Mechanism Of Photodynamic Therapy Research Articles

Recent development of nanomaterials-based PDT to improve immunogenic cell death.

Photodynamic therapy (PDT) is a clinically approved therapeutic modality for treating oncological and non-oncological disorders. PDT has proclaimed multiple benefits over further traditional cancer therapies including its minimal systemic toxicity and selective ability to eliminate irradiated tumors. In PDT, a photosensitizing substance localizes in tumor tissues and becomes active when exposed to a particular wavelength of laser light. This produces reactive oxygen species (ROS), which induce neoplastic cells to die and lead to the regression of tumors. The contributions of ROS to PDT-induced tumor destruction are described by three basic processes including direct or indirect cell death, vascular destruction,and immunogenic cell death. However, the efficiency of PDT is significantly limited by the inherent nature and tumor microenvironment. Combining immunotherapy with PDT has recently been shown to improve tumor immunogenicity while decreasing immunoregulatory repression, thereby gently modifying the anticancer immune response with long-term immunological memory effects. This review highlights the fundamental ideas, essential elements, and mechanisms of PDT as well as nanomaterial-based PDT to boost tumor immunogenicity. Moreover, the synergistic use of immunotherapy in combination with PDT to enhance immune responses against tumors is emphasized.

Applications and challenges of photodynamic therapy in the treatment of skin malignancies.

Photodynamic Therapy (PDT), as a minimally invasive treatment method, has demonstrated its distinct advantages in the management of skin malignant tumors. This article examines the current application status of PDT, assesses its successful cases and challenges in clinical treatment, and anticipates its future development trends. PDT utilizes photosensitizers to interact with light of specific wavelengths to generate reactive oxygen species that selectively eradicate cancer cells. Despite PDT's exceptional performance in enhancing patients' quality of life and prognosis, the limitation of treatment depth and the side effects of photosensitizers remain unresolved issues. With the advancement of novel photosensitizers and innovative treatment technology, the application prospects of PDT are increasingly expansive. This article delves into the mechanism of PDT, its application in various skin malignancies, its advantages and limitations, and envisions its future development. We believe that through continuous technological enhancements and integration with other treatment technologies, PDT has the potential to assume a more pivotal role in the treatment of skin malignancies.

Experimental and clinical combined photodynamic therapy for malignant and premalignant lesions using various types of radiation

The aim of the study was to present various types of radiation that can increase the effectiveness of combined photodynamic therapy (PDT) for malignant and premalignant lesions. Material and Methods. The Web of Science, Scopus, MedLine, Library, and RSCI databases were used for finding publications on this topic, mainly over the last 10 years. Of 230 sources, 64 were included in the review. Results. Photodynamic therapy is a new cancer treatment technology that has become increasingly popular in recent years. It is often an alternative method of treating cancer when there is a high risk of side effects and complications during traditional treatments such as surgery, radiation therapy and chemotherapy. PDT requires a photosensitizer, light energy, and oxygen to create reactive oxygen species that destroy cancer cells. This review examines the basic principles and mechanisms of PDT used alone and in combination with other traditional therapies. Despite the fact that PDT is an effective and non-invasive cancer treatment, it has some limitations, such as low light penetration depth, ineffective photosensitizers and tumor hypoxia. Our study examines new strategies that use other energy sources, such as infrared- and x-rays, ultrasound, as well as electric and magnetic fields, to enhance the PDT effect and overcome its limitations. Great hopes are also associated with the use of a combination of PDT and neutron capture therapy (NСT). Currently, chlorin derivatives associated with boron carriers have been developed. They can be used for both fluorescence diagnostics and PDT, as well as for NСT. The synthesized compounds have a high selectivity of accumulation in the tumor. To date, encouraging preclinical results of high efficiency of combined use of NСT and PDT have already been obtained. Conclusion. Combination with various energy sources is a key factor for further development of PDT. Future research aimed at overcoming the limitations of PDT will contribute to unlocking the full potential of this technology in clinical practice.

Effects of 630nm laser on apoptosis, metastasis, invasion and epithelial-to-mesenchymal transition of human lung squamous cell carcinoma H520 cells mediated by hematoporphyrin derivatives.

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant lung tumors. The research on the mechanism of PDT mediated by hematoporphyrin derivatives (HPD) and its cytotoxic effects on lung cancer cells has primarily focused on lung adenocarcinoma cells. However, the impact of HPD-PDT on lung squamous cell carcinoma has not been thoroughly studied. This study aimed to investigate the effects of 630nm laser on apoptosis, metastasis, invasion, and epithelial-mesenchymal transition (EMT) in human lung squamous cell carcinoma H520 cells mediated by HPD. H520 cells were divided into four groups: control group, photosensitizer group, irradiation group, and HPD-PDT group. Cell proliferation was assessed using CCK8 assay; cell apoptosis was detected by Hoechst33258 staining and flow cytometry; cell migration and invasion abilities were evaluated using wound-healing and invasion assays; and protein and mRNA expressions were analyzed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR)respectively. Results showed that HPD-PDT significantly inhibited cell proliferation, promoted apoptosis (P < 0.05), suppressed cell migration and invasion (P < 0.05), decreased Bcl-2 mRNA expression, and increased Bax and Caspase-9 mRNA expression(P < 0.05). Western blotting analysis indicated increased expression of Bax, Caspase-9, and E-cadherin, and decreased expression of Bcl-2, N-cadherin, and Vimentin (P < 0.05). In conclusion, 630nm laser mediated by HPD promoted cell apoptosis via upregulation of Bax and caspase-9, and downregulation of Bcl-2, and inhibited cell migration and invasion by regulating EMT in H520 cells.

Synergistic induction of ferroptosis by targeting HERC1-NCOA4 axis to enhance the photodynamic sensitivity of osteosarcoma

Over the past 30 years, the survival rate for osteosarcoma (OS) has remained stagnant, indicating persistent challenges in diagnosis and treatment. Photodynamic therapy (PDT) has emerged as a novel and promising treatment modality for OS. Despite apoptosis being the primary mechanism attributed to PDT, it fails to overcome issues such as low efficacy and resistance. Ferroptosis, a Fe2+-dependent cell death process, has the potential to enhance PDT's efficacy by increasing reactive oxygen species (ROS) through the Fenton reaction. In this study, we investigated the anti-tumor mechanism of PDT and introduced an innovative therapeutic strategy that synergistically induces apoptosis and ferroptosis. Furthermore, we have identified HERC1 as a pivotal protein involved in the ubiquitination and degradation of NCOA4, while also uncovering a potential regulatory factor involving NRF2. Ultimately, by targeting the HERC1-NCOA4 axis during PDT, we successfully achieved full activation of ferroptosis, which significantly enhanced the anti-tumor efficacy of PDT. In conclusion, these findings provide new theoretical evidence for further characterizing mechanism of PDT and offer new molecular targets for the treatment of OS.

In situ pain relief during photodynamic therapy by ROS-responsive nanomicelle through blocking VGSC

Pain in photodynamic therapy (PDT), resulting from the stimulation of reactive oxygen species (ROS) and local acute inflammation, is a primary side effect of PDT that often leads to treatment interruption or termination, significantly compromising the efficacy of PDT and posing an enduring challenge for clinical practice. Herein, a ROS-responsive nanomicelle, poly(ethylene glycol)-b-poly(propylene sulphide) (PEG-PPS) encapsulated Ce6 and Lidocaine (LC), (ESCL) was used to address these problems. The tumor preferentially accumulated micelles could realize enhanced PDT effect, as well as in situ quickly release LC due to its ROS generation ability after light irradiation, which owes to the ROS-responsive property of PSS. In addition, PSS can suppress inflammatory pain which is one of the mechanisms of PDT induced pain. High LC-loaded efficiency (94.56 %) owing to the presence of the thioether bond of the PPS made an additional pain relief by inhibiting excessive inflammation besides blocking voltage-gated sodium channels (VGSC). Moreover, the anti-angiogenic effect of LC offers further therapeutic effects of PDT. The in vitro and in vivo anti-tumor results revealed significant PDT efficacy. The signals of the sciatic nerve in mice were measured by electrophysiological study to evaluate the pain relief, results showed that the relative integral area of neural signals in ESCL-treated mice decreased by 49.90 % compared to the micelles without loaded LC. Therefore, our study not only develops a very simple but effective tumor treatment PDT and in situ pain relief strategy during PDT, but also provides a quantitative pain evaluation method.

Enhancing PDT efficacy in NMIBC: Efflux inhibitor mediated improvement of PpIX levels and efficacy of the combination of PpIX-PDT and SO-cleavable prodrugs.

Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX-PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX-PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation.

Mechanisms of photodynamic therapy with applications in tumor cells

Mechanisms of photodynamic therapy with applications in tumor cells

Modulation of heat shock protein expression and cytokine levels in MCF-7 cells through photodynamic therapy.

In this study, we assess the impact of photodynamic therapy (PDT) using aluminum phthalocyanine tetrasulfonate (AlPcS4) on the viability and cellular stress responses of MCF-7 breast cancer cells. Specifically, we investigate changes in cell viability, cytokine production, and the expression of stress-related genes. Experimental groups included control cells, those treated with AlPcS4 only, light-emitting diode (LED) only, and combined PDT. To evaluate these effects on cell viability, cytokine production, and the expression of stress-related genes, techniques such as 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, enzyme-linked immunosorbent assays (ELISA), and real-time quantitative PCR (RT‒qPCR) were employed. Our findings reveal how PDT with AlPcS4 modulates mitochondrial activity and cytokine responses, shedding light on the cellular pathways essential for cell survival and stress adaptation. This work enhances our understanding of PDT's therapeutic potential and mechanisms in treating breast cancer.

Photodynamic therapy inhibits cancer progression and induces ferroptosis and apoptosis by targeting P53/GPX4/SLC7A11 signaling pathways in cholangiocarcinoma

BackgroundCholangiocarcinoma (CCA) is a malignant tumor with a poor prognosis. The specific mechanism of photodynamic therapy (PDT) in treating CCA remains unclear. This study aims to investigate the mechanisms of PDT in the treatment of CCA and try to improve the therapeutic effect of PDT by intervening associated signaling pathways. MethodsThe Cell Counting Kit-8 (CCK-8) was used to examine the cytotoxicity of CCA cell lines following PDT. Apoptosis and reactive oxygen species (ROS) levels were measured by flow cytometry. A transmission electron microscope was used to study the changes in cell mitochondria after PDT. The levels of glutathione (GSH), malondialdehyde (MDA), ferrous iron (Fe2+), lactate dehydrogenase (LDH), and lipid peroxide (LPO) were determined. Changes in the expression of apoptosis and ferroptosis-related proteins were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Xenograft tumor models were developed to investigate the effects of PDT on tumor proliferation, apoptosis, and ferroptosis in vivo. ResultsPDT inhibited tumor proliferation and induced apoptosis both in vivo and in vitro. This treatment led to swelling and damage of the mitochondria in affected cells. Furthermore, ROS levels rose, accompanied by an increase in the proportion of apoptotic-positive cells. The expressions of Bax and Caspase-3 were upregulated, while the Bcl-2 was downregulated. Meanwhile, PDT triggered ferroptosis, marked by decreased expressions of GPX4 and SLC7A11, and reduced GSH levels. This was accompanied by upregulation of P53 expression and heightened levels of Fe2+, LPO, MDA, and LDH. After inducing the ferroptosis pathway, the therapeutic effect of PDT was enhanced, the tumor tissue was further reduced, and the degree of malignancy was reduced. ConclusionPDT promotes apoptosis and ferroptosis of cholangiocarcinoma cells by activating the P53/SLC7A11/GPX4 signaling pathway and inhibits the growth of cholangiocarcinoma. Inducing ferroptosis can enhance the effectiveness of photodynamic therapy.

The effects of photodynamic therapy on the immune response of women with cervical high-grade squamous intraepithelial lesions

ObjectiveTo evaluate and elucidate the effects and mechanism of photodynamic therapy (PDT) on the immune response of women with cervical high-grade squamous intraepithelial lesions (HSILs). Materials and methodsImmunofluorescence staining was used to compare immune infiltration before and after PDT in 23 patients with cervical HSILs. The infiltration of immune cells into the cervical tissues of patients with different outcomes was also compared at the 6-month follow-up period. Immune cell counts in samples collected before and after treatment were compared. ResultsWe found an increased number of CD8+ T cell infiltration, an increased proportion of CD8+ T cells expressing Granzyme B (GrB), Chemokine receptor 3 (CXCR3), and CD8+ tissue-resident memory T (TRM) cells, and a decreased proportion of CD8+ T cells expressing PD-1 in patients with cervical HSIL compared to that before PDT. Moreover, at the 6-month follow-up, there was higher infiltration of CD8+ T and CD8+ TRM cells, higher expression of GrB and CXCR3, and lower expression of PD-1 on CD8+ T cells in the HPV and cervical HSIL clearance groups than in the persistent HPV infection and cervical HSIL regression groups. However, no significant difference was observed in the number of CD8+ TSCM following PDT. ConclusionPDT activates immune responses mediated by CD8+ T cells. The degree of the immune response is correlated with the prognosis of cervical HSIL.

Identification of Ru-based PDT resistance mechanisms by CRISPR/Cas9 screen in HNSCC

SignificanceThis project provides an in-depth knowledge of the mode of action of novel designed Ruthenium photodynamic therapy (PDT) complex, and provides information about how head and neck squamous cell carcinomas (HNSCC) cells resist to these treatments. ApproachTo obtain a comprehensive view of the molecular bases of Ru-based photocytotoxicity in HNSCC, we performed a genome-wide randomly knock-out clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen. The comparison of sequencing data from treated and non-treated conditions will identify deleted sequences in challenged SQ20B cells by next-generation sequencing (NGS). ResultsWe have identified HSPE1 gene is associated to resistance mechanisms induced by RuII-based PDT treatment. Further investigation of the candidate gene on apoptosis induction through gain- and loss- of function assays. ConclusionsIn this study, we employed a genome-wide CRISPR/Cas9 screen to decipher molecular response mechanisms of Ru-based PDT in HNSCC cells.

Oxygen-independent organic photosensitizer with ultralow-power NIR photoexcitation for tumor-specific photodynamic therapy

Photodynamic therapy (PDT) is a promising cancer treatment but has limitations due to its dependence on oxygen and high-power-density photoexcitation. Here, we report polymer-based organic photosensitizers (PSs) through rational PS skeleton design and precise side-chain engineering to generate •O2− and •OH under oxygen-free conditions using ultralow-power 808 nm photoexcitation for tumor-specific photodynamic ablation. The designed organic PS skeletons can generate electron-hole pairs to sensitize H2O into •O2− and •OH under oxygen-free conditions with 808 nm photoexcitation, achieving NIR-photoexcited and oxygen-independent •O2− and •OH production. Further, compared with commonly used alkyl side chains, glycol oligomer as the PS side chain mitigates electron-hole recombination and offers more H2O molecules around the electron-hole pairs generated from the hydrophobic PS skeletons, which can yield 4-fold stronger •O2− and •OH production, thus allowing an ultralow-power photoexcitation to yield high PDT effect. Finally, the feasibility of developing activatable PSs for tumor-specific photodynamic therapy in female mice is further demonstrated under 808 nm irradiation with an ultralow-power of 15 mW cm−2. The study not only provides further insights into the PDT mechanism but also offers a general design guideline to develop an oxygen-independent organic PS using ultralow-power NIR photoexcitation for tumor-specific PDT.

Near-infrared light-activated smart nanogels for remotely controlled cytochrome c release and photodynamic therapy

The utilization of reactive oxygen species (ROS) generated through photodynamic therapy (PDT) for remote-controlled release of protein drugs at specific sites using near-infrared light represents a groundbreaking development in protein delivery system innovation. To illustrate this principle, we engineered near-infrared light-activated smart nanogels (NASNs) by chemically cross-linking ROS-responsive linkages within hyaluronic acid-graft-methoxy poly(ethylene glycol)-diethylenetriamine-grafted-chlorine e6 (Ce6) polymer (HA-PEG-Dien-g-Ce6) and carboxylated thioketal (TK) serving as a cross-linker to enable PDT-driven cytochrome c (CC) liberation. The NASNs demonstrated substantial loading capacity and exceptional stability across diverse biological settings, attributed to the robust nature of the TK bond. Notably, CC-loaded NASNs effectively penetrated A549 cells via CD44-mediated endocytosis and rapidly escaped from the endo-lysosomal compartment. Upon light activation, the Ce6 produced ROS, leading to TK bond disruption in NASNs, and consequent release of encapsulated CC. This precise, photo-induced PDT mechanism and CC liberation markedly enhanced antitumor efficacy while maintaining minimal toxicity, establishing a solid foundation for remote, as-needed protein delivery systems and potential integration with additional therapeutic modalities.

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer

BackgroundThe effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study...

Exploration of new models for primary dysmenorrhea treatment: low-power visible-light-activated photodynamic therapy and oral contraceptives.

Primary dysmenorrhea (PD) is one of the most common reasons that affect the life quality of women during childbearing age. This research aims to explore the efficacy and curative effect characteristics of oral contraceptives and low-power visible-light-activated photodynamic therapy (PDT). Besides investigating the possible mechanism of PDT, we expected to find a treatment model with better efficacy and fewer side effects. It was a multicenter, randomized, parallel-controlled study. Eligible participants were randomly assigned to three groups: placebo group, oral contraceptive (Marvelon) group, and the PDT group. They were treated continuously for three menstrual cycles and followed up for two cycles after treatment. The scores of the visual analog scale (VAS) and the concentration of pain-related small molecules in blood before and after treatment were recorded in each group, which can evaluate the therapeutic characteristics of different treatments. Both Marvelon and PDT were effective. The effect of Marvelon appears quickly which can significantly relieve symptoms at the beginning, while PDT shows a relatively slow role. There was no significant difference in the final efficacy two cycles after treatment. The therapeutic effect was achieved by reducing the concentrations of prostaglandin 2 (PGE2) and endothelin (ET) in the blood. Marvelon and PDT are effective methods for the treatment of PD. The long-term efficacy of the two is similar, while the therapeutic characteristics and the side effects are different. Patients can choose the suitable way according to their individual needs.

Recent advances for enhanced photodynamic therapy: from new mechanisms to innovative strategies.

Photodynamic therapy (PDT) has been developed as a potential cancer treatment approach owing to its non-invasiveness, spatiotemporal control and limited side effects. Currently, great efforts have been made to improve the PDT effect in terms of safety and efficiency. In this review, we highlight recent advances in innovative strategies for enhanced PDT, including (1) the development of novel radicals, (2) design of activatable photosensitizers based on the TME and light, and (3) photocatalytic NADH oxidation to damage the mitochondrial electron transport chain. Additionally, the new mechanisms for PDT are also presented as an inspiration for the design of novel PSs. Finally, we discuss the current challenges and future prospects in the clinical practice of these innovative strategies. It is hoped that this review will provide a new angle for understanding the relationship between the intratumoural redox environment and PDT mechanisms, and new ideas for the future development of smart PDT systems.

Cyclometalated iridium(III) tetrazine complexes for mitochondria-targeted two-photon photodynamic therapy.

The fast-moving field of photodynamic therapy (PDT) has provided fresh opportunities to expand the potential of metallodrugs to combat cancers in a light-controlled manner. As such, in the present study, a series of cyclometalated Ir(III) complexes modified with a tetrazine functional group (namely, Ir-ppy-Tz, Ir-pbt-Tz, and Ir-dfppy-Tz) are developed as potential two-photon photodynamic anticancer agents. These complexes target mitochondria but exhibit low toxicity towards HLF primary lung fibroblast normal cells in the dark. When receiving a low-dose one- or two-photon PDT, they become highly potent towards A549 lung cancer cells (with IC50 values ranging from 24.0 nM to 96.0 nM) through the generation of reactive oxygen species (ROS) to induce mitochondrial damage and subsequent apoptosis. Our results indicated that the incorporation of tetrazine with cyclometalated Ir(III) matrices would increase the singlet oxygen (1O2) quantum yield (ΦΔ) and, meanwhile, enable a type I PDT mechanism. Ir-pbt-Tz, with the largest two-photon absorption (TPA) cross-section (σ2 = 102 GM), shows great promise in serving as a two-photon PDT agent for phototherapy.

A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis.

Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence.

Rational design of type-I photosensitizer molecules for mitochondrion-targeted photodynamic therapy.

Photodynamic therapy (PDT) has emerged as a promising approach for tumor treatment. However, traditional type II PDT faces limitations due to its oxygen-dependent nature. Type-I photosensitizers (PSs) exhibit superiority over conventional type-II PSs owing to their diminished oxygen dependence. Nevertheless, designing effective type-I PSs remains a significant challenge. In this work, we provide a novel strategy to tune the PDT mechanism of an excited photosensitizer through aryl substituent engineering. Using S-rhodamine as the base structure, three PSs were synthesized by incorporating phenyl, furyl, or thienyl groups at the meso position. Interestingly, furyl- or thienyl-substituted S-rhodamine are type-I-dominated PSs that produce O2˙-, while phenyl S-rhodamine results in O2˙- and 1O2 through type-I and type-II mechanisms, respectively. Experimental analyses and theoretical calculations showed that the introduction of a five-membered heterocycle at the meso position promoted intersystem crossing (ISC) and electron transfer, facilitating the production of O2˙-. Furthermore, furyl- or thienyl-substituted S-rhodamine exhibited high phototoxicity at ultralow concentrations. Thienyl-substituted S-rhodamine showed promising PDT efficacy against hypoxic solid tumors. This innovative strategy provides an alternative approach to developing new type-I PSs without the necessity for creating entirely new skeletons.