An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT is still limited in its success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) were conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy in SH-SY5Y human neuroblastoma cells. The AuNP-mTHPC complex is biocompatible, soluble, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650-nm laser, which decreased mitochondrial membrane potential (^∆ψ_m). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Our study aimed at applying the AuNP-mTHPC approach as a potential treatment of cancer in the biomedical field.     

Photodynamic Therapy of Up-Conversion Nanomaterial Doped with Gold Nanoparticles

Two key concerns exist in contemporary cancer chemotherapy: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating the revolutionary cancer treatment techniques of photodynamic therapy (PDT) and photothermal therapy (PTT) proposed by many scholars. A photothermal treatment of cancer was synthesized using the hydrothermal method which has high photothermal conversion efficiency and can generate reactive oxygen species (ROS) in cells. Photothermal treatment of tumors has a good short-term effect and photodynamic therapy lasts longer. However, both PTT and PDT have their inevitable shortcomings and it is difficult to completely eradicate a tumor using a single mode of treatment. PTT and PDT synergistic treatment not only inherits the advantages of low toxicity and side effects of phototherapy but also enables the two treatment methods to complement each other. It is an effective strategy to improve curative effects and reduce toxic and side effects. Furthermore, gold doped UCNPs have an exceptionally high target recognition for tumor cells. The gold doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy and exceptionally low side effects. These findings may encourage the creation of fresh, effective imaging-guided approaches to meet the goal of photothermal cancer therapy.     

Label-Free,Longitudinal Visualization of PDT Response In Vitro with Optical Coherence Tomography

A major challenge in creating and optimizing therapeutics in the fight against cancer is visualizing and understanding the microscale spatiotemporal treatment response dynamics that occur in patients. This is especially true for photodynamic therapy (PDT), where therapeutic optimization relies on understanding the interplay between factors such as photosensitizer localization and uptake, in addition to light dose and delivery rate. In vitro 3D culture systems that recapitulate many of the biological features of human disease are powerful platforms for carrying out detailed studies on PDT response and resistance. Current techniques for visualizing these models, however, often lack accuracy due to the perturbative nature of the sample preparation, with light attenuation complicating the study of intact models. Optical coherence tomography (OCT) is an ideal method for the long-term, non-perturbative study of in vitro models and their response to PDT. Monitoring the response of 3D models to PDT by time-lapse OCT methods promises to provide new perspectives and open the way to cancer treatment methodologies that can be translated towards the clinic.     

Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer

Colorectal cancer (CRC) involving a malignant tumour remains one of the greatest contributing causes of fatal mortality and has become the third globally ranked malignancy in terms of cancer-associated deaths. Conventional CRC treatment approaches such as surgery, radiation, and chemotherapy are the most utilized approaches to treat this disease. However, they are limited by low selectivity and systemic toxicity, so they cannot completely eradicate this disease. Photodynamic therapy (PDT) is an emerging therapeutic modality that exerts selective cytotoxicity to cancerous cells through the activation of photosensitizers (PSs) under light irradiation to produce cytotoxic reactive oxygen species (ROS), which then cause cancer cell death. Cumulative research findings have highlighted the significant role of traditional PDT in CRC treatment; however, the therapeutic efficacy of the classical PDT strategy is restricted due to skin photosensitivity, poor cancerous tissue specificity, and limited penetration of light. The application of nanoparticles in PDT can mitigate some of these shortcomings and enhance the targeting ability of PS in order to effectively use PDT against CRC as well as to reduce systemic side effects. Although 2D culture models are widely used in cancer research, they have some limitations. Therefore, 3D models in CRC PDT, particularly multicellular tumour spheroids (MCTS), have attracted researchers. This review summarizes several photosensitizers that are currently used in CRC PDT and gives an overview of recent advances in nanoparticle application for enhanced CRC PDT. In addition, the progress of 3D-model applications in CRC PDT is discussed.     

Stromal Interactions as Regulators of Tumor Growth and Therapeutic Response: A Potential Target for Photodynamic Therapy?

It has become increasingly widely recognized that the stroma plays several vital roles in tumor growth and development and that tumor-stroma interactions can in many cases account for poor therapeutic response. Inspired by an emerging body of literature, we consider the potential role of photodynamic therapy (PDT) in targeting interactions with stromal fibroblasts and mechanosensitive signaling with the extracellular matrix as a means to drive tumors toward a more therapeutically responsive state and synergize with other treatments. This concept is particularly relevant for cancer of the pancreas, which is characterized by tumors with a profoundly dense, rigid fibrous stroma. Here we introduce new in vitro systems to model interactions between pancreatic tumors and their mechanical microenvironment and restore signaling with stromal fibroblasts. Using one such model as a test bed it is shown here that PDT treatment is able to destroy fibroblasts in an in vitro 3D pancreatic tumor-fibroblast coculture. These results and the literature suggest the further development of PDT as a potential modality for stromal depletion.     

Carbon-Based Materials in Photodynamic and Photothermal Therapies Applied to Tumor Destruction

Within phototherapy, a grand challenge in clinical cancer treatments is to develop a simple, cost-effective, and biocompatible approach to treat this disease using ultra-low doses of light. Carbon-based materials (CBM), such as graphene oxide (GO), reduced GO (r-GO), graphene quantum dots (GQDs), and carbon dots (C-DOTs), are rapidly emerging as a new class of therapeutic materials against cancer. This review summarizes the progress made in recent years regarding the applications of CBM in photodynamic (PDT) and photothermal (PTT) therapies for tumor destruction. The current understanding of the performance of modified CBM, hybrids and composites, is also addressed. This approach seeks to achieve an enhanced antitumor action by improving and modulating the properties of CBM to treat various types of cancer. Metal oxides, organic molecules, biopolymers, therapeutic drugs, among others, have been combined with CBM to treat cancer by PDT, PTT, or synergistic therapies.     

Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models

Photodynamic therapy (PDT) is a promising non-invasive phototherapeutic approach for cancer therapy that can eliminate local tumor cells and produce systemic antitumor immune responses. In recent years, significant efforts have been made in developing strategies to further investigate the immune mechanisms triggered by PDT. The majority of in vitro experimental models still rely on the two-dimensional (2D) cell cultures that do not mimic a three-dimensional (3D) cellular environment in the human body, such as cellular heterogeneity, nutrient gradient, growth mechanisms, and the interaction between cells as well as the extracellular matrix (ECM) and therapeutic resistance to anticancer treatments. In addition, in vivo animal studies are highly expensive and time consuming, which may also show physiological discrepancies between animals and humans. In this sense, there is growing interest in the utilization of 3D tumor models, since they precisely mimic different features of solid tumors. This review summarizes the characteristics and techniques for 3D tumor model generation. Furthermore, we provide an overview of innate and adaptive immune responses induced by PDT in several in vitro and in vivo tumor models. Future perspectives are highlighted for further enhancing PDT immune responses as well as ideal experimental models for antitumor immune response studies.     

Combination of Immunotherapy and Photo-pyroptosis as Novel Anticancer Strategy

Immunotherapy has made great progress in clinical cancer treatment in recent years, but its therapeutic efficacy is significantly limited by the lack of immunogenicity in the tumor microenvironment. Pyroptosis is a type of programmed cell death in which the dying cancer cells produce inflammatory cytokines to relieve the immuno-suppressive microenvironment and thus increase anti-tumor immunity. Reactive oxygen species (ROS) produced during photodynamic therapy (PDT) are one of the efficient activators that induce pyroptosis. Recently, a few photosensitizers have emerged with the ability to induce immunogenic cancer cell death via pyroptosis, opening a new field for PDT. This highlight introduces the latest research on antitumor strategies achieved by the combination of immunotherapy and photodynamic therapy through photo-pyroptosis.     

Nanoparticle-Based Drug Delivery Systems for Photodynamic Therapy of Metastatic Melanoma: A Review

Metastatic melanoma (MM) is a skin malignancy arising from melanocytes, the incidence of which has been rising in recent years. It poses therapeutic challenges due to its resistance to chemotherapeutic drugs and radiation therapy. Photodynamic therapy (PDT) is an alternative non-invasive modality that requires a photosensitizer (PS), specific wavelength of light, and molecular oxygen. Several studies using conventional PSs have highlighted the need for improved PSs for PDT applications to achieve desired therapeutic outcomes. The incorporation of nanoparticles (NPs) and targeting moieties in PDT have appeared as a promising strategy to circumvent various drawbacks associated with non-specific toxicity, poor water solubility, and low bioavailability of the PSs at targeted tissues. Currently, most studies investigating new developments rely on two-dimensional (2-D) monocultures, which fail to accurately mimic tissue complexity. Therefore, three-dimensional (3-D) cell cultures are ideal models to resemble tumor tissue in terms of architectural and functional properties. This review examines various PS drugs, as well as passive and active targeted PS nanoparticle-mediated platforms for PDT treatment of MM on 2-D and 3-D models. The overall findings of this review concluded that very few PDT studies have been conducted within 3-D models using active PS nanoparticle-mediated platforms, and so require further investigation.     

Self-Assembled Porphyrinoids: One-Component Nanostructured Photomedicines

Photodynamic therapy (PDT) is becoming a promising way to treat various kinds of cancers, with few side effects. Porphyrinoids are the most relevant photosensitizers (PS) in PDT, because they present high extinction coefficients, biocompatibility, and excellent photochemical behavior. To maximize therapeutic effects, polymer-PS conjugates, and PS-loaded nanoparticles have been developed, with insights in improving tumor delivery. However, some drawbacks such as non-biodegradability, multistep fabrication, and low reagent loadings limit their clinical application. A novel strategy, noted by some authors as the “one-for-all” approach, is emerging to circumvent the use of additional delivery agents. This approach relies on the self-assembly of amphiphilic PS to fabricate nanostructures with improved transport properties. In this review we focus on different rational designs of porphyrinoid PS to achieve some of the following attributes in nanoassembly: i) selective uptake, through the incorporation of recognizable biological vectors; ii) responsiveness to stimuli; iii) combination of imaging and therapeutic functions; and iv) multimodal therapy, including photothermal or chemotherapy abilities.     

Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer.     

Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I–II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC.     

Photodynamic and Antibiotic Therapy in Combination to Fight Biofilms and Resistant Surface Bacterial Infections

Although photodynamic therapy (PDT), a therapeutic approach that involves a photosensitizer, light and O₂, has been principally considered for the treatment of specific types of cancers, other applications exist, including the treatment of infections. Unfortunately, PDT does not always guarantee full success since it exerts lethal effects only in cells that have taken up a sufficient amount of photosensitizer and have been exposed to adequate light doses, conditions that are not always achieved. Based on our previous experience on the combination PDT/chemotherapy, we have explored the possibility of fighting bacteria that commonly crowd infected surfaces by combining PDT with an antibiotic, which normally does not harm the strain at low concentrations. To this purpose, we employed 5-aminolevulinic acid (5-ALA), a pro-drug that, once absorbed by proliferating bacteria, is converted into the natural photosensitizer Protoporphyrin IX (PpIX), followed by Gentamicin. Photoactivation generates reactive oxygen species (ROS) which damage or kill the cell, while Gentamicin, even at low doses, ends the work. Our experiments, in combination, have been highly successful against biofilms produced by several Gram positive bacteria (i.e., Staphylococcus aureus, Staphylococcus epidermidis, etc.). This original approach points to potentially new and wide applications in the therapy of infections of superficial wounds and sores.     

Regulation of miRNA Expression by Low-Level Laser Therapy (LLLT) and Photodynamic Therapy (PDT)

Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression.     

Aminolevulinic Acid-Mediated Photodynamic Therapy of Human Meningioma: An in Vitro Study on Primary Cell Lines

Objective: Five-aminolevulinic acid (5-ALA)-induced porphyrins in malignant gliomas are potent photosensitizers. Promising results of ALA-PDT (photodynamic therapy) in recurrent glioblastomas have been published. Recently, 5-ALA-induced fluorescence was studied in meningioma surgery. Here, we present an experimental study of ALA-PDT in an in vitro model of primary meningioma cell lines. Methods: We processed native tumor material obtained intra-operatively within 24 h for cell culture. Epithelial membrane antigen (EMA) immunohistochemistry was performed after the first passage to confirm that cells were meningioma cells. For 5-ALA-PDT treatment, about 5000 cells per well were seeded in 20 wells of a blank 96-well plate. Each block of 4 wells was inoculated with 150 µL of 0, 25, 50 and 100 µg/mL 5-ALA solutions; one block was used as negative control without 5-ALA and without PDT. Following incubation for 3 h PDT was performed using a laser (635 nm, 18.75 J/cm²). The therapeutic response was analyzed by the water soluble tetrazolium salt (WST-1) cell viability assay 90 min after PDT. Results: 5-ALA-PDT was performed in 14 primary meningioma cell lines. EMA expression was verified in 10 primary cell cultures. The remaining 4 were EMA negative and PDT was without any effect in these cultures. All 10 EMA-positive cell lines showed a significant and dose-dependent decrease in viability rate (p < 0.001). Cell survival at 5-ALA concentrations of 12.5, 25, 50 and 100 μg/mL was 96.5% ± 7.6%, 67.9% ± 29.9%, 24.0% ± 16.7% and 13.8% ± 7.5%, respectively. For the negative controls (no 5-ALA/PDT and ALA/no PDT), the viability rates were 101.72% ± 3.5% and 100.17% ± 3.6%, respectively. The LD₅₀ for 5-ALA was estimated between 25 and 50 µg/mL. Conclusion: This study reveals dose-dependent cytotoxic effects of 5-ALA-PDT on primary cell lines of meningiomas. Either 5-ALA or PDT alone did not affect cell survival. Further efforts are necessary to study the potential therapeutic effects of 5-ALA-PDT in vivo.     

Verteporfin-Loaded Mesoporous Silica Nanoparticles’ Topical Applications Inhibit Mouse Melanoma Lymphangiogenesis and Micrometastasis In Vivo

Photodynamic therapy (PDT) has been pointed out as a candidate for improving melanoma treatment. Nanotechnology application in PDT has increased its efficacy by reducing side effects. Herein, mesoporous silica nanoparticles (MSNs) conjugated with verteporfin (Ver-MSNs), in use with PDT, were administered in mice to evaluate their efficacy on lymphoangiogenesis and micrometastasis in melanoma. Melanoma was induced in mice by the subcutaneous injection of B16-F10 cells. The mice were transcutaneously treated with MSNs, Ver-MSNs, or glycerol and exposed to red light. The treatment was carried out four times until day 20. Lymphangiogenesis and micrometastasis were identified by the immunohistochemical method. Lymphoangiogenesis was halved by MSN treatment compared with the control animals, whereas the Ver-MSN treatment almost abolished it. A similar reduction was also observed in lung micrometastasis. PDT with topically administrated Ver-MSNs reduced melanoma lymphoangiogenesis and lung micrometastasis, as well as tumor mass and angiogenesis, and therefore their use could be an innovative and useful tool in melanoma clinical therapy.     

Erlotinib-Modified BODIPY Photosensitizers for Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is an innovative, non-invasive and highly selective therapeutic modality for tumours and non-malignant diseases. BODIPY based molecules can function as new generation photosensitizers (PSs) in various PDT applications. Despite numerous conjugated PS systems are available, BODIPYs containing erlotinib lagged behind other photosensitizer units. In this study, smart photosensitizers containing BODIPY, erlotinib and hydrophilic units were prepared for the first time, their physicochemical properties and PDT effects were investigated. Compared with non-halogenated compound, halogenated derivatives possessed much lower fluorescence profile as well as the good ROS generation ability under red light. In vitro PDT studies were performed on both healthy (PNT1a) and prostate cancerous cells (PC3) to determine the selectivity of the compounds on cancerous cells and their effects under light. The halogenated conjugates, exposed to low dose of light illumination exhibited potent activity on cancer cell viability and the calculated IC₅₀ values proved the high phototoxicity of the photosensitizers. It was also determined that the PSs have very low dark toxicity and that the light illumination and ROS formation are required for the initiation of the cell death mechanism. As a result, erlotinib modified BODIPYs could serve as promising agents in anticancer photodynamic therapy.     

Critical PDT Theory III: Events at the Molecular and Cellular Level

Photodynamic therapy (PDT) is capable of eradicating neoplastic cells that are accessible to sufficient light and oxygen. There is adequate information now available for assessing conditions where PDT might be the therapy of choice, but limited access to clinical facilities and impediments to regulatory approval of new agents have limited clinical usage. Early reports mainly involved clinical data with few thoughts towards finding death pathways. In 2022, there is a clear understanding of the determinants of successful tumor eradication. While PDT may be the optimal method for many clinical indications, support for this approach has lagged. This report provides a commentary on some elements of recent progress in PDT at the molecular and cellular levels, along with a discussion of some of the limitations in current research efforts.     

Photodynamic Therapy and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with AuNPs

Two key concerns exist in contemporary cancer chemotherapy in clinic: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating a revolutionary cancer treatment technique, and photodynamic therapy (PDT) has been proposed by many scholars. A drug for photodynamic cancer treatment was synthesized using the hydrothermal method, which has a high efficiency to release reactive oxygen species (ROS). It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI) due to its photothermal effect, computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, Au-doped up-conversion nanoparticles (UCNPs) have an exceptionally high luminous intensity. The Au-doped UCNPs, in particular, are non-toxic to tissues without laser at an 808 nm wavelength, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage fresh effective imaging-guided approaches to meet the goal of photodynamic cancer therapy to be created.     

Reduction electrochimique de la (Pyridyle-2)-3-diphenyle-5,6-triazine-1,2,4

The electrochemical reduction of the triazine PDT [3-(2-pyridyl)-5,6-diphenyl-1,2,4 triazine] in dimethylformamide indicates that the first reduction potential and the corresponding mechanism depend tremendously on the medium acidity. In the presence of protic acid, the first reduction of PDT is a two electron process which involves two protons per mole of PDT. The reduction products were characterized by thin layer chromatography and by NMR, thus allowing to identify the reduction sites in the PDT.