cells), occurring the production of oxygen in this process [9][10][11]. For more details on the molecular basis, photosensitizers in medicine, the reaction mechanism, and the various modifications in PDT can be found in the literature [12][13][14][15][16][17][18]. The photosensitizers most used in PDT are the drug families: Porphyrin, Chlorin and Dyes [19]. ...
... The irradiation times were: 5,10,15,20,25,30,35,40,45, and 50 min, which correspond to the doses: 0.60, 1.20, 1.80, 2.40, 3.00, 3.60, 4.20, 4.80, 5.40, and 6.00 kJ/ cm 2 , respectively. ...
Photodynamic therapy has been recently studied, bringing innovations regarding the reduction of exposure time to light by the patient. This work aimed to investigate the feasibility of using Coutarea hexandra (Jacq.) K. Schum (CHS) as a detector in photodynamic therapy measurements. For this, an irradiator containing a blue LED bulb lamp was utilized. The CHS samples were irradiated with ten doses from 0.60 up to 6.0 kJ/cm2, and six concentrations were prepared (1, 2, 3, 4, 5, and 6 mg/ml) for the CHS detector samples. After irradiation, the detector samples were evaluated using UV–Vis spectrophotometry. The results showed the behavior of the CHS detector with doses and concentrations, its sensitivity, and its linearity was also evaluated both by Wavelength Method (WM) and the Kernel Principal Component Regression (KPCR) Statistical Method. The values obtained indicate that this method can be applied to the CHS sample detector. In conclusion, the CHS is a promising detector in the field of photodynamic therapy.
... Several studies have demonstrated PDT as a viable treatment option against earlystage esophageal dysplasia, lung, HNSC, anal, bladder, peritoneal ovarian, and non-melanoma skin cancers (NMSC) [18]. Despite the encouraging clinical results of PDT, some PSs themselves have been reported to have prolonged skin phototoxicity, low lesion selectivity, hydrophobic nature, aggregation proneness, poor bioavailability, high-dose requirements, adverse side effects, off-targeting, and development of drug resistance [19][20][21]. The use of drug delivery systems (DDS) to overcome these shortcomings has been examined. ...
... Several studies have demonstrated PDT as a viable treatment option against earlystage esophageal dysplasia, lung, HNSC, anal, bladder, peritoneal ovarian, and nonmelanoma skin cancers (NMSC) [18]. Despite the encouraging clinical results of PDT, some PSs themselves have been reported to have prolonged skin phototoxicity, low lesion selectivity, hydrophobic nature, aggregation proneness, poor bioavailability, high-dose requirements, adverse side effects, off-targeting, and development of drug resistance [19][20][21]. The use of drug delivery systems (DDS) to overcome these shortcomings has been examined. ...
Photodynamic therapy is one of the more unique cancer treatment options available in today’s arsenal against this devastating disease. It has historically been explored in cutaneous lesions due to the possibility of focal/specific effects and minimization of adverse events. Advances in drug delivery have mostly been based on biomaterials, such as liposomal and hybrid lipoidal vesicles, nanoemulsions, microneedling, and laser-assisted photosensitizer delivery systems. This review summarizes the most promising approaches to enhancing the photosensitizers’ transdermal delivery efficacy for the photodynamic treatment for cutaneous pre-cancerous lesions and skin cancers. Additionally, discussions on strategies and advantages in these approaches, as well as summarized challenges, perspectives, and translational potential for future applications, will be discussed.
... Second-generation PS have notable features compared to firstgeneration PS [34,35]. First, they exhibit superior chemical purity and singlet oxygen generation rates, making them more effective in PDT. ...
Cancer has emerged as a formidable challenge in the 21st century, impacting society, public health, and the economy. Conventional cancer treatments often exhibit limited efficacy and considerable side effects, particularly in managing the advanced stages of the disease. Photodynamic therapy (PDT), a contemporary non-invasive therapeutic approach, employs photosensitizers (PS) in conjunction with precise light wavelengths to selectively target diseased tissues, inducing the generation of reactive oxygen species and ultimately leading to cancer cell apoptosis. In contrast to conventional therapies, PDT presents a lower incidence of side effects and greater precision in targeting. The integration of intelligent nanotechnology into PDT has markedly improved its effectiveness, as evidenced by the remarkable synergistic antitumor effects observed with the utilization of multifunctional nanoplatforms in conjunction with PDT. This paper provides a concise overview of the principles underlying PS and PDT, while also delving into the utilization of nanomaterial-based PDT in the context of cancer treatment.
... Concerning the photophysical processes of the photosensitizers, a particular wavelength of light is required for its absorption by the photosensitizer, so that it can transit from the ground single state (S 0 ) to the excited single state (S 1 or S 2 ). As previously mentioned, once in this state (typically defined as the S 1 state for almost all compounds), the molecule can transit to the excited triplet state (T 1 ) through the intersystem crossing or it can release the absorbed energy in the form of fluorescence, in an attempt to return to the relaxed ground state [19]. Alternatively, the molecule can also release this energy through non-radiative decay. ...
... Certain classes of non-porphyrin photosensitizers, such as boron complexes of dipyrromethenes (e.g., 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, abbreviated as BODIPY) and their aza-analogues, cyanines, anthraquinones, phenothiazines, and xanthene dyes, have also gained significant attention. This is mainly due to their ease of structural modification, enabling adjustment of the light absorption maximum towards the near-infrared (NIR) region [22]. Based on differences in chemical structure and characteristics, photosensitizers are classified into three generations ( Figure 5). ...
Over the past few decades, photodynamic therapy (PDT) has evolved as a minimally invasive treatment modality offering precise control over cancer and various other diseases. To address inherent challenges associated with PDT, researchers have been exploring two promising avenues: the development of intelligent photosensitizers activated through light-induced energy transfers, charges, or electron transfers, and the disruption of photosensitive bonds. Moreover, there is a growing emphasis on the bioorthogonal delivery or activation of photosensitizers within tumors, enabling targeted deployment and activation of these intelligent photosensitive systems in specific tissues, thus achieving highly precise PDT. This concise review highlights advancements made over the last decade in the realm of light-activated or bioorthogonal photosensitizers, comparing their efficacy and shaping future directions in the advancement of photodynamic therapy.
... This results in poor solubility in aqueous media and rapid clearance in blood circulation, severely compromising the therapeutic effectiveness of PDT. In this context, organic dyes, such as polymethine dyes (squaraine and cyanine dyes), represent a promising alternative to PS thanks to the higher selectivity, purity, and absorption at longer wavelengths compared to porphyrin-derived PS [18][19][20][21][22]. Indeed, both cyanine and squaraine dyes have shown excellent light-induced toxicity on different types of tumors. ...
Photodynamic therapy is a non-invasive therapeutic strategy that combines external light with a photosensitizer (PS) to destroy abnormal cells. Despite the great progress in the development of new photosensitizers with improved efficacy, the PS’s photosensitivity, high hydrophobicity, and tumor target avidity still represent the main challenges. Herein, newly synthesized brominated squaraine, exhibiting intense absorption in the red/near-infrared region, has been successfully incorporated into Quatsome (QS) nanovesicles at different loadings. The formulations under study have been characterized and interrogated in vitro for cytotoxicity, cellular uptake, and PDT efficiency in a breast cancer cell line. The nanoencapsulation of brominated squaraine into QS overcomes the non-water solubility limitation of the brominated squaraine without compromising its ability to generate ROS rapidly. In addition, PDT effectiveness is maximized due to the highly localized PS loadings in the QS. This strategy allows using a therapeutic squaraine concentration that is 100 times lower than the concentration of free squaraine usually employed in PDT. Taken together, our results reveal the benefits of the incorporation of brominated squaraine into QS to optimize their photoactive properties and support their applicability as photosensitizer agents for PDT.
... 26 Other classes of photosensitizer include the fluorones, 27,28 azadipyrromethenes, 29,30 metal coordination complexes, 31,32 and cyanine dyes, 33 although of these only a few candidates have so far received approval for use in humans. 34,35 A significant current disadvantage in the implementation of photosensitizers based on conjugated chromophore molecules is their tendency to aggregate in aqueous media because of either general insolubility or enhancement of hydrophobic intermolecular interactions. 36 Aggregation typically causes deactivation of photosensitizers in vivo even if excellent 1 O 2 generation properties are found in vitro. ...
Chromophores that generate singlet oxygen (1O2) in water are essential to developing noninvasive disease treatments using photodynamic therapy (PDT). A facile approach for formation of stable colloidal nanoparticles of 1O2 photosensitizers, which exhibit aggregation enhanced 1O2 generation in water toward applications as PDT agents, is reported. Chromophore encryption within a fuchsonarene macrocyclic scaffold insulates the photosensitizer from aggregation induced deactivation pathways, enabling a higher chromophore density than typical 1O2 generating nanoparticles. Aggregation enhanced 1O2 generation in water is observed, and variation in molecular structure allows for regulation of the physical properties of the nanoparticles which ultimately affects the 1O2 generation. In vitro activity and the ability of the particles to pass through the cell membrane into the cytoplasm is demonstrated using confocal fluorescence microscopy with HeLa cells. Photosensitizer encryption in rigid macrocycles, such as fuchsonarenes, offers new prospects for the production of biocompatible nanoarchitectures for applications involving 1O2 generation.
... although antimicrobial activity has been reported with blue light [18], it barely penetrates 1 mm through the skin, while red light can reach 4-5 mm beneath the surface of skin and other tissues [19]; which limits the application of blue light and many efficient photosenstizers against deep localized infections e.g. Curcumin that is activated with blue light around 440 nm [20] and xanthenes, activated using green light [21]. To this end advances in nanotechnology can allow the use of photosenstizers activated in the visible region using photon upconversion; this is discussed later. ...
Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach to aid the fight against looming antibiotic resistance. aPDT harnesses the energy of light through photosenstizers to generate highly reactive oxygen species that can inactivate bacteria and fungi with no resistance. To date aPDT has shown great efficacy against microbes causing localized infections in the skin and the oral cavity. However, its wide application in clinical settings has been limited due to both physicochemical and biological challenges. Over the past decade nanomaterials have contributed to promoting photosensitizer performance and aPDT efficiency, yet further developments are required to establish accredited treatment options. In this review we discuss the challenges facing the clinical application of aPDT and the opportunities that nanotechnology may offer to promote the safety and efficiency of aPDT.
... However, their use has disadvantages and side effects, such as liver toxicity and skin reactions, a long half-life, and tissue bioaccumulation [19][20][21]. The advantages of natural source PS include high biocompatibility, as their cytotoxic potential is directed towards tumor cells, and being more environmentally sustainable [20,22]. Therefore, it is relevant to investigate new natural PS extracted from plants that can be used in PDT for cancer. ...
Background
Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to the treatment of cancer. The interaction between a photosensitizer (PS), ideal wavelength radiation and tissue molecular oxygen, triggers a series of photochemical reactions that are responsible for the production of reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells.
Objective
Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near infrared radiation, in tumor models.
Methods
A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, using inclusion, exclusion, and eligibility criteria, 25 eligible articles were included in this systematic review.
Results
CUR, whether in its free state, associated with metal complexes or other PS, and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters.
Conclusion
The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in the field of PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.
... Squaraines are characterized by sharp and intense absorption bands [20] and narrow emission bands with high extinction coefficients (ε ~ 10 5 [24,25]. Different reviews have been published reporting on squaraine dyes synthesis strategies [18,26] and potential applications [19,27,28] including photoconductivity, data storage, optical detection [29], solar cells [17], bioimaging [24,30], and photodynamic therapy [31][32][33][34]. ...
It has been proved that the effectiveness of photodynamic therapy (PDT) is closely related to the intrinsic features of the photosensitizer (PS). Over the recent years, several efforts have been devoted to the discovery of novel and more efficient photosensitizers showing higher efficacy and lower side effects. In this context, squaraine and cyanine dyes have been reported to potentially overcome the drawbacks related to the traditional PSs. In fact, squaraines and cyanines are characterized by sharp and intense absorption bands and narrow emission bands with high extinction coefficients typically in the red and near-infrared region, good photo and thermal stability and a strong fluorescent emission in organic solvents. In addition, biocompatibility and low toxicity make them suitable for biological applications. Despite these interesting intrinsic features, their chemical instability and self-aggregation properties in biological media still limit their use in PDT. To overcome these drawbacks, the self-assembly and incorporation into smart nanoparticle systems are forwarded promising approaches that can control their physicochemical properties, providing rational solutions for the limitation of free dye administration in the PDT application. The present review summarizes the latest advances in squaraine and cyanine dyes for PDT application, analyzing the different strategies, i.e.the self-assembly and the incorporation into nanoparticles, to further enhance their photochemical properties and therapeutic potential. The in vivo assessments are still limited, thus further delaying their effective application in PDT.
Graphical abstract
... It is a compound from the xanthan group that is anionic and hydrophilic, characterized by the ability to absorb light in the NIR range. Thus far, it has been used in diagnosis of liver diseases and as a candidate for a drug for melanoma using the sono-photodynamic therapy approach (SPDT) [138]. Ambiguous results from studies on PACT using 10 against fungi were obtained. ...
Superficial and systemic fungal infections are essential problems for the modern health care system. One of the challenges is the growing resistance of fungi to classic antifungals and the constantly increasing cost of therapy. These factors force the scientific world to intensify the search for alternative and more effective methods of treatment. This paper presents an overview of new fungal inactivation methods using Photodynamic Antimicrobial Chemotherapy (PACT). The results of research on compounds from the groups of phenothiazines, xanthanes, porphyrins, chlorins, porphyrazines, and phthalocyanines are presented. An intensive search for a photosensitizer with excellent properties is currently underway. The formulation based on the existing ones is also developed by combining them with nanoparticles and common antifungal therapy. Numerous studies indicate that fungi do not form any specific defense mechanism against PACT, which deems it a promising therapeutic alternative.
Modulating the photophysical properties of photosensitizers is an effective approach to enhance singlet oxygen generation for photodynamic therapy. Porphyrins are the most widely used photosensitizers due to their biocompatible nature. Aggregation‐induced emission (AIE) characteristics of photosensitizers are one of the advantageous features that will enhance fluorescence, intersystem crossing, and efficient triplet state generation. Herein, we demonstrate two glycosylated porphyrin photosensitizers, ZnGEPOH (with two ethynyl groups) and ZnGPOH (without two ethynyl groups), which exhibit AIE. Detailed studies revealed that ZnGEPOH exhibited a two‐fold increase in singlet oxygen production than ZnGPOH due to AIE. The photo‐cytotoxicity of ZnGPOH and ZnGEPOH were evaluated using cancer cell lines A549 and AGS. ZnGEPOH shows superior photo‐cytotoxicity with cell viability of 21% and 19% for A549 and AGS, respectively, at 250 μg/mL concentration in 48 h. Moreover, ZnGEPOH exhibits minimal photo‐cytotoxicity towards the control cell line HEK 293.
Photothermal therapy (PTT) and photodynamic therapy (PDT) are potential cancer treatment methods that are minimally invasive with high specificity for malignant cells. Emerging research has concentrated on the application of metal nanoparticles encapsulated in porphyrin and their derivatives to improve the efficacy of these treatments. Gold and silver nanoparticles have distinct optical properties and biocompatibility, which makes them efficient materials for PDT and PTT. Conjugation of these nanoparticles with porphyrin derivatives increases their light absorption and singlet oxygen generation that create a synergistic effect that increases phototoxicity against cancer cells. Porphyrin encapsulation with gold or silver nanoparticles improves their solubility, stability, and targeted tumor delivery. This paper provides comprehensive review on the design, functionalization, and uses of plasmonic silver and gold nanoparticles in biomedicine and how they can be conjugated with porphyrins for synergistic therapeutic effects. Furthermore, it investigates this dual-modal therapy’s potential advantages and disadvantages and offers perspectives for future prospects. The possibility of developing gold, silver, and porphyrin nanotechnology-enabled biomedicine for combination therapy is also examined.
The synthesis of a new bis-BF2 tetrafluorobenzo-[α]-fused BOPYPY dye from 4,5,6,7-tetrafluoroisoindole and 2-hydrazinopyrazine is reported. The regioselectivity of nucleophilic substitution reactions at the periphery of the tetrafluorinated BOPYPY and its α-bromo derivative were investigated using N-, O-, S-, and C-based nucleophiles. Among the aromatic fluorine atoms, the F² atom is consistently regioselectively substituted, except when the α-position contains a thiophenol group; in this case, F⁴ is substituted instead due to stabilizing π–π-stacking between the two aromatic groups. The α-bromo BOPYPY derivative also reacts under Stille cross-coupling reaction conditions to produce the corresponding α-substituted product. The spectroscopic properties of these new fluorinated BOPYPYs were investigated and compared with nonfluorinated analogs.
Photosensitizers (PSs) with aggregation‐induced emission (AIE) characteristics are competitive candidates for bioimaging and therapeutic applications. However, their short emission wavelength and nonspecific organelle targeting hinder their therapeutic effectiveness. Herein, a donor–acceptor modulation approach is reported to construct a series of ionic AIE photosensitizers with enhanced photodynamic therapy (PDT) outcomes and fluorescent emission in the second near‐infrared (NIR‐II) window. By employing dithieno[3,2‐b:2′,3′‐d]pyrrole (DTP) and indolium (In) as the strong donor and acceptor, respectively, the compound DTP‐In exhibits a substantial redshift in absorption and fluorescent emission reach to NIR‐II region. The reduced energy gap between singlet and triplet states in DTP‐In also increases the reactive oxygen species (ROS) generation rate. Further, DTP‐In can self‐assemble in aqueous solutions, forming positively charged nanoaggregates, which are superior to conventional encapsulated nanoparticles in cellular uptake and mitochondrial targeting. Consequently, DTP‐In aggregates show efficient photodynamic ablation of 4T1 cancer cells and outstanding tumor theranostic in vivo under 660 nm laser irradiation. This work highlights the potential of molecular engineering of donor–acceptor AIE PSs with multiple functionalities, thereby facilitating the development of more effective strategies for cancer therapy.
The scientific literature contains many accounts of application of polymethine dyes, including cyanine dyes, as imaging agents, i.e., "biological stains," for microscopic investigation of biological materials. Currently, many such dyes are used as probes for living cells, i.e., "fluorescent probes." Polymethine dyes are defined here by two criteria. First, they possess a conjugated chain of (2n + 1) sp2-hybridized carbon atoms that connect a terminal π-electron-accepting (π-electron withdrawing) group with a terminal π-electron-donating group. Second, they have an odd number (2n + 3) of π-centers and an even number (2n + 4) of π-electrons in this chain, where n equals the number of -CR2=CR3- groups, usually vinylene groups -CH=CH-. Commercialization of diverse chemical types of many polymethine dyes has been attempted. The dyes that have achieved wide application, however, are limited in number and it is these dyes that are emphasized here. Because these polymethine dyes sometimes have been described by confusing, and sometimes confused, names, we clarify here the chemical categories and names of such dyes for the nonchemist, biomedical end user of such imaging agents. Nevertheless, the nomenclature presented here is not intended to replace the traditional "chromophore" categories of dyestuff chemistry, because the latter are held in place both by wide usage and by venerable authorities, such as the Colour Index.
Photodynamic therapy (PDT) has the characteristics of being simple and non-invasive, and with on-demand light control. However, most photosensitizers exhibit strong hydrophobicity, low quantum yields in water and low tumor selectivity. In this study, carbon network-hosted porphyrins (CPs) with high biocompatibility and efficient singlet oxygen (1O2) generation were developed to reduce the biotoxicity of photosensitizers and avoid quenching caused by hydrophobic aggregation for enhanced PDT. The CPs were prepared by a simple solid-phase synthesis method using porphyrin, green non-toxic citric acid and urea as the raw materials. The CPs exhibited excellent water solubility and high biocompatibility. Even when the concentration reached 1.5 mg mL-1, cells still had good biological activity. By separately fixing the porphyrins in the carbon network, the CPs avoided aggregation-induced inactivation and had high generation efficiency of 1O2. Furthermore, in order to improve the PDT effect, the CPs were modified with the upper nuclear targeting peptide TAT (T-CPs), which was used to target the nucleus and generate 1O2in situ to directly destroy genetic material. The proposed strategy provides a simple and green path to prepare nanophotosensitizers with high biocompatibility and efficient 1O2 generation for PDT.
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides in length. Although they were considered non-functional by products of transcription in the past, a new function of these molecules is emerging each day. Perhaps, one of the most intriguing lncRNA functions is their nuclear function in coordinating various nuclear processes. Weak splicing signals, polyA signals within the molecules and specific sequences such as Alu repeats can cause lncRNAs to localize in the nucleus. Interestingly, a fraction of nuclear lncRNAs modulate chromatin dynamics in the nucleus. They can either directly interact with DNA or chromatin structure, or function via protein localization. These interactions can lead to changes in chromatin folding under various cellular conditions. iMARGI is a recently developed method employed to investigate such interactions in a genome-wide manner. Crosslinked lncRNA-DNA molecules are ligated inside the nucleus to probe lncRNA; chromatin interactions. In this study, we prepared a library of lncRNA-chromatin hybrids from adenocarcinoma, HeLa cells. Cloning of certain fragments showed combined DNA-RNA sequences. This approach can be applied to other cancer cell lines. Gaining insight into the lncRNA function in chromatin dynamics can increase our understanding on chromatin folding and gene expression, facilitating a better understanding of cancer molecular biology.
The development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission, excellent photostability, and specific organelle targeting is in great demand for the enhancement of PDT treatment efficiency. This study designed and synthesized a new two-photon photosensitizer chlorophenyl thiophene axially substituted silicon (IV) phthalocyanine (CBT-SiPc). CBT-SiPc showed specific targeting of lysosomes in living cells and good biocompatibility. Furthermore, high ¹O2 generation efficiency and high PDT efficiency in MCF-7 breast cancers under irradiation were also demonstrated. The novel CBT-SiPc showed great potential in the application of lysosome-targeted and two-photon bioimaging-guided photodynamic cancer therapy.
Glioblastomas (GBM) are considered one of the most aggressive tumors of the central nervous system. The standard treatment for GBM-diagnosed patients implies surgery, followed by radio and chemotherapy, with a survival of 12 to 15 months after treatment. Photodynamic Therapy (PDT) is an alternative approach to treating several diseases, including tumors. The study of PDT to treat GBM has been gaining attention over the last few years. In this work, we reviewed the cellular and molecular features and current treatment modalities for GBM as well as the most used photosensitizers for GBM-PDT reported in the last five years, such as porphyrins, chlorins, and phthalocyanines, and also their precursors, as in the case of aminolaevulinic acid. Moreover, an analysis of cellular targets, mechanisms mediating the response and resistance to PDT, and clinical application of this strategy for GBM treatment have been discussed.
In photodynamic therapy (PDT), reactive oxygen species (ROS) are generated through dynamic interactions between light of a specific wavelength, a photosensitizer (PS) and molecular oxygen. Nowadays, there has been an increment in the number of studies evaluating the possible utilization of BF2 chelated tetraarylazadipyrromethanes (aza-BODIPYs) as photosensitizers in PDT. In this study, a novel aza-BODIPY with phthalonitrile substituents was synthesized by the esterification reaction of a phthalonitrile derivative namely, 4-((3,4-dicyanophenyl)sulphanyl)benzoic acid with an aza-BODIPY bearing hydroxy groups on the para positions of distal phenyl groups. Aza-BODIPY compound bearing phthalonitrile substituents was characterized by using UV–Vis, fluorescence, ¹H-NMR and mass spectroscopy techniques. Photophysical and photochemical properties including fluorescence quantum yield and singlet oxygen yield were determined. In order to explore its photodynamic efficacy, it was tested on a breast cancer cell line (MCF-7 cells) and on a normal healthy cell line (L929 cells) through dark and light cytotoxicity.
Boron dipyrromethene dyes are highly attractive for image-guided photodynamic therapy. Nevertheless, their clinical breakthrough as theranostic agents is still obstructed by several limitations. Here, we report a series of strongly absorbing, heavy-atom-free, distyryl-BODIPY donor–acceptor dyads operating within the phototherapeutic window. Whereas diphenylamine and carbazole donors lead to strong fluorescence, dimethylacridine, phenoxazine, and phenothiazine units afford a decent fluorescence combined with the efficient formation of singlet oxygen. Dedicated photophysical analysis and quantum-chemical calculations are performed to elucidate the excited state dynamics responsible for the pronounced differences within the BODIPY series. Femtosecond transient absorption spectra reveal the nature of the excited state processes and the involvement of charge-transfer states in triplet formation.
Aza-boron-dipyrromethenes (Aza-BODIPYs) represent an important class of chromophores absorbing and emitting in the near-infrared (NIR) region. They have unique optical and electronic features and higher physiological and photo stability than other NIR dyes. Especially after the development of facile synthetic routes, Aza-BODIPYs have become indispensable fluors that can find various applications ranging from chemosensors, bioimaging, phototherapy, solar energy materials, photocatalysis, photon upconversion, lasers, and optoelectronics. Herein, we review Aza-BODIPY based fluorescent and colorimetric chemosensors. We show the potential and untapped toolbox of Aza-BODIPY based fluorescent and colorimetric chemosensors. Hence, we divide the fluorescent and colorimetric chemosensors and probes into five sections according to the target analytes. The first section begins with the chemosensors developed for pH. Next, we discuss Aza-BODIPY based ion sensors including, metal ions and anions. Finally, we present the chemosensors and probes concerning reactive oxygen (ROS) and nitrogen species (RNS) along with biologically relevant species in the last two sections. We believe that Aza-BODIPYs are still in their infancy, and they have a promising future for translation from the bench to real biomedical and materials science applications. After two decades of intensive research, it seems that there are many more to come in this already fertile field. Overall, we hope that future work will further expand the applications of Aza-BODIPY in many areas.
Photochromism is a well-researched phenomenon that accounts for alteration in the structure, polarity, appearance and other physio-chemical properties of a compound upon light stimulation. It has proved its competence in diverse fields like ophthalmics, data storage, molecular switches, environmental monitoring, superior bioimaging etc. Now to add another feature to its function list, photodynamic therapy (a cancer cure therapy) has been explored in the light of photochromism in this review. In recent years, PDT has become the most desirable subject of research owing to its dire need in the present scenario. Even though several reviews have been published to date, this review has yet a lot novel to offer. On account of the light/heat-responsive structural transformation, photochromic species have been found to play three different roles in advancing the efficacy of PDT– i) photochromes as photosensitizers, ii) as switches to the conventional photosensitizers and iii) as singlet oxygen reserves. Among the wide classes of photochromic molecules, spiropyran, dimethyldihydropyrene (DHP), diarylethene (DAE), azobenzene & anthracene are some that have displayed potential for exploitation as PDT agents in some or the other way.
The development of drugs that target specific proteins has been mainly promoted for molecular-targeted therapies but there are many examples of proteins that are difficult to target owing to their structural characteristics. However, the development of drugs targeting non-canonical nucleic acid structures, including G-quadruplexes (G4), has progressed and is expected to have applications in new cancer treatment methods. In this review, we explain why G4 is attracting attention as a therapeutic target molecule and how to introduce antitumor activity in G4 ligands with photosensitizing abilities that can be adapted for photodynamic cancer therapies.
We have designed and synthesized a family of Ir(III) metal complexes coordinated with two cyclometalated bis-fluorophenylpyridine ligands and an ancillary dipyrromethene which is functionalized with a mesityl group (Ir(dipy)-1), an α-chloroacetyl ester (Ir(dipy)-2) or a chain containing an ammonium cation (Ir(dipy)-3). The Ir(III) complexes feature a high triplet state population enabling red phosphorescence and efficient singlet oxygen generation. Ir(dipy)-2 and Ir(dipy)-3 are demonstrated to stain cells in both one-photon and two-photon confocal imaging. Moreover, Ir(dipy)-2 and Ir(dipy)-3 produce ROS in cells upon irradiation, inducing cell death by apoptosis. Colocalization studies in SK-Mel-103 cells show that Ir(dipy)-3 is partially accumulated in mitochondria and induces upon irradiation a disruption in their morphology. Overall our studies demonstrate that the prepared Ir(III) act as photosensitizers able to kill cells under irradiation, being suitable candidates for photodynamic therapy applications.
The identification of ruthenium(II) polypyridyl complexes as photosensitizers in photodynamic therapy (PDT) for the treatment of cancer is progressing rapidly. Due to their favorable photophysical and photochemical properties, Ru(II)-based photosensitizers have absorption in the visible spectrum, can be irradiated via one- and two-photon excitation within the PDT window, and yield potent oxygen-dependent and/or oxygen-independent photobiological activities. Herein, we present a current overview of the mechanisms of action and subcellular localization of Ru(II)-based photosensitizers in the treatment of cancer. These photosensitizers are highlighted from a medicinal chemistry and chemical biology perspective. However, although this field is burgeoning, challenges and limitations remain in the photosensitization strategies and clinical translation.
The neuronal cytoskeleton plays a crucial role in maintaining cell integrity and functioning of neurons. Cytoskeleton deformities have been reported to be associated with neurodegenerative diseases thus; cytoskeleton can be targeted for therapeutic strategies. The therapeutic application of photosensitive molecule is termed as Photodynamic therapy (PDT). PDT has been applied in the field of dermatology, cancer biology and antimicrobial therapy. PDT induces several changes in cells, which include induction of apoptosis, DNA damage, and induction of inflammatory response. PDT has been also reported to modulate cytoskeleton such as actin dynamics. The in‐vitro studies suggested that PDT using dyes such as Toluidine Blue and Rose Bengal effectively modulated the actin cytoskeleton, neurite outgrowth, tubulin and Tau aggregation. In this review, we focused on the effect of photosensitized molecules on various cytoskeleton proteins. We hypothesize that PDT could have potency against Alzheimer's disease and other neurodegenerative disorders. This article is protected by copyright. All rights reserved.
Background:
Photodynamic therapy (PDT) is an anticancer therapy that associates the photosensitizer (PS), oxygen and light to destroy cancer cells. Methylene blue (MB) is considered a second generation phenothiazine dye with excellent photochemical properties.
Aim:
To evaluate whether MB-mediated PDT can induce oxidative stress and inflammation, therefore, interfering tumor growth.
Materials and methods:
The study was conducted on Wistar rats transplanted with Walker 256 carcinosarcoma (W256). The proinflammatory interleukins levels (IL-1β, IL-6, IL-10, TNF-α) were determined by ELISA, mRNA expression of COX-1, COX-2, iNOS and eNOS by RT-PCR, lipid peroxidation was measured by the TBARS method. Moreover, myeloperoxidase (MPO) activity in neutrophils was determined by MPO activity assay. All indices mentioned above were determined in tumor tissue. Kaplan - Meier and Gehan - Breslow - Wilcoxon tests were used for survival analysis.
Results:
We found that the treatment of W256 with 0.1% MB + 1 J/cm2 provoked a significant increase in the interleukins levels (IL-1β, IL-6, IL-10, TNF-α), prostaglandin E2, the mRNA expression of COX-2, iNOS, lipid peroxidation and MPO activity in tumor tissue, which were statistically different (p < 0.05) compared to other experimental and control groups. The results of the estimation of survival curves show a greater probability of survival in 0.1% MB + 1 J/cm2 (total energy dose =142.8 J/cm2) treated group.
Conclusion:
Our results suggest that treatment of W256 with 0.1% MB + 1 J/cm2 was able to promote cytotoxic effects in tumor tissue by the generation of reactive oxygen species causing inflammation and thus interfering in the tumor growth.
In this work, several benzothiazole-based aminosquaraine dyes, displaying strong absorption within the so-called phototherapeutic window (650–800 nm), were synthesized. The ability, of all the new dyes, to generate singlet oxygen was assessed by determining the correspondent phosphorescence emission and through the comparison with a standard. The quantum yields of singlet oxygen generation were determined and exhibited to be strongly dependent on the nature of the amino substituents introduced in the squaric ring. The photodynamic activity of the synthesized dyes was tested against four human tumor cell lines: breast (MCF-7), lung (NCI-H460), cervical (HeLa) and hepatocellular (HepG2) carcinomas; and a non-tumor porcine liver primary cell culture (PLP2). All the compounds synthesized were found to be able to inhibit tumor cells growth upon irradiation more than in the dark, in most of the cases, very significantly. Considering the photodynamic activity exhibited and the low toxicity displayed for the non-tumor cells, some of the synthetized dyes can be regarded as potential candidates as photosensitizers for PDT.
Improving the deep-tissue phototherapy (PDT) efficiency in the near-infrared (NIR) region has become one of the major challenges in clinic for cancer treatment. Developing intelligent photosensitizers (PSs) responding to tumor-specific signals sensitively to minimize side effects is another major problem for tumor phototherapy. Herein, three phenyl-based boron dipyrromethene (BODIPY) compounds with different number of diethylaminophenyl groups introduced onto the BODIPY core have been designed and synthesized by the knoevenagel condensation reaction. The absorbance of these compounds (BDPmPh, BDPbiPh, BDPtriPh) can be controlled easily for realizing tunable penetration depth. Moreover, the diethylamino groups in these designed PSs can serve as proton receptor triggered by the low pH in lysosomes which can enhance the efficacy of photodynamic and photothermal therapy. The corresponding nanoparticles (NPs) of the compounds are prepared through nanoprecipitation method and in vitro studies demonstrate that BDPtriPh NPs with an ultra-low drug dosage (half-maximal inhibitory concentration, IC50 = 4.16 μM) is much lower than that of BDPmPh NPs (50.09 μM) and BDPbiPh NPs (22.4 μM), respectively. In vivo fluorescence imaging shows that these NPs can be passively targeted to tumors by enhanced permeability and retention (EPR) effect, and BDPtriPh NPs exhibit the fastest accumulation (about 4 hours). In vivo phototherapy indicates that BDPtriPh NPs with the longest NIR absorbance (813 nm) and highest photothermal conversion efficiency (60.5%) can effectively inhibit tumor growth and reduce side effects to normal tissues. This study provides a strategy to modulate photoconversion characteristics of PSs for both penetration-depth-tunable and pH-dependent PDT/PTT synergistic cancer therapy in clinic.
Photobiomodulation (PBM) and photodynamic therapy (PDT) are two major methods, which use light in medicine and dentistry. PBM uses low-level laser light to induce cell proliferation and activity. In contrast, PDT use laser light combined with a photosensitizer (PS) to cause cell death. Due to similar, not fully understood mechanisms and biphasic response of light, unexpected and complex outcomes may be observed. In the present study, the effect of 635 nm laser light, with power density 50 mW/cm², at three different energy densities (0.5, 1, and 2 J/cm² which last 10, 20, and 40 s, respectively) mediated by methylene blue (MB) on the human osteoblast cell line (ATCC-CRL-11372, Rockville, MD, USA) was investigated. Cell viability (MTT assay and acridine orange/propidium iodide staining) and proliferation (Alamar Blue assay) were assessed at 24, 48, and 72 h post irradiation. Alkaline phosphatase (ALP) activity, mineralization (Alizarin Red staining) and gene expressions (RT-PCR analysis) were analyzed at 7th and 14th days after treatment. Five groups were formed as the control group (no MB, no irradiation), MB (only 0.05 μM MB), MB + 0.5 J/cm², MB + 1 J/cm², and MB + 2 J/cm². Cell viability was decreased at 72 h (ANOVA; p < 0.05) for MB + 0.5 J/cm², MB + 1 J/cm², and MB + 2 J/cm² groups. Although proliferation does not seem to be effected by MB-mediated laser application, osteo-anabolic activity is altered. ALP activity was significantly increased at day 7 (ANOVA; p < 0.05) for MB-combined laser groups; on the other hand, mineralization was significantly decreased (ANOVA; p < 0.05) in all treatment groups. Alkaline phosphatase and collagen-I expressions were upregulated in MB + 2 J/cm² group at 7th and 14th days, respectively. These results may contribute to the low-dose PDT researches and understanding PBM effects on osteoblast behavior but further studies are needed since inappropriate conditions may lead to undesirable results for both therapies.
Background
Breast cancer is the main cause of mortality among women. The disease presents high recurrence mainly due to incomplete efficacy of primary treatment in killing all cancer cells. Photodynamic therapy (PDT), an approach that causes tissue destruction by visible light in the presence of a photosensitizer (Ps) and oxygen, appears as a promising alternative therapy that could be used adjunct to chemotherapy and surgery for curing cancer. However, the efficacy of PDT to treat breast tumours as well as the molecular mechanisms that lead to cell death remain unclear. Methods
In this study, we assessed the cell-killing potential of PDT using methylene blue (MB-PDT) in three breast epithelial cell lines that represent non-malignant conditions and different molecular subtypes of breast tumours. Cells were incubated in the absence or presence of MB and irradiated or not at 640 nm with 4.5 J/cm2. We used a combination of imaging and biochemistry approaches to assess the involvement of classical autophagic and apoptotic pathways in mediating the cell-deletion induced by MB-PDT. The role of these pathways was investigated using specific inhibitors, activators and gene silencing. ResultsWe observed that MB-PDT differentially induces massive cell death of tumour cells. Non-malignant cells were significantly more resistant to the therapy compared to malignant cells. Morphological and biochemical analysis of dying cells pointed to alternative mechanisms rather than classical apoptosis. MB-PDT-induced autophagy modulated cell viability depending on the cell model used. However, impairment of one of these pathways did not prevent the fatal destination of MB-PDT treated cells. Additionally, when using a physiological 3D culture model that recapitulates relevant features of normal and tumorous breast tissue morphology, we found that MB-PDT differential action in killing tumour cells was even higher than what was detected in 2D cultures. Conclusions
Finally, our observations underscore the potential of MB-PDT as a highly efficient strategy which could use as a powerful adjunct therapy to surgery of breast tumours, and possibly other types of tumours, to safely increase the eradication rate of microscopic residual disease and thus minimizing the chance of both local and metastatic recurrence.
The efficacy of photodynamic therapy (PDT) in some solid tumors is limited by the poor biodistributive properties of conventional photosensitizers and a natural predisposition of tumor cells to survive hypoxia and oxidative stress. This study investigated the therapeutic potential of a third-generation photosensitizer, liposomal zinc phthalocyanine (ZnPC), in combination with the hypoxic cytotoxin tirapazamine (TPZ). TPZ induces DNA double strand breaks (DSBs) under hypoxic conditions and subsequent apoptosis via p53 signaling. Experiments were performed in tumor cells with functional p53 (Sk-Cha1) and dysfunctional p53 (A431). The combination therapy of TPZ and PDT induced DNA DSBs and cell cycle stalling and enhanced the cytotoxicity of PDT by exacerbating apopotic and non-apoptotic tumor cell death. These phenomena occurred regardless of oxygen tension and the mechanism of cell death differed per cell line. Liposomes containing both ZnPC and TPZ exhibited no dark toxicity but were more lethal to both cell types after PDT compared to ZnPC-liposomes lacking TPZ—an effect that was more pronounced under hypoxic conditions. In conclusion, TPZ is a suitable pharmaceutical compound to increase PDT efficacy by exploiting the post-PDT tumor hypoxia. The inclusion of TPZ and ZnPC into a single liposomal delivery system was feasible. The PDT strategy described in this study may be valuable for the treatment of PDT-recalcitrant tumors.
Photodynamic therapy (PDT) is a promising treatment in cancer therapy, with a photosensitizer activated by visible light. Aloe-emodin (AE) is a promising photosensitive agent. In this study, the photosensitizing effects and possible mechanisms of AE-PDT in MG63 cells were evaluated. The efficiency of AE-PDT was analyzed by MTT assay. The mode of cell death was investigated by Hoechst 33,342 staining and flow cytometer. The intracellular distribution of AE was detected with confocal microscopy. The formation of reactive oxygen species (ROS) was detected by DCFH-DA. The mitochondrial membrane potential (MMP) was measured by Rhodamine 123. The expression of proteins including cytochrome c, caspase-3, -9, and -12, CHOP and GRP78 was detected by western blot. Apoptosis is the primary mode of cell death in our study, which occurs in a manner of depending on AE concentration and irradiation dose. Confocal microscopy showed that AE was primarily localized on the mitochondria and endoplasmic reticulum (ER) of MG63 cells. AE-PDT resulted in rapid increases of intracellular ROS production, which reached a peak at 2 h, followed by declining of mitochondrial membrane potential, releasing of cytochrome c from mitochondria into the cytoplasm, and up-regulation of caspase-3, -9, and -12, CHOP and GRP78. These results suggest that death of MG63 cells induced by AE-PDT is triggered by ROS. Meanwhile, Mitochondria and ER serve as the subcellular targets, which are responsible for AE-PDT-induced death of MG63 cells.
We describe here the development of time-correlated single-photon counting techniques from the early use of spark discharge lamps as light sources through to the use of femtosecond mode-locked lasers through the personal work of the author. We used laser-excited fluorescence in studies on energy migration and rotational relaxation in synthetic polymer solutions, in biological probe molecules and in supersonic jet expansions. Time-correlated single-photon counting was the first method used in early fluorescence lifetime imaging microscopy (FLIM), and we outline the development of this powerful technique, with a comparison of techniques including wide-field microscopy. We employed these modern forms of FLIM to study single biological cells, and applied FLIM also to gain an understanding the distribution in tissue, and fates of photosensitizer molecules used in photodynamic therapy. We also describe the uses and instrumental design of laser systems for the study of ultrafast time-resolved vibrational spectroscopy.
Hypericin (4,5,7,4′,5′,7′-hexahydroxy-2,2′-dimethylnaphtodianthrone) is a naturally occurring chromophore found in some species of the genus Hypericum, especially Hypericum perforatum L. (St. John's wort), and in some basidiomycetes (Dermocybe spp.) or endophytic fungi (Thielavia subthermophila). In recent decades, hypericin has been intensively studied for its broad pharmacological spectrum. Among its antidepressant and light-dependent antiviral actions, hypericin is a powerful natural photosensitizer that is applicable in the photodynamic therapy (PDT) of various oncological diseases. As the accumulation of hypericin is significantly higher in neoplastic tissue than in normal tissue, it can be used in photodynamic diagnosis (PDD) as an effective fluorescence marker for tumor detection and visualization. In addition, light-activated hypericin acts as a strong pro-oxidant agent with antineoplastic and antiangiogenic properties, since it effectively induces the apoptosis, necrosis or autophagy of cancer cells. Moreover, a strong affinity of hypericin for necrotic tissue was discovered. Thus, hypericin and its radiolabeled derivatives have been recently investigated as potential biomarkers for the non-invasive targeting of tissue necrosis in numerous disorders, including solid tumors. On the other hand, several light-independent actions of hypericin have also been described, even though its effects in the dark have not been studied as intensively as those of photoactivated hypericin. Various experimental studies have revealed no cytotoxicity of hypericin in the dark; however, it can serve as a potential antimetastatic and antiangiogenic agent. On the contrary, hypericin can induce the expression of some ABC transporters, which are often associated with the multidrug resistance (MDR) of cancer cells. Moreover, the hypericin-mediated attenuation of the cytotoxicity of some chemotherapeutics was revealed. Therefore, hypericin might represent another St. John's wort metabolite that is potentially responsible for negative herb–drug interactions. The main aim of this review is to summarize the benefits of photoactivated and non-activated hypericin, mainly in preclinical and clinical applications, and to uncover the “dark side” of this secondary metabolite, focusing on MDR mechanisms.
Combining the concept of magnetic drug targeting and photodynamic therapy is a promising approach for the treatment of cancer. A high selectivity as well as significant fewer side effects can be achieved by this method, since the therapeutic treatment only takes place in the area where accumulation of the particles by an external electromagnet and radiation by a laser system overlap. In this article, a novel hypericin-bearing drug delivery system has been developed by synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) with a hypericin-linked functionalized dextran coating. For that, sterically stabilized dextran-coated SPIONs were produced by coprecipitation and crosslinking with epichlorohydrin to enhance stability. Carboxymethylation of the dextran shell provided a functionalized platform for linking hypericin via glutaraldehyde. Particle sizes obtained by dynamic light scattering were in a range of 55–85 nm, whereas investigation of single magnetite or maghemite particle diameter was performed by transmission electron microscopy and X-ray diffraction and resulted in approximately 4.5–5.0 nm. Surface chemistry of those particles was evaluated by Fourier transform infrared spectroscopy and ζ potential measurements, indicating successful functionalization and dispersal stabilization due to a mixture of steric and electrostatic repulsion. Flow cytometry revealed no toxicity of pure nanoparticles as well as hypericin without exposure to light on Jurkat T-cells, whereas the combination of hypericin, alone or loaded on particles, with light-induced cell death in a concentration and exposure time-dependent manner due to the generation of reactive oxygen species. In conclusion, the combination of SPIONs’ targeting abilities with hypericin’s phototoxic properties represents a promising approach for merging magnetic drug targeting with photodynamic therapy for the treatment of cancer.
Context:
Bacterial resistance to antibiotics is increasing and alternative antibacterial treatments like antimicrobial photodynamic therapy (aPDT) are needed. Curcumin is under investigation as a potential photosensitizer in aPDT.
Objective:
The purpose of this study was to develop rapidly dissolving formulations of curcumin that could photoinactivate both Gram-positive and Gram-negative bacteria.
Materials and methods:
Curcumin solid dispersions with methyl-β-cyclodextrin and hyaluronic acid (HA), hydroxypropyl methylcellulose (HPMC) or both HA and HPMC were prepared through lyophilization. The lyophilizates were characterized by curcumin drug load [% (w/w)], differential scanning calorimetry, photostability, thermal stability, their ability to form supersaturated solutions and by in vitro photoinactivation of Enterococcus faecalis and Escherichia coli.
Results and discussion:
The lyophilizates were amorphous solid dispersions with a curcumin drug load in the range of 1.4-5.5% (w/w) depending on the included polymer and the ratio between curcumin and the cyclodextrin. The lyophilizates were photolabile, but thermally stable and dissolved rapidly in contact with water to form supersaturated solutions. Selected lyophilizates demonstrated >log 6 reduction of colony forming units/ml of both E. faecalis and E. coli after exposure to low curcumin concentrations (0.5-10 µM) and blue light dose (11-16 J/cm(2)). The high drug load of the lyophilizates, rapid dissolution, ability to form relatively stable supersaturated solutions and the very high phototoxicity towards both E. faecalis and E. coli make these lyophilizates suitable for in vivo aPDT.
Conclusions:
This treatment with optimized curcumin formulations should be explored as an alternative to topical antibiotics in the treatment of wound infections.
Photofrin (R) was first approved in the 1990s as a sensitizer for use in treating cancer via photodynamic therapy (PDT). Since then a wide variety of dye sensitizers have been developed and a few have been approved for PDT treatment of skin and organ cancers and skin diseases such as acne vulgaris. Porphyrinoid derivatives and precursors have been the most successful in producing requisite singlet oxygen, with Photofrin (R) still remaining the most efficient sensitizer (quantum yield = 0.89) and having broad food and drug administration (FDA) approval for treatment of multiple cancer types. Other porphyrinoid compounds that have received approval from US FDA and regulatory authorities in other countries include benzoporphyrin derivative monoacid ring A (BPD-MA), meta-tetra(hydroxyphenyl) chlorin (m-THPC), N-aspartyl chlorin e6 (NPe6), and precursors to endogenous protoporphyrin IX (PpIX): 1,5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), hexaminolevulinate (HAL). Although no non-porphyrin sensitizer has been approved for PDT applications, a small number of anthraquinone, phenothiazine, xanthene, cyanine, and curcuminoid sensitizers are under consideration and some are being evaluated in clinical trials. This review focuses on the nature of PDT, dye sensitizers that have been approved for use in PDT, and compounds that have entered or completed clinical trials as PDT sensitizers.
Boron-dipyrromethene (BODIPY) compounds have been used extensively. However, their application in photocatalysis has not been well-studied. In this report, iodo-BODIPYs were utilized as visible-light-driven photocatalysts. They demonstrated very high catalytic efficiency and reaction rate for photocatalyzed oxidation of thioanisole under visible light.
BF2 Chelated azadipyrromethene dyes fluoresce in the near infrared and have potential applications in photodynamic therapy. When irradiated above 600nm these aza-BODIPY compounds react with triplet O2 in the body to form a reactive singlet oxygen species which leads to cell death. A small library has been synthesized of these potential PDT agents via a four step process, with varying substituent's on the aromatic ring of the starting benzaldehyde and acetophenone. In vitro studies on HeLa cells have revealed an effective photosensitive compound with low dark cytotoxicity and promotion of apoptotic cell death when exposed to light.
BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with (3)O(2). In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.
The design and development of novel squaraine dyes as sensitisers for photodynamic therapy (PDT) applications has grown tremendously in the last decade from the time when a squaraine dye was proposed to be a potential candidate, to-date when the use of such dyes have been demonstrated in animal models for skin cancer. This perspective article highlights the basic design, tuning of absorption, triplet excited state and two-photon absorption properties and recent developments of the squaraines as PDT sensitisers.
Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse the hypoxia-driven resistance by designing superoxide radical (O2−•) generator targeting mitochondria respiration, termed SORgenTAM. Such PDOE system is able to block the intracellular O2 consumption and down-regulate HIF-1 ex-pression, which successfully rescue cancer cells from becoming hypoxia and relieve the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has ideal intersystem crossing rate and triplet excited state lifetime for generating O2−• through type-I photochemistry, and the generated O2−• can further trigger bio-cascade to reduce the PDT’s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, dramatically enhanced therapeutic responses toward hypoxic tumors are realized. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutic.
Organic-metal complexes are promising molecules for using in photodynamic therapy (PDT). The aim of this study was to investigate in vitro effects of novel Ru(II) and Ir(III) BODIPY complexes for PDT. These hybrid oganic-metal molecules (Ru-BD and Ir-BD) have been synthesized via reactions of a BODIPY precursor (BD) with a phenanthroline unit bearing Ru(II) (3) and novel Ir(III) (4) compounds. The crystal structures of new distyryl BODIPY (BD) and Ru(II) complex (3) are also reported. The photophysical and singlet oxygen generation properties of the Ru-BD and Ir-BD were investigated in comparison with unsubstituted BODIPY (BD). Moreover, Ru-BD and Ir-BD have been biologically evaluated in vitro in chronic myleoid leukemia and cervical cancer cell lines in terms of photodynamic therapy efficacy in the presence of BD control. These complexes were not toxic in the dark but the red light was needed to induce the cell death. This data supports that Ru-BD could be accepted as a valuable photosensitizer-drug for further PDT treatment.
Singlet oxygen (¹O2) is the focus of study in many fields, including phototoxicity, antioxidant activity, pollutant weathering, photodynamic therapy, and water disinfection. The imidazole plus RNO (Imd/RNO) method, originated by Kraljic and El Mohsni, is commonly used to monitor singlet oxygen production. In this method, ¹O2 is quenched by an acceptor, imidazole (Imd), during the formation of a trans-annular peroxide intermediate that bleaches the sensor, p-nitrosodimethylaniline (RNO). Though the method has been widely used, including to monitor ¹O2 production in complex environments, such as surfactants and cells, studies reporting the efficiency of the assay in complex solvents have not been reported. In this research, the Imd/RNO method in complex, biorelevant solvents, i.e., sodium dodecyl sulfate, octanol, and phosphate buffer-saturated octanol, was compared with reference solvents, i.e., phosphate buffer, ethanol, and methanol, for monitoring ¹O2 produced by Rose Bengal photosensitization using time-resolved, broadband UV–Vis absorbance measurements. Rates of sensor bleaching and sensitizer photodegradation were simultaneously monitored in each solvent to investigate correlations between the disappearance rates of sensor and sensitizer. The quantum yields of ¹O2 production (ϕ∆) in each solvent were calculated using a relative actinometric method. The dependence of sensor bleaching and sensitizer degradation on acceptor concentration and solvent polarity, and the results of assay controls suggest mechanistic differences underlying the reactions comprising the Imd/RNO method. These results demonstrate the need for caution and controls when using the method in complex samples including those containing cells, tissues, or nanoscale particles.
Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are attractive natural occurring vehicles for drug delivery and targeting tumor cells. Here we have investigated the encapsulation and interaction of a well-known anticancer agent curcumin with LDL and HDL. LDL particles have been found to accumulate more curcumin molecules inside their structure than HDL. The chemical stability of curcumin is enhanced and its photo-physical properties are altered due to encapsulation inside both lipoproteins. Combining photodynamic therapy with chemotherapy can improve anticancer treatment by overcoming drug resistance in cancer therapy. Therefore, we have also investigated a co-loading of curcumin with a natural potent photosensitizer hypericin into molecules of LDL using fluorescence resonance energy transfer. The loading patterns of curcumin and hypericin into LDL particles were found to be different as revealed by the fluorescence resonance energy transfer experiments. Present study illustrates the potential of LDL nanoparticles in combination therapy because of simultaneous loading of more than one type of drugs into these nanoparticles with high level of efficiency.
A new family of water-soluble and bioconjugatable aza-BODIPY fluorophores was designed and synthesized using a boron- functionalization strategy. These dissymmetric bis-ammonium aza-BODIPY dyes present optimal properties for a fluorescent probe; i.e., they are highly water-soluble, very stable in physiological medium; they do not aggregate in PBS, possess high quantum yield; and finally, they can be easily bioconjugated to antibodies. Preliminary in vitro and in vivo studies were performed for one of these fluorophores to image PD-L1 (Programmed Death-Ligand 1), highlighting the high potential of these new probes for future in vivo optical imaging studies.
Phototherapy, as an important class of noninvasive tumor treatment methods, has attracted extensive research interest. Although a large amount of the near-infrared (NIR) phototherapeutic agents have been reported, the low efficiency, complicated structures, tedious synthetic procedures, and poor photostability limit their practical applications. To solve these problems, herein, a donor−acceptor−donor (D−A−D) type organic phototherapeutic agent (B-3) based on NIR aza-boron-dipyrromethene (aza-BODIPY) dye has been constructed, which shows the enhanced photothermal conversion efficiency and high singlet oxygen generation ability by simultaneously utilizing intramolecular photoinduced electron transfer (IPET) mechanism and heavy atom effects. After facile encapsulation of B-3 by amphiphilic DSPE−mPEG5000 and F108, the formed nanoparticles (B-3 NPs) exhibit the excellent photothermal stabilities and reactive oxygen and nitrogen species (RONS) resistance compared with indocyanine green (ICG) proved for theranostic application. Noteworthily, the B-3 NPs can remain outstanding photothermal conversion efficiency (η = 43.0%) as well as continuous singlet oxygen generation ability upon irradiation under a single-wavelength light. Importantly, B-3 NPs can effectively eliminate the tumors with no recurrence via synergistic photothermal/photodynamic therapy under mild condition. The exploration elaborates the photothermal conversion mechanism of small organic compounds and provides a guidance to develop excellent multifunctional NIR phototherapeutic agents for the promising clinical applications.
Photodynamic therapy (PDT) is a modern and non-invasive form of therapy, used in the treatment of non-oncological diseases as well as cancers of various types and locations. It is based on the local or systemic application of a photosensitive compound-the photosensitizer, which is accumulated in pathological tissues. The photosensitizer molecules absorb the light of the appropriate wavelength, initiating the activation processes leading to the selective destruction of the inappropriate cells. The photocytotoxic reactions occur only within the pathological tissues, in the area of photosensitizer distribution, enabling selective destruction. Over the last decade, a significant acceleration in the development of nanotechnology has been observed. The combination of photosensitizers with nanomaterials can improve the photodynamic therapy efficiency and eliminate its side effects as well. The use of nanoparticles enables achievement a targeted method which is focused on specific receptors, and, as a result, increases the selectivity of the photodynamic therapy. The object of this review is the anticancer application of PDT, its advantages and possible modifications to potentiate its effects.
Photothermal therapy (PTT) as a kind of noninvasive tumor treatment has attracted increasing research interest. However, the efficiency of existing PTT agents in the near-infrared (NIR) region is the major problem that has hindered further development of PTT. Herein, we present an effective strategy to construct the efficient photothermal agent by utilizing an intramolecular photoinduced electron transfer (PeT) mechanism, which is able to dramatically improve photothermal conversion efficiency in NIR region. Specifically, a NIR dye (A1) constructed with dimethylamine (DMA) moiety as electron donor and aza-BODIPY core as electron acceptor is designed and synthesized, which can be used as a class of imaging-guided PTT agents via intramolecular PeT. After encapsulation with biodegradable polymer DSPE-mPEG5000, nano-photothermal agents with small size exhibit excellent water solubility, photostability and long-time retention in tumor. Importantly, such nanoparticles exhibit excellent photothermal conversion efficiency of ~35.0%, and the PTT effect in vivo still remains very well even with a low dosage of 0.05 mg kg-1 upon 808 nm NIR laser irradiation (0.5 W cm-2). Therefore, this reasonable design via intramolecular PeT offers a guidance to construct excellent photothermal agents and subsequently may provide a novel opportunity for future clinical cancer treatment.
Object:
Photodynamic therapy is an exciting treatment modality that combines the effects of a chemical agent with the physical energy from light or radiation to result in lysis of cells of interest. Acridine orange is a molecule with fluorescence properties that was demonstrated to possess photosensitizing properties. The objective of this study was to investigate the photodynamic effect of acridine orange on glioblastoma cell viability and growth.
Methods:
Glioblastoma cells (n = 8000 cells/well at 0 hours) were exposed to acridine orange followed by white unfiltered light-emitting diodes (LED) light. Cultures were exposed to either 10 or 30 minutes of light. The cell number per well was determined at 0, 24, 48, and 72 hours after exposure.
Results:
A dramatic cytocidal effect of acridine orange after exposure to as little as 10 minutes of white light was observed. There was almost complete eradication of the glioblastoma cells over a 72-hour period. Although acridine orange or light alone exhibited some effect on cell growth, it was not as pronounced as the combination of acridine orange and light.
Conclusions:
This is the first study to demonstrate the photodynamic effect of acridine orange in glioblastoma cells. This data supports the need for further studies to characterize and evaluate whether this striking cytotoxic effect can be achieved in vivo. The combination of acridine orange and exposure to white unfiltered LED light may have potential future applications in management of glioblastoma.
Synergistic cancer therapy is of great interest for multiple advantages, such as excellent targeting accuracy, low side effects, and enhanced therapeutic efficiency. Herein, a near-infrared photosensitizer aza-BODIPY (AB) with high singlet oxygen quantum yield (ΦΔ = 82%) is designed and synthesized. With Schiff's base obtained from condensation reaction between doxorubicin (DOX) and polyethylene glycol-benzaldehyde (PEG–CHO) as the polymer matrix, aza-BODIPY is encapsulated to afford hydrophilic nanoparticles (DAB NPs). The DAB NPs exhibit high reactive oxygen species (ROS) generation rate and outstanding photothermal conversion efficiency (η = 38.3%) under irradiation. In vivo fluorescence- and photothermal-imaging (PTI) results demonstrate that DAB NPs can specifically accumulate at tumor sites and serve as dual-modal imaging probe for cancer diagnosis. Particularly, triggered by acidic tumor microenvironment, the HCN bond of Schiff's base would be broken simultaneously, resulting in the efficient release of DOX from DAB NPs at tumor sites as well as enhancing the targeting performance of chemotherapeutics. Compared with free DOX and aza-BODIPY nanoparticles, DAB NPs can inhibit tumor growth more effectively through pH-responsive photodynamic/photothermal/chemo synergistic therapy. This report may also present a practicable strategy to develop a pH-responsive nanotheranostic agent for tumor targeting, imaging, and therapy.
Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.
The synthesis of several aminosquaraine cationic dyes displaying strong absorption within the so-called phototherapeutic window (650-850 nm) is described. Their cytotoxicity, under dark and illuminated conditions, was tested against several human tumor cell lines (breast, lung, cervical and hepatocellular carcinomas) and non-tumor porcine liver primary cells. All compounds showed to inhibit the growth of the tumor cells upon irradiation more than in the absence of light, in more or less extension, clearly exhibiting photodynamic activity. The photosensitizing ability against some cell lines, together with the low toxicity for the non-tumor primary PLP2 cells displayed by some of the compounds synthetized, turns them into potential candidates as photosensitizers for PDT.
Squaraine rotaxanes are mechanically interlocked molecules comprised of a dumbbell shaped squaraine dye inside a tetralactam macrocycle. Previous squaraine rotaxanes have employed planar squaraine dyes with 4-aminophenyl, 2-aminothiophene or N-amino units appended to the central C4O2 core. Here we describe two rotaxanes that encapsulate a 3,3-dimethylindoline squaraine inside a tetralactam with anthracene sidewalls. The rotaxanes were prepared by a templated clipping reaction and an X-ray crystal structure shows that the squaraine gem-dimethyl groups force a relatively wide separation between the macrocycle anthracene sidewalls. The decreased interaction between the encapsulated squaraine and the anthracene sidewalls leads to a smaller red-shift of the squaraine absorption and emission bands. Solution-state studies show that the gem-dimethyl groups in 3,3-dimethylindoline squaraine dyes are large enough to prevent macrocyle threading or rotaxane unthreading. One of the new rotaxanes emits orange light (560-650 nm) and there is a ten-fold enhancement in squaraine fluorescence quantum yield upon encapsulation as a rotaxane. This orange-emitting dye completes the palette of known squaraine rotaxane fluorophores whose emission profiles span the color range from green to near-infrared.
Photodynamic therapy (PDT) is a non-invasive antitumor treatment that uses the combination of a photosensitizer, tissue oxygen, and visible light irradiation to produce cytotoxic reactive oxygen species, predominantly singlet oxygen. Currently, first-generation PDT using porfimer sodium with an excimer dye laser, and second-generation PDT using talaporfin sodium PDT with a semiconductor laser are approved by health insurance for use in Japan. However, the cancer cell specificity and selectivity of these treatments are inadequate. Cancer cells consume higher levels of glucose than normal cells and this phenomenon is known as the Warburg effect. Thus, we developed a third-generation PDT, based on the Warburg effect, by synthesizing a novel photosensitizer, sugar-conjugated chlorin, with increased cancer cell-selective accumulation. Glucose-conjugated chlorin (G-chlorin) PDT showed significantly stronger antitumor effects than second-generation talaporfin PDT. We also found that PDT with G-chlorin induced immunogenic cell death which is characterized by the secretion, release, or surface exposure of damage-associated molecular patterns (DAMPs), including calreticulin (CRT) and the high-mobility group box 1 (HMGB1) protein. Mannose-conjugated chlorin (M-chlorin) PDT which targets the mannose receptors on the surface of cancer cells and tumor-associated macrophages (TAMs) in cancer tissue stroma also showed very strong antitumor effects. These novel PDTs using glucose or M-chlorins stand as new candidates for very effective, next-generation PDTs.
With the development of nonlinear optics and new imaging methods, near-infrared (NIR) light can excite contrast agents to probe biological specimens both functionally and structurally with a deeper imaging depth and a higher spatial resolution than linear optical approaches. There is considerable and growing interest in how biological specimens respond to NIR light. Moreover, the visible absorption band of most functional nanomaterials becomes NIR-excitable through multiphoton processes, thus allowing multifunctional imaging and combined therapy with noble metal and magnetic nanoparticles both in vitro and in vivo. A groundbreaking example is the use of different laser techniques to excite single-type NIR-absorbing/emitting nanomaterials to produce multiphoton emission by femtosecond lasers using either a remote control system for photodynamic therapy or photo-induced chemical bond dissociation. These techniques provided superior anatomical resolution and detection sensitivity for in vivo tumor-targeted imaging than those offered by conventional methods. Here we summarize the most recent progress in the development of smart NIR-absorbing/emitting nanomaterials for in vivo bioapplications.
Indocyanine green (ICG) is a near-IR fluorescent dye with a great potential for application as photosensitizer in topical photodynamic therapy (PDT) of skin diseases. Despite its merits, its use has been hampered by its high degradation rate. Therefore, in the current article, ICG was encapsulated in a vesicular colloidal nanocarrier (transfersomes), with the aim of enhancing its therapeutic efficacy. Transfersomes were characterized for their entrapment efficiency, particle size, zeta potential, morphology, in vitro release and histopathological effect on mice skin. A pilot clinical study was conducted to test its therapeutic potential for PDT of basal cell carcinoma (BCC). Transfersomal ICG displayed particle size (∼125 nm) and a negative zeta potential (∼-31 mV). Transfersomes were also able to sustain the release of ICG >2 h. Upon incorporation of transfersomal ICG in gel form, it was found to maintain the normal histology of mice skin post-irradiation with diode laser 820 nm. Moreover, ICG transfersomal PDT achieved 80% clearance rate for BCC patients with minimal pain reported during treatment. The previous findings suggest that transfersomal nanoencapsulated ICG is a promising treatment modality for BCC.
Merocyanine 540-mediated photodynamic therapy (MC540-PDT) has been used in clinical trials for the purging of autologous hematopoietic stem cells grafts. When the same combinations of dye and light were applied to human peripheral blood lymphocytes, a broad range of T- and B-cell functions were impaired, prompting speculations about a potential role of MC540-PDT in the prophylaxis of graft-versus-host disease (GVHD). We here report on the effects of MC540-PDT on in vitro functions of murine lymphocytes as well as a preliminary evaluation of MC540-PDT for the prevention of GVHD in murine models of allogeneic bone marrow transplantation. Mixed lymphocyte reactions, proliferative responses to lectins, interleukin-2 and lipopolysaccharide, T-cell-mediated lysis, and NK activity were all inhibited by moderate doses of MC540-PDT. Whether MC540-PDT reduced the incidence and/or the severity of GVHD in murine models of allogeneic hematopoietic stem cell transplantation depended on the composition of the mismatched grafts and the intensity of the preparative regimen. MC540-PDT was only beneficial (i.e. reduced the incidence and/or severity of GVHD) when the spleen cell content of grafts was low and/or the radiation dose of the preparative regimen was not myeloablative, and, therefore, may have encouraged mixed chimerism.
Over the past decade the science has studied synthetic photosensitizers used in photodynamic therapy (PDT) or photochemotherapy as anticancer candidates. In this context, compounds extracted from vegetable species present interesting potential in the cancer field. In our laboratory, we studied Heterophyllaea pustulata a phototoxic shrub that habit the northwest of Argentina. From this vegetal, by in vitro germination, we obtained Rubiadin and Soranjidiol, two anthraquinones that exhibited significant photocytotoxicity on human cancer cells. In addition, the fraction obtained from callus cultures allowed us to get a satisfactory content of these compounds compared to those found from the original plant. Under PDT regimen, we found that cell destruction resulted in a dose-dependent manner and occasioned apoptosis on photosensitized cells. Biochemical analysis revealed the involvement of caspase-3, PARP cleavage and DNA fragmentation in Rubiadin induced apoptosis. Moreover, Soranjidiol-PDT led to μ-calpain-induced apoptosis involving caspases-3-independent DNA fragmentation. We also showed that both anthraquinones are cytoplasmatically distributed and out of nucleus. In addition, we demonstrated a synergic cytotoxic effect when we combined them.
Our data demonstrated that Rubiadin and Soranjidiol could be further considered as natural photocytotoxic compounds against cancer cells and callus cultures are a plausible source of these anthraquinonic compounds.a
The use of non-toxic dyes or photosensitizers (PS) in combination with harmless visible light that is known as photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In a series of three reviews we will discuss the mechanisms that operate in the field of PDT. Part one discusses the recent explosion in discovery and chemical synthesis of new PS. Some guidelines on how to choose an ideal PS for a particular application are presented. The photochemistry and photophysics of PS and the two pathways known as Type I (radicals and reactive oxygen species) and Type II (singlet oxygen) photochemical processes are discussed. To carry out PDT effectively in vivo, it is necessary to ensure sufficient light reaches all the diseased tissue. This involves understanding how light travels within various tissues and the relative effects of absorption and scattering. The fact that most of the PS are also fluorescent allows various optical imaging and monitoring strategies to be combined with PDT. The most important factor governing the outcome of PDT is how the PS interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. Examples of PS that localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes are given. Finally the use of 5-aminolevulinic acid as a natural precursor of the heme biosynthetic pathway, stimulates accumulation of the PS protoporphyrin IX is described.
The absorption and fluorescence properties of a variety of cyanine dyes in dimethyl sulfoxide solutions have been determined. The wavelengths of the absorption and fluorescence maxima and the fluorescence quantum yield relative to sodium fluorescein have been measured. The results are discussed in relation to the molecular structure.
Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. Rose Bengal (RB) is the most potent known VGLUT inhibitor (Ki 25 nM); therefore we designed, synthesized and tested in brain preparations, a series of analogs based on this scaffold. We showed that among the two tautomers of RB, the carboxylic and not the lactonic form is active against VGLUTs and generated a pharmacophore model to determine the minimal structure requirements. We also tested RB specificity in other neurotransmitter uptake systems. RB proved to potently inhibit VMAT (Ki 64 nM) but weakly VACHT (Ki>9.7 microM) and may be a useful tool in glutamate/acetylcholine co-transmission studies.
Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a natural yellow-orange dye derived from the rhizome of Curcuma longa, an East Indian plant. In order to understand the photobiology of curcumin better we have studied the spectral and photochemical properties of both curcumin and 4-(4-hydroxy-3-methoxy-phenyl)-3-buten-2-one (hC, half curcumin) in different solvents. In toluene, the absorption spectrum of curcumin contains some structure, which disappears in more polar solvents, e.g. ethanol, acetonitrile. Curcumin fluorescence is a broad band in acetonitrile (lambda max = 524 nm), ethanol (lambda max = 549 nm) or micellar solution (lambda max = 557 nm) but has some structure in toluene (lambda max = 460, 488 nm). The fluorescence quantum yield of curcumin is low in sodium dodecyl sulfate (SDS) solution (phi = 0.011) but higher in acetonitrile (phi = 0.104). Curcumin produced singlet oxygen upon irradiation (lambda > 400 nm) in toluene or acetonitrile (phi = 0.11 for 50 microM curcumin); in acetonitrile curcumin also quenched 1O2 (kq = 7 x 10(6) M-1 s-1). Singlet oxygen production was about 10 times lower in alcohols and was hardly detectable when curcumin was solubilized in a D2O micellar solution of Triton X-100. In SDS micelles containing curcumin no singlet oxygen phosphorescence could be observed. Curcumin photogenerates superoxide in toluene and ethanol, which was detected using the electron paramagnetic resonance/spin-trapping technique with 5,5-dimethyl-pyrroline-N-oxide as a trapping agent. Unidentified carbon-centered radicals were also detected.(ABSTRACT TRUNCATED AT 250 WORDS)
The synthesis of some bromine-substituted rhodamine derivatives viz., 4,5-dibromorhodamine methyl ester (dye 2) and 4,5-dibromorhodamine n-butyl ester (dye 3) are reported. These dyes were synthesized to promote a more efficient cancer cell photosensitizer for potential use in in vitro bone marrow purging in preparation for autologous bone marrow transplantation. Spectroscopic and photophysical characterization of these dyes together with rhodamine 123 (dye 1) are reported in water, methanol, ethanol and also in a microheterogeneous system, sodium dodecyl sulfate. The possible mechanism of photosensitization is characterized in terms of singlet oxygen efficiency of these dyes. Singlet oxygen quantum yields for bromine-substituted dyes are in the range of 0.3-0.5 depending on the solvent. For dye 1 no singlet oxygen production is found. The photodynamic actions of these dyes in different cell lines are tested. It was found that dye 2 and dye 3 are efficient photosensitizers and mediate eradication of K562, EM2, myeloid cell lines (CML) and the SMF-AI rhabdomyosarcoma line.
The spectroscopy and photophysics of the photosensitizer hypericin when in homogeneous solutions and when bound to liposomes were studied. Hypericin was found to partition efficiently into DMPC liposomes, with a binding constant of 58 (mg lipid/mL)-1. In these liposomes the singlet oxygen production quantum yield was 0.43 +/- 0.09. To determine the deactivation constant of singlet oxygen in lipid bilayers for the first time, we calculated extrapolated values from its quenching by DMPC and lecithin in homogeneous solutions and obtained decay times of 36.4 and 12.2 microseconds, respectively. We also measured the quenching of singlet oxygen, sensitized by hypericin in DMPC liposomes, by NaN3, diphenyl isobenzofuran and H2O:D2O mixtures and explained the results on the basis of singlet oxygen diffusing rapidly out of the lipid bilayer into the aqueous medium. The observed temperature effect on the lifetime of singlet oxygen of about 50% over a 15 degrees C range in liposome suspension contrasts with a 3% change in a homogeneous solution in 1-nonanol and is explained by the temperature effect on the diffusion out of the liposome. A strong pH effect was observed, indicating that the deprotonated species formed above about pH 10 is a much weaker photosensitizer of singlet oxygen than the native, protonated species.
High-dose chemotherapy combined with autologous transplantation using bone marrow or peripheral blood-derived stem cells (PBSC) is now widely used in the treatment of hematologic malignancies as well as some solid tumors like breast cancer (BC). However, some controversial results were recently obtained in the latter case. The presence of malignant cells in the autograft has been associated with the recurrence of the disease, and purging procedures are needed to eliminate this risk. The aim of this study was to evaluate the potential of the photosensitizer 4,5-dibromorhodamine methyl ester (TH9402), a dibrominated rhodamine derivative, to eradicate multiple myeloma (MM) and BC cell lines, while sparing more than 50% of normal pluripotential blood stem cells from healthy volunteers. The human BC MCF-7 and T-47D and MM RPMI 8226 and NCI-H929 cell lines were used to optimize the photodynamic purging process. Cell concentration and the cell suspension thickness as well as the dye and light doses were varied in order to eventually treat 1-2 L of apheresis. The light source consisted of two fluorescent scanning tubes emitting green light centered about 515 nm. The cellular uptake of TH9402 was measured during the incubation and washout periods and after photodynamic treatment (PDT) using spectrofluorometric analysis. The limiting dilution assay showed that an eradication rate of more than 5 logs is obtained when using a 40 min incubation with 5-10 microM dye followed by a 90 min washout period and a light dose of 5-10 J/cm2 (2.8 mW/cm2) in all cell lines. Agitating the 2 cm thick cell suspension containing 20 x 10(6) cells/mL during PDT was essential for maximal photoinactivation. Experiments on mobilized PBSC obtained from healthy volunteers showed that even more drastic purging conditions than those found optimal for maximal eradication of the malignant cell lines were compatible with a good recovery of hematopoietic progenitors cells. The absence of significant toxicity towards normal hematopoietic stem cells, combined with the 5 logs eradication of cancer cell lines induced by this procedure suggests that TH9402 offers an excellent potential as an ex vivo photodynamic purging agent for autologous transplantation in MM and BC treatment.
(Chemical Equation Presented) To dye for: A highly fluorescent, photostable aza-dipyrromethene dye 1 (λ em = 751 nm) with sharp and intense absorption (full width at half maximum height = 30.4 nm; ε = 159 000) in the near-infrared (NIR) region (λ max = 740 nm) is reported. The dye is insensitive to solvent polarity, meets the requirements of a NIR chromophore, and has potential use in biological probes.