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Effect of Photodynamic Therapy on Tumor Necrosis Factor Production by Murine Macrophages
Abstract
Photodynamic therapy (PDT) involves the treatment of tumors in the presence of sensitizer, light, and oxygen, causing energy-dependent cytotoxicity. A vascular effect that causes hemorrhagic tumor necrosis has been described with PDT, but its basis remains undefined. To investigate the possible role of tumor necrosis factor (TNF) production in the generation of such a vascular effect and/or a direct tumor effect, we treated thioglycollate-elicited murine macrophages with PDT, and we measured the possible production of TNF using the L929 assay. An energy-dependent production of TNF by macrophage treated with PDT, stimulated or unstimulated with endotoxin, was demonstrated, and TNF production was inhibited at the highest treatment energy levels. These data represent the first description of cytokine production by PDT-treated macrophages, and may serve as another mechanism of PDT cytotoxicity in vivo, either directly by TNF-mediated tumor necrosis, or indirectly by vascular effects on tumor vessels.
... Several studies have obtained peritoneal MΦ after induction of leukocyte extravasation following 3-4 days of thioglycolate administration, using concentrations from 2.9 to 4.5% (Evans et al., 1990;Zampronio et al., 1994;Soudi et al., 2013;Miranda et al., 2013). These studies used the trypan blue exclusion technique to analyze cell viability. ...
... Our results showed a decrease in MΦ viability in the PpIX-mediated PDT group. Two other research groups showed the same results with MΦ and explained that cytotoxicity by PDT using ALA and Photofrin II can increase programming or no-programming of cell death caused by ROS and RNS, although the MΦ were exposed to light dosages, drug concentrations or drug concentration per unit of time at levels much higher than those used in our light-drug study (Evans et al., 1990;Kawczyk-Krupka et al., 2011). Evans et al. (1990) showed that a higher dose of PDT exposure prevents MΦ from producing TNF-α. ...
... Two other research groups showed the same results with MΦ and explained that cytotoxicity by PDT using ALA and Photofrin II can increase programming or no-programming of cell death caused by ROS and RNS, although the MΦ were exposed to light dosages, drug concentrations or drug concentration per unit of time at levels much higher than those used in our light-drug study (Evans et al., 1990;Kawczyk-Krupka et al., 2011). Evans et al. (1990) showed that a higher dose of PDT exposure prevents MΦ from producing TNF-α. This did not occur in our study, as a lower dose was used. ...
Little is known regarding whether photodynamic therapy (PDT)-induced cell death can substantially compromise macrophages (MΦ), which are important cells in PDT-induced immune responses. Here, parameters of PDT-mediated MΦ cytotoxicity and cytokine production in response to protoporphyrin IX (PpIX) were evaluated. Peritoneal MΦ from BALB/c mice were stimulated in vitro with PDT, light, PpIX, or lipopolysaccharide (LPS). After that, cell viability, lipid peroxidation, Nitric Oxide (NO), DNA damage, TNF-α, IL-6 and IL-10 were evaluated. Short PDT exposure reduced cell viability by 10–30%. There was a two-fold increase in NO and DNA degradation, despite the non-increase in lipoperoxidation. PDT increased TNF-α and IL-10, particularly in the presence of LPS, and decreased the production of IL-6 to 10-fold. PDT causes cellular stress, induces NO radicals and leads to DNA degradation, generating a cytotoxic microenvironment. Furthermore, PDT modulates pro- and anti-inflammatory cytokines in MΦ.
... The dying cells and leakage of cellular debris result in the release of cytokines and tumor necrosis factors (TNFs) that enhance the inflammation and initiate a cascade of other immune response mechanisms [83,84]. Other chemical mediators of inflammation and immune reaction, including leukotrienes, acute phase proteins, complement system factors, histamine, granulocyte colony-stimulating factors (G-CSF), prostaglandins, and many others are also released post-PDT cytotoxicity [84,85]. ...
... The dying cells and leakage of cellular debris result in the release of cytokines and tumor necrosis factors (TNFs) that enhance the inflammation and initiate a cascade of other immune response mechanisms [83,84]. Other chemical mediators of inflammation and immune reaction, including leukotrienes, acute phase proteins, complement system factors, histamine, granulocyte colony-stimulating factors (G-CSF), prostaglandins, and many others are also released post-PDT cytotoxicity [84,85]. Furthermore, dying cells in the body, including tumor cells upon treatment, always release molecules such as alarming and damage-associated molecular patterns (DAMPs), into the vascular system, which in turn, alerts the human body about a potential threat at the injured site [86,87]. ...
Breast cancer is the second most common cancer globally and the pioneering cause of mortality among women. It usually begins from the ducts or lobules, referred to as ductal carcinoma in situ, or lobular carcinoma in situ. Age, mutations in Breast Cancer Gene 1 or 2 (BRCA1 or BRCA2) genes, and dense breast tissue are the highest risk factors. Current treatments are associated with various side effects, relapse, and a low quality of life. Although conventional treatments, such as surgery and chemotherapy, have been used for decades, their adverse side effects on normal cells and tissues pose a major weakness, which calls for a non-invasive treatment option. Photodynamic therapy (PDT) has proven to be a promising form of cancer therapy. It is less invasive, target-specific, and with reduced cytotoxicity to normal cells and tissues. It involves the use of a photosensitizer (PS) and light at a specific wavelength to produce reactive oxygen species. One of the reasons for the target specificity is associated with the dense vascularization of cancer tissues, which tends to increase the surface area for the PS uptake. Photosensitizers are light-sensitive molecules, which result in cancer cell destruction followed by light irradiation. Depending on the localization of the PS within the cancer cell, its destruction may be via apoptosis, necrosis, or autophagy. This review focuses on the breast cancer etiopathology and PDT-induced cell death mechanisms in breast cancer cells.
... The multidirectional nature of IL-6 interactions includes the participation in the activation of antigen-recognizing T lymphocytes (also LIF) as well as the production of acute-phase proteins indicating the early reaction in response to tissue damage. IL-6 expression was strongly and consistently enhanced in PDT-treated mice, although the role of IL-6 in PDT-induced inflammation may vary depending on the PS, protocol or type of tumor treated [61][62][63]. Increased IL-6 concentration in plasma can be considered as early and sensitive, although nonspecific, indicators of various inflammations, which in this case should be identified with the destruction of tumor tissue [64]. In the experimental groups that underwent PDT, these also exhibited a significant increase in IL-15 level, Figure 11d. ...
... It is widely known that TNFα upregulation may induce changes in the tumor vasculature and stimulate the antitumor immune response [73]. Moreover, these data can also suggest the activity of macrophages triggering in these cells Toll-like receptor (TLR)-based signal transduction activity resulting in the production of TNFα [61,62]. Figure 13. ...
: Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F2BMet and Cl2BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1β, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F2BOH) and amphiphilic (F2BMet) PSs were equally effective in V-PDT (>80 cure rate). F2BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl2BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm2.
... 130,153,154 PDT has also been shown to regulate adhesion molecules, 155 surface receptors such as major histocompatibility complex (MHC) classes I and II, 156 and a number of cytokines. [157][158][159] Cytokine induction by PDT has been shown to be under control of various transcription factors, such as AP-1 and NFκB. 160 These cellular changes probably play a role in the induction of an immune response after PDT, which is being exploited for developing new therapies. ...
... Damage is believed to be initiated by release of factors such as eicosanoids, in particular thromboxane, 165 histamines, and tumor necrosis factor-α (TNFα). 159 Macroscopically, the vascular PDT response is characterized by acute erythema, edema, blanching, and sometimes necrosis. Microscopically, the tumor tissue is characterized by endothelial cell damage, 18,166 platelet aggregation, vasoconstriction, and hemorrhage following PDT. ...
... Among cytokines, IL-6 mRNA and protein were found to be strongly enhanced in PDT treated mouse tumors, as well as in exposed spleen and skin (70). There is also evidence for PDT induced or up-regulated IL-1, IL-2, tumor necrosis factor-␣ (TNF-␣) and granulocyte colony-stimulating factor (G-CSF) (150)(151)(152)(153). The observed inconsistencies in the detection of these mediators in different PDT-treated tumors and difficulties to detect other such substances are caused by the following: 1) differences in the up-regulation control for the respective genes in different tumors and 2) very short lifetime of these proteins due to extremely high levels of proteinase and RNase activity in tumor tissue after PDT. ...
... The tumoricidal activity of these cells was found to be potentiated by PDT in vivo and in vitro (155,159,160). Macrophages were reported to release TNF-␣ following PDT treatment (152) and to preferentially recognize PDT treated cancer cells as their targets (161). Adjuvant treatment with a selective vitamin D3-binding protein macrophage activating factor (DBPMAF) was shown to potentiate the cures of PDT-treated tumors (162). ...
... Among cytokines, IL-6 mRNA and protein were found to be strongly enhanced in PDT treated mouse tumors, as well as in exposed spleen and skin (70). There is also evidence for PDT induced or up-regulated IL-1, IL-2, tumor necrosis factor-␣ (TNF-␣) and granulocyte colony-stimulating factor (G-CSF) (150)(151)(152)(153). The observed inconsistencies in the detection of these mediators in different PDT-treated tumors and difficulties to detect other such substances are caused by the following: 1) differences in the up-regulation control for the respective genes in different tumors and 2) very short lifetime of these proteins due to extremely high levels of proteinase and RNase activity in tumor tissue after PDT. ...
... The tumoricidal activity of these cells was found to be potentiated by PDT in vivo and in vitro (155,159,160). Macrophages were reported to release TNF-␣ following PDT treatment (152) and to preferentially recognize PDT treated cancer cells as their targets (161). Adjuvant treatment with a selective vitamin D3-binding protein macrophage activating factor (DBPMAF) was shown to potentiate the cures of PDT-treated tumors (162). ...
... They observed that the benzoporphyrin derivative as PS caused DNA damage and apoptosis in DBA/2 mouse thymocytes. In addition, Evans et al. reported that PDT-induced macrophage stimulation and cytotoxicity via tumor necrosis factor (TNF) (Evans et al., 1990). PDT products can also contribute to increased expression in some interleukins such as IL-6 and IL-10, and lead to local and systemic acute inflammation due to elevated expression of some cytokines and chemokines including interleukin IL-6, E-selectin, and intracellular adhesion molecule (ICAM)-1 (Gollnick et al., 2003). ...
The oxygen level in the tumor is a critical marker that determines response to different treatments. Cancerous cells can adapt to hypoxia and low pH conditions within the tumor microenvironment (TME) to regulate tumor metabolism, proliferation, and promote tumor metastasis as well as angiogenesis, consequently leading to treatment failure and recurrence. In recent years, widespread attempts have been made to overcome tumor hypoxia through different methods, such as hyperbaric oxygen therapy (HBOT), hyperthermia, O 2 carriers, artificial hemoglobin, oxygen generator hydrogels, and peroxide materials. While oxygen is found to be an essential agent to improve the treatment response of photodynamic therapy (PDT) and other cancer treatment modalities, the development of hypoxia within the tumor is highly associated with PDT failure. Recently, the use of nanoparticles has been a hot topic for researchers and exploited to overcome hypoxia through Oxygen‐generating hydrogels, O 2 nanocarriers, and O 2 ‐generating nanoparticles. This review aimed to discuss the role of nanotechnology in tumor oxygenation and highlight the challenges, prospective, and recent advances in this area to improve PDT outcomes.
This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
... Multiple in°ammatory factors, such as CXCL2, IL-6, IL-1b and TNF-, can be upregulated after PDT. [39][40][41] In addition, it has been reported in the literature that hypoxia could induce upregulation of CTLA-4, TIM-3 and PD-L1 on tumor-associated macrophages, bone marrow-derived macrophages and Treg cells. 42 4T1 breast cancer is a hypoxic tumor and requires oxygen consumption during PDT; therefore, the elevation of multiple immune checkpoints observed in this experiment may be hypoxia-related. ...
Photodynamic therapy (PDT) has limited effects in treating metastatic breast cancer. Immune checkpoints can deplete the function of immune cells; however, the expression of immune checkpoints after PDT is unclear. This study investigates whether the limited efficacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the efficacy. A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives (HpD-PDT). The anti-tumor effect of HpD-PDT was observed, as well as CD4+T, CD8+T and calreticulin (CRT) by immunohistochemistry and immunofluorescence. Immune checkpoints on T cells were analyzed by flow cytometry after HpD-PDT. When combining PDT with immune checkpoint inhibitors, the antitumor effect and immune effect were assessed. For HpD-PDT at 100mW/cm² and 40, 60 and 80J/cm², primary tumors were suppressed and CD4+T, CD8+T and CRT were elevated; however, distant tumors couldn’t be inhibited and survival could not be prolonged. Immune checkpoints on T cells, especially PD1 and LAG-3 after HpD-PDT, were upregulated, which may explain the reason for the limited HpD-PDT effect. After PDT combined with anti-PD1 antibody, but not with anti-LAG-3 antibody, both the primary and distant tumors were significantly inhibited and the survival time was prolonged, additionally, CD4+T, CD8+T, IFN-γ+CD4+T and TNF-α+CD4+T cells were significantly increased compared with HpD-PDT. HpD-PDT could not combat metastatic breast cancer. PD1 and LAG-3 were upregulated after HpD-PDT. Anti-PD1 antibody, but not anti-LAG-3 antibody, could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.
... Macrophages treated with low doses of PDT seem to be activated and have greater activity, while those treated with higher doses lose their functionality (142). In addition, the macrophages treated with PDT generate a high amount of TNF-a, which entails the cytotoxic effect associated to this cytokine (146). Other mediators that are generated during PDT in the presence of TAMs and neoplastic cells are complement proteins (C3, C5 and C9), pentraxin, sphingolipids or toll-like receptors (TLR2, TLR4 and C3aR). ...
Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cancer.
... CNPs are able to induce apoptosis (early and late apoptosis taken together) and necrosis in A2780 cell line from a concentration of 1μM after 24h. As PDT is generally leading to cell death by necrosis, the presence of apoptotic cells (about 20%) must indicate the existence of another mechanism of cell damage, such as DNA damages or p53-dependent apoptosis pathways 44,45 . The ability of CNPs to modify DNA was investigated by high-throughput image analysis. ...
The ability of cancer cells to develop resistance to anti-cancer drugs, known as multidrug resistance, remains a major cause of tumor recurrence and cancer metastasis. This work explores the double mechanism of toxicity of (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles encapsulating a molybdenum cluster compound, namely Cs2[{Mo6I8}(OOCC2F5)6] (CMIF). Hemocompatibility and biocompatibility assays show the safe potential of CMIF loaded nanoparticles (CNPs) as delivery systems intended for tumor targeting for PDT of ovarian cancer with a slight hemolytic activity and a lack of toxicity up to 50µM CMIF concentration. Cellular uptake shows a preferential uptake of CNPs in lysosomes, which is not interfering with CMIF activity. The double mechanism of CNPs consists in a production of ROS and a DNA damage activity, from 5µM and 0.5µM respectively (CMIF concentration). The cellular death mechanism comprises 80% of necrosis and 20% of direct apoptosis by direct DNA damages. This work confirms CMIF loaded PLGA nanoparticles as an efficient and relevant delivery system for PDT
... Several studies showed that PDT can potentiate immunotherapy (23)(24)(25)(26)(27)(28). PDT kills cancer cells, induces immunogenic cell death, releases tumor antigens, and stimulates innate immunity as well as adaptive immune response (reviewed in ref. 29). ...
Purpose:
Immune checkpoint inhibitors (ICIs) in general have shown poor efficacy in bladder cancer (BCa). The purpose of this project was to determine whether photodynamic therapy (PDT) with BCa-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI.
Experimental design:
SV40 T/Ras double-transgenic mice bearing spontaneous BCa and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies.
Results:
PDT with PNP generated reactive oxygen species, induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared to 44.8 (p=0.0123), 52.6 (p=0.0054) and over 75 (p=0.0001) days in the anti-programmed cell death-1 antibody(anti-PD-1), PNP PDT and combination groups, respectively. At Day 75 when all mice in other groups died, only one in 7 mice in the combination group died. For the direct anti-tumor activity, compared to the control, the ani-PD-1, PNP PDT and combination groups induced a 40.25% (p=0.0003), 80.72% (p<0.0001) and 93.03% (p<0.0001) tumor reduction, respectively. For the abscopal anti-cancer immunity, the anti-PD-1, PNP PDT and combination groups induced tumor reduction of 45.73% (p=0.0001), 54.92% (p<0.0001) and 75.96% (p<0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial.
Conclusions:
In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.
... PDT can exert effects on both monocytes/macrophages and lymphocytes (Steubing et al., 1991;Jiang et al., 1999). Evans et al. demonstrated tumor necrosis factor (TNF) production by PDT treated macrophages, and proposed that this process might serve as a mechanism of PDT cytotoxicity in vivo (Evans et al., 1990). Gollnick et al. showed that PDT in vivo causes significant changes in the expressions of interleukin (IL)-6 and IL-10, but not TNF-α (Gollnick et al., 1997). ...
Photodynamic therapy (PDT) mostly relies on the generation of singlet oxygen, via the excitation of a photosensitizer, so that target tumor cells can be destroyed. PDT can be applied in the settings of several malignant diseases. In fact, the earliest preclinical applications date back to 1900’s. Dougherty reported the treatment of skin tumors by PDT in 1978. Several further studies around 1980 demonstrated the effectiveness of PDT. Thus, the technique has attracted the attention of numerous researchers since then. Hematoporphyrin derivative received the FDA approval as a clinical application of PDT in 1995. We have indeed witnessed a considerable progress in the field over the last century. Given the fact that PDT has a favorable adverse event profile and can enhance anti-tumor immune responses as well as demonstrating minimally invasive characteristics, it is disappointing that PDT is not broadly utilized in the clinical setting for the treatment of malignant and/or non-malignant diseases. Several issues still hinder the development of PDT, such as those related with light, tissue oxygenation and inherent properties of the photosensitizers. Various photosensitizers have been designed/synthesized in order to overcome the limitations. In this Review, we provide a general overview of the mechanisms of action in terms of PDT in cancer, including the effects on immune system and vasculature as well as mechanisms related with tumor cell destruction. We will also briefly mention the application of PDT for non-malignant diseases. The current limitations of PDT utilization in cancer will be reviewed, since identifying problems associated with design/synthesis of photosensitizers as well as application of light and tissue oxygenation might pave the way for more effective PDT approaches. Furthermore, novel promising approaches to improve outcome in PDT such as selectivity, bioengineering, subcellular/organelle targeting, etc. will also be discussed in detail, since the potential of pioneering and exceptional approaches that aim to overcome the limitations and reveal the full potential of PDT in terms of clinical translation are undoubtedly exciting. A better understanding of novel concepts in the field (e.g. enhanced, two-stage, fractional PDT) will most likely prove to be very useful for pursuing and improving effective PDT strategies.
... PDT combines light and a photosensitizer to achieve the therapeutic goal of cell or tissue damage and even death caused by molecular oxygen [13,14]. Selective accumulation of a photosensitizer in the tumor tissues is the most important characteristic of PDT [15]. Photosensitizer uptake in the cells can achieve relatively high accumulation in the tumor cells. ...
We aimed to investigate the mechanism and effect of photodynamic treatment mediated by 5-aminoketovalerate (5-ALA-PDT) on human ovarian cancer cells (OVCAR3 cells) and to provide a theoretical basis for the subsequent experimental step in vivo. Human ovarian cancer OVCAR3 cells were randomly divided into four groups: control group, laser irradiation alone group, photosensitizer alone group, and photodynamic treatment group. Alterations in cell morphology were observed with an inverted light microscope; cell viability was examined by CCK-8 assays. The ROS content and apoptosis rate were examined by flow cytometry analysis. Western blot was used to detect the expression of apoptosis-related proteins, such as caspase-3, Bax, and Bcl-2, and the expression of cleaved caspase-3 in live cells was detected by a cleaved caspase-3 assay kit. Inverted light microscopy showed alterations in cell morphology in different stages. Comparison with the three other groups indicated that tumor cell proliferation was significantly decreased in the photodynamic treatment group (P < 0.05). Flow cytometry analysis revealed that the content of ROS was higher in the photodynamic group than in the other three groups, and the apoptosis rate was higher in the photodynamic treatment group. The difference compared with the other three groups was statistically significant (P < 0.001). The western blot results indicated that the protein expression of Bcl-2 and caspase-3 was decreased in the photodynamic treatment group, and the protein expression level of Bax was increased (P < 0.05). The expression of cleaved caspase-3 was increased in the photodynamic treatment group compared with the other groups according to the data obtained with a microplate reader. Thus, our results demonstrated that the apoptosis and viability of OVCAR3 cells are altered in response to 5-ALA-PDT; however, no remarkable effects were observed in ovarian cancer cells treated with laser irradiation or photosensitizer alone. 5-ALA-PDT can significantly inhibit the growth of human ovarian cancer cells, and the mechanism of this effect is related to the tumor cell apoptosis mediated by the downregulation of Bcl-2 and caspase-3 and upregulation of Bax protein expression.
... As such, the specificity of an mt-PNM system may in fact unintentionally elicit a multi-angular assault on the tumor microenvironment by promoting both the immunomodulatory effects of PDT, in addition to tumor tissue-specific photodamage [120][121][122]. In addition to the re-polarization of TAMs, PDT has been shown to stimulate macrophage secretion of pro-inflammatory prostaglandin-E2 and TNF-α, increase nitric oxide production and enhance tumor cell lysis and phagocytosis by macrophages [123][124][125][126]. All of these secondary effects have the potential to directly promote tumor tissue damage if occurring in TAMs that preferentially sequester mt-PNMs [127]. ...
Near infrared (NIR) photodynamic activation is playing increasingly critical roles in cutting-edge anti-cancer nanomedicines, which include spatiotemporal control over induction of therapy, photodynamic priming, and phototriggered immunotherapy. Molecular targeted photonanomedicines (mt-PNMs) are tumor-specific nanoscale drug delivery systems, which capitalize on the unparalleled spatio-temporal precision of NIR photodynamic activation to augment the accuracy of tumor tissue treatment. mt-PNMs are emerging as a paradigm approach for the targeted treatment of solid tumors, yet remain highly complex and multifaceted. While ligand targeted nanomedicines in general suffer from interdependent challenges in biophysics, surface chemistry and nanotechnology, mt-PNMs provide distinct opportunities to synergistically po-tentiate the effects of ligand targeting. This review provides what we believe to be a much-need demarcation between the processes involved in tumor specificity (biomolecular recognition events) and tumor selectivity (preferential tumor accumulation) of ligand targeted nanomedicines, such as mt-PNMs, and elaborate on what NIR photodynamic activation has to offer. We discuss the interplay between both tumor specificity and tumor selectivity and the degree to which both may play central roles in cutting-edge NIR photoactivable nanotechnologies. A special emphasis is made on NIR photoactivable biomimetic nano-technologies that capitalize on both specificity and selectivity phenomena to augment the safety and efficacy of photodynamic anti-tumor regimens.
... La PDT peut conduire à la diminution ou l'augmentation de l'expression des cytokines [164]. La première description de l'influence de la PDT sur la production des cytokines a été rapportée par Evans et al., [165] qui démontra une inhibition de la [176]. Ce qui est appuyé par le fait qu'in vitro les cellules de rate des souris MRL/1rp activées par l'adjuvant sont plus sensibles à la PDT que les cellules de rate non activées à cause d'une accumulation élevée de PS [180]. ...
Les maladies inflammatoires chroniques de l’intestin (MICI) sont des pathologies incurables et de surcroit associées à un risque élevé de cancer colorectal (CCR). Les thérapies actuellement disponibles pour le traitement des MICI et la prévention du CCR associé, sont loin d’être optimales. Récemment la thérapie photodynamique (PDT) utilisant de faibles doses de photosensibilisateur et/ou de lumière, appelée alors LDPDT (Low dose-PDT), est apparue comme une nouvelle modalité de traitement pour des pathologies inflammatoires telles que le psoriasis ou l’arthrite rhumatoïde. Dans cette étude, nous avons évalué sur modèles murins l’effet thérapeutique de la LDPDT à l’aide d’une formulation liposomale de mTHPC (méta-tetra-hydroxyphenylchlorine, connu sous le nom de Foslip®), dans le traitement des MICI et la prévention du CCR. Des analyses endoscopiques, macroscopiques et histologiques ont été réalisées et le taux de myéloperoxidase (MPO) au sein de la muqueuse colique a été quantifié par test ELISA. L’expression des cytokines a été quantifiée par RT-PCR, la perméabilité de la barrière intestinale a été évaluée par immuno-marquage et une analyse du microbiote intestinal a été effectuée par pyrosequençage. La LDPDT-Foslip® a significativement réduit la sévérité de la colite en supprimant l’inflammation intestinale notamment par diminution des cytokines pro-inflammatoires et suppression de l’infiltration par les neutrophiles. Elle a également permis de corriger la perméabilité de la barrière intestinale. De plus, la LDPDT-Foslip® a clairement démontré un effet préventif sur le développement du cancer colorectal en supprimant l’inflammation chronique et en corrigeant la dysbiose. En conséquence, la LDPDT-Foslip® pourrait être considérée comme une nouvelle modalité de traitement pour supprimer l’inflammation intestinale et prévenir le développement du cancer colorectal chez les patients atteints de MICI.
... Consequently, the direct killing effect of PDT on the Leishmania parasite appears unlikely. Alternatively, there is convincing experimental evidence that a systemic immune response is perhaps responsible for the clearance of Leishmania parasite and subsequently the CL lesions [26][27][28]. Specifically, PDT triggers vascular damage, acute erythema and necrosis, among others, in the treated region of skin, resulting in a strong decrease in the number of infected macrophages and subsequent production of tumor necrosis factor-alpha (TNF-α) [26]. In addition, there is an increase in the production of monocyte chemo-attractant protein-1 and interleukin-6, and a significant influx of neutrophils to the treated area, as supported by preclinical data [29]. ...
... The characteristics of photosensitization, which selectively accumulates in tumor tissue and selectively irradiates the lesion tissue to form a dual targeting of photodynamic therapy, constitutes dual targeting of photodynamic therapy; that is, drug targeted enrichment and light-targeted activation. 8 PDT can also induce anti-tumor immune effects, enhance the anti-tumor effect of various immune cells of the body, and cause local inflammatory reactions, activate various immune molecules such as chemotactic cytokines and activated complement, thereby effectively removing tumor cells and inhibiting tumor recurrence. Drugs and equipment needed for photodynamic therapy 1. Photosensitizers 9 Photosensitizers currently used in lung cancer include the first generation of photosensitizers which are derivatives of hematoporphyrin. ...
With the development of interventional pulmonology, photodynamic therapy (PDT) is gradually being used in the treatment of respiratory malignant tumors because of its low level of trauma, high specificity, and compatibility with traditional or common therapies. However, at present, the data of clinical evidence‐based medicine for PDT applied in central airway tumors is very limited, and derives mainly from case reports or series of case studies which lack consensus on clinical diagnosis and treatment. In order to further disseminate China's experience, the Tumor Photodynamic Therapy Committee of China Anti‐Cancer Association and the World Endoscopy Association‐Respiratory Endoscopy Association invited experts from relevant fields to form an expert committee. After several rounds of discussion and revision by this committee, and following a vote, the consensus was formulated for reference by physicians in respiratory, oncology and other related disciplines to refer to the practice of tumor photodynamic therapy.
... The red arrows in the figure show apoptotic cells which in turn trigger a series of biological effects, causing irreversible damage to subcellular structures such as cell membrane, mitochondria, and lysosomes, resulting in cell death and destruction of tumor tissue [22][23][24]. HPD is a mixed form of the porphyrin containing monomers, double isomer, and oligomers; all of which have corresponding photosensitive effects, and it is able to focus on tumor cells [25,26]. Due to the selective absorption of photosensitizers by tumor cells and little or no absorption by normal tissue cells, therefore, PDT almost no or is easy to recover after slight injury to the human body and PDT is increasingly regarded as a non-invasive treatment for a variety of cancers [27,28]. ...
To investigate the effect and mechanism of 630-nm laser on human lung adenocarcinoma cell xenograft model in nude mice mediated by hematoporphyrin derivatives (HPD) and provide theoretical basis for clinical photodynamic therapy (PDT). Human lung adenocarcinoma cell xenograft model in nude mice was established and randomly divided into four groups: control group, pure photosensitizer group, pure irradiation group, and photodynamic treatment group. The tumor volume growth was compared, and the tumor growth inhibition rate was calculated. HE staining was used for routine pathological observation of tumor sections, and gross conditions of cells, interstitium, and blood vessels in several groups of tumor tissues were observed. TUNEL staining was used to observe and compare the apoptosis induced by photodynamic therapy. Real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression level of angiogenesis-related factors VEGF, HIF-1α and apoptosis-related factors Bax and Bcl-2 mRNA in the transplanted tumor tissues. Western blot was employed to detect the expression of angiogenesis-related proteins VEGF, HIF-1α and apoptosis-related proteins Bax, Caspase-3, and Bcl-2. Compared with the other three groups, the tumor growth inhibition rate of the photodynamic treatment group was significantly increased and the difference was statistically significant (P < 0.05). HE staining showed that the animal model of lung adenocarcinoma A549 was successfully established. TUNEL staining revealed that more apoptotic cells were found in the photodynamic treatment group, and the apoptosis index was calculated. Compared with the other three groups, the difference was statistically significant (P < 0.05). RT-PCR results showed that compared with the other three groups, the mRNA expressions of VEGF, HIF-1α, and Bcl-2 in the photodynamic treatment group decreased, while the expression of Bax mRNA increased(P < 0.05), and the differences were statistically significant. Western blot results showed that protein expressions of VEGF, HIF-1α, and Bcl-2 decreased in the photodynamic treatment group, while protein expression level of Bax and Caspase-3 increased (P < 0.05), indicating statistically significant differences. The 630-nm laser mediated by hematoporphyrin derivatives can significantly inhibit the growth of human lung adenocarcinoma xenograft tumor in nude mice, the mechanism of which is related to the inhibition of tumor angiogenesis by down-regulating VEGF and HIF-1α gene expression, and the promotion of tumor apoptosis by up-regulating Bax, Caspase-3, and down-regulating Bcl-2 gene expression.
... We found that in the our group where this polyphenol was not photoactivated, actually occurred a reduction in the release of TNF-α. Different studies have shown the importance of the TNF-α release, a pro-inflammatory cytokine, with the reduction of MRSA infection associated with laser therapy [72][73][74][75]. Furthermore, aPDT stimulates macrophages to release TNF-α in great quantities, leading to an increase of this cytokine at the site of inflammation [76][77][78][79]. ...
... Photodynamic therapy (PDT) is well characterized to stimulate innate immunity, most obviously apparent through the generation of inflammation (1). This inflammation is associated with the release of cytokines, for example, IL-6, IL-10 and TNF-a (2)(3)(4), and an accompanying increase in tumor levels of macrophages and granulocytes (2,3). Induction of neutrophil influx to the tumor has been observed in mammary carcinomas (2,3), squamous cell carcinomas (5) and colon carcinomas (6), as detected by Ly6G + and other neutrophil-identifying antibodies (7). ...
Inflammatory cells, most especially neutrophils, can be a necessary component of the anti‐tumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered PDT dose is insufficient. In these cases, the release of neutrophil granules and engagement of anti‐tumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to non‐invasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin‐PDT. Luminol‐generated chemiluminescence increased transiently 1h after PDT, followed by a subsequent decrease at 4h after PDT. The production of luminol signal was not associated with the influx of Ly6G⁺ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1h after PDT was prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G⁺ cells in the generation of long‐term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.
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... An adverse effect of high dose PDT in bladder cancer is that it may cause fibrosis and shrinkage of adjacent normal bladder tissues. Evans et al. 24 first described the stimulation of cytokine (TNF) release by macrophages following PDT. Sub lethal doses of PDT have also been shown to cause macrophage activation. ...
Purpose:
Muscarinic acetylcholine receptors (mAChRs) regulate a number of important physiological functions. Alteration of mAChR expression or function has been associated in the etiology of several pathologies including functional bladder disorders (e.g bladder pain syndrome/interstitial cystitis - BPS/IC). In a previous study we found specific mAChR expression patterns associated with BPS/IC, while correlation between protein and gene expression was lacking. Posttranslational regulatory mechanisms, e.g. altered intracellular receptor trafficking, could explain those differences. In addition, alternative G protein (GP) coupling could add to the pathophysiology via modulation of muscarinic signaling. In our proof-of-principle study, we addressed these questions in situ. We established PLA in combination with confocal laserscanning microscopy (CLSM) and 3D object reconstruction for highly specific detection and analysis of muscarinic 3 receptors (M3), G protein (GP) coupling and intracellular trafficking in human detrusor samples.
Material and methods:
Paraffin sections of formalin-fixed bladder tissue (FFPE) of BPS/IC patients receiving transurethral biopsy were examined by Cy3-PLA for M3 expression, coupling of M3 to GPs (Gαq/11, Gαs, Gαi) and interaction of M3 with endocytic regulator proteins. Membranes were labeled with wheat germ agglutinin-Alexa Fluor®488, nuclei were stained with DAPI. Object density and co-localization were analyzed in 3D-reconstruction of high resolution confocal z-stacks.
Results:
Confocal image stack processing resulted in well demarcated objects. Calculated receptor densities correlated significantly with existing confocal expression data, while significantly improved specificity of M3 detection by PLA was verified using bladder tissue samples from transgenic mice. 50-60% of the M3 receptor complexes were plasma membrane associated in human bladder detrusor. Application of PLA for M3 and GPs allowed visualization of M3-GP interactions and revealed individual GP-subtype coupling patterns. Detection of M3 interactions with endocytic trafficking proteins by PLA resulted in object sizes correlating with well-documented vesicle sizes of the endocytosis pathway.
Conclusion:
PLA enabled highly specific detection of M3 receptor expression, demonstration of M3/GP differential coupling and intracellular M3 trafficking in human detrusor smooth muscle cells. This new approach minimized background fluorescence and antibody cross-reactions resulting from single antibody application, and enhanced specificity due to the use of two primary antibodies. Use of subcellular markers allowed visualization of subcellular receptor location. PLA/CLSM allows analyses of muscarinic "receptor - G protein - promiscuity" and intracellular trafficking even in bladder paraffin sections and may give new insights into the etiology and pathology of BPS/IC.
... Evans et al. first described the stimulation of cytokine (TNF) release by macrophages following PDT. 24 Sub lethal doses of PDT have also been shown to cause macrophage activation. Chen et al. demonstrated that PDT may induce tumor-specific antibodies resulting in metastasis regression and resistance to tumor re-challenge. ...
Prostate and bladder cancers are one of the cancers occurring worldwide. In addition to radical surgery, the past decade has also focussed on targeted therapy of overexpressed cancer proteins that are lethal and critical for cancer cell survival. However, targeted therapy cannot adapt for changing of cancer molecular characteristics and, ultimately, a clone that bypasses the targeted therapy emerges. This can be overcome by immunotherapy. New studies on ablative therapy of cancers show presence of immunomodulatory effect in these modalities. Tumor ablation prime the immune system for further destruction of persistent primary tumor in addition to destruction of concurrent metastatic disease and also reduce recurrence. Ablative therapies can achieve a state of increased antigenicity. Its combination with a novel macrophage targeted therapy may enhance immune priming, trafficking, and/or effector phases; thereby improving clinical outcomes. Tumor associated macrophages or M2 phenotype are now known to mediate this immunosuppressive pro-tumorigenic effect. Alteration of macrophage differentiation may enhance tumor destruction of ablative therapy. This breakthrough in immunotherapy opens up arenas for further robust clinical trials on combinatorial therapies. In the present review, we aim to elucidate the major aspects of immune stimulatory minimal invasive approaches by combining with macrophage directed pathways.
... Photodynamic therapy (PDT) involves utilizing a specific wavelength of light to activate a intravenously given photosensitizing agent and cause ablation by directly damaging tumor cells, interfering with microvasculature of the tumor bed, and potentiating an immune response [95][96][97][98][99] . The photosensitizer-dependent wavelength light is typically delivered via optical fibers placed in the target tissue, with the penetrance dependent on the wavelength of light and the specific light source used [100] . ...
Malignant biliary strictures often present late after the window for curative resection has elapsed. In such patients, the goal of therapy is typically focused on palliation. While historically, palliative measures were performed surgically, the advent of endoscopic intervention offers minimally invasive options to provide relief of symptoms, improve quality of life, and in some cases, increase survival of these patients. Some of these therapies, such as endoscopic biliary decompression, have become mainstays of treatment for decades, whereas newer modalities, including radiofrequency ablation, and photodynamic therapy offer additional options for patients with incurable biliary malignancies.
... Moreover, the gene expression of inflammatory cytokines analyses demonstrated an increase in tumor necrosis factor-a (TNF-a) expression in the group with oral candidiasis that underwent PDT with PS encapsulated in cationic nanoemulsion (P+L+ ClAlP-NE) when compared with the positive control group (PÀLÀ). These results are in agreement with the studies that show that the efficacy of PDT seems to be strongly related to the degree and nature of inflammation induced by the therapy (Brackett and Gollnick, 2011) and that PDT may induce a short term inflammation characterized by an increase in the cytokine TNF-a expression (Evans et al, 1990;Gollnick et al, 1997Gollnick et al, , 2003. Thus, it is possible to suggest that antimicrobial PDT induces an increase of TNF-a by increasing the inflammatory reaction. ...
This study evaluated the photoinactivation of Candida albicans in a murine model of oral candidiasis using chloro-aluminum phthalocyanine (ClAlP) encapsulated in cationic nanoemulsions (NE) and chloro-aluminum phthalocyanine (ClAlP) diluted in DMSO (DMSO) as photosensitizer (PS). Seventy-five 6-week-old female Swiss mice were immunosuppressed and inoculated with C. albicans to induce oral candidiasis. PDT was performed on the tongue by the application of the photosensitizers and LED light (100 J cm(-) ² - 660 nm). Twenty-four hours and 7 days after treatments, microbiological evaluation was carried out by recovering C. albicans from the tongue of animals (CFU mL(-1) ). Then, mice were sacrificed and the tongues were surgically removed for histological and biomolecular analysis of pró and anti-inflammatory cytokines. Data were analyzed by ANOVA followed by Tukey post-hoc test. ClAlP NE-mediated PDT reduced 2.26 log10 of C. albicans recovered from the tongue when compared with the control group (P-L-) (p<0.05). PDT did not promote adverse effects on the tongue tissue. Seven days after treatment all animals were completely healthy. In summary, PDT mediated by chloro-aluminum phthalocyanine entrapped in cationic nanoemulsions was effective in reducing C. albicans recovered from the oral lesions of immunocompromised mice. This article is protected by copyright. All rights reserved.
Photodynamic therapy (PDT) is a selective tumor treatment that consists of a photosensitive compound—a photosensitizer (PS), oxygen, and visible light. Although each component has no cytotoxic properties, their simultaneous use initiates photodynamic reactions (PDRs) and sequentially generates reactive oxygen species (ROS) and/or free radicals as cytotoxic mediators, leading to PDT-induced cell death. Nevertheless, tumor cells develop various cytoprotective mechanisms against PDT, particularly the adaptive mechanism of antioxidant status. This review integrates an in-depth analysis of the cytoprotective mechanism of detoxifying ROS enzymes that interfere with PDT-induced cell death, including superoxide dismutase (SOD), catalase, glutathione redox cycle, and heme oxygenase-1 (HO-1). Furthermore, this review includes the use of antioxidant enzymes inhibitors as a strategy in order to diminish the antioxidant activities of tumor cells and to improve the effectiveness of PDT. Conclusively, PDT is an effective tumor treatment of which its effectiveness can be improved when combined with a specific antioxidant inhibitor.
As a result of recent advances in endoscopes and optical fibers, optical engineering has been introduced to medical treatment in these years. Photodynamic therapy (PDT) is a promising treatment method that irradiates a tumor with a highly tumor-accumulating photosensitive agent and a laser with a specific wavelength and shows a cell-killing effect only on tumor cells with high drug concentration. It has already been applied clinically in the fields of pulmonary and digestive surgery, neurosurgery, ophthalmology, dermatology, and urology. As described in other chapters, photodynamic diagnosis (PDD), which is a method to diagnose the localization of tumors by irradiating biological tissues with light and detecting the fluorescence generated by photosensitive agents accumulated in tumors, is also being actively studied and applied clinically.
Objective:
To systematically review the efficacy of photodynamic therapy (PDT) in the treatment of cutaneous leishmaniasis (CL).
Methods:
PubMed, Embase and Cochrane Library databases were searched for articles published by November 16, 2022, with no time restrictions. 'Cutaneous leishmaniasis' and 'photodynamic therapy' were searched using predefined search strings.
Inclusion criteria:
(i) Randomized control trials; (ii) controlled clinical trials; (iii) case series; (iv) case reports; (v) participants were humans; (vi) clinical diagnosis was CL; (vii) treatment method used was PDT; and (viii) articles published in English.
Results:
In total, 303 articles were identified, including 14 papers meeting the criteria. The number of patients in each study ranged from 1 to 60 and the age ranged from 1 to 82 years. Aminolevulinic acid and methyl aminolevulinate were used as photosensitizers. Red light and sunlight were used as light sources. All reported satisfactory clinical effects. Side effects of treatment included burning sensation, pain and pigmentation after treatment. However, they were tolerable and temporary. The follow-up time ranged between 9 weeks and 24 months. A total of two patients recurred, but one did not recur after another round of PDT during the follow-up period.
Conclusions:
The present study suggests that PDT is a safe and effective method for the treatment of CL, with tolerable side effects and good efficacy. As an alternative treatment method of CL, PDT has great potential. However, to verify the efficacy and specific mechanism of PDT for the optimal treatment strategy of CL, further research with larger sample sizes and longer follow-up times are needed.
Photodynamic therapy (PDT) is one of the most prominent therapies in the cancer treatment. PDT is a treatment that makes use of a drug, called photosensitizer or photosensitizing agent, and a peculiar type of light. When photosensitizers are irradiated by a specific wavelength of light, they produce a kind of oxygen that kills nearby cells. Needs-based research has been carried out on in the field of luminescence depending upon the disease undergoing treatment. It has the main advantage that it has no long-term side effects. Rare-earth doped upconversion (UC) materials are suitable for a vast range of potential biological applications in PDT, biological imaging, drug delivery, and sensing. The conversion of a higher wavelength photon (near infra-red [NIR] or red light region) into a lower wavelength photon (ultraviolet [UV] or near UV) is used in UC PDT. Absorbance of NIR wavelengths allow light to penetrate into deeper tissues, hence PDT of deeper tissues can be effectively done. The phosphor efficiency has been increased by the beneficial effect by co-doping and decreasing the particle size of the UC PD phosphors (UC nanoparticles). In this chapter, the mechanism of PDT, the history and scientific development related to PDT in the cancer treatment are discussed.
Photodynamic therapy (PDT) is a minimally to noninvasive treatment modality that has emerged as a promising alternative to conventional cancer treatments. PDT induces hyperoxidative stress and disrupts cellular homeostasis in photosensitized cancer cells, resulting in cell death and ultimately removal of the tumor. However, various survival pathways can be activated in sublethally afflicted cancer cells following PDT. The acute stress response is one of the known survival pathways in PDT, which is activated by reactive oxygen species and signals via ASK-1 (directly) or via TNFR (indirectly). The acute stress response can activate various other survival pathways that may entail antioxidant, pro-inflammatory, angiogenic, and proteotoxic stress responses that culminate in the cancer cell's ability to cope with redox stress and oxidative damage. This review provides an overview of the immediate early stress response in the context of PDT, mechanisms of activation by PDT, and molecular intervention strategies aimed at inhibiting survival signaling and improving PDT outcome.
Photodynamic therapy (PDT) is an effective procedure for the treatment of lesions diseases based on the selectivity of a photosensitising compound with the ability to accumulate in the target cell. Atherosclerotic plaque is a suitable target for PDT because of the preferential accumulation of photosensitisers in atherosclerotic plaques. Dendrimers are hyperbranched polymers conjugated to drugs. The dendrimers of ALA hold ester bonds that inside the cells are cleaved and release ALA, yielding PpIX production. The dendrimer 6m-ALA was chosen to perform this study since in previous studies it induced the highest porphyrin macrophage: endothelial cell ratio (Rodriguez et al. in Photochem Photobiol Sci 14:1617–1627, 2015). We transformed Raw 264.7 macrophages to foam cells by exposure to oxidised LDLs, and we employed a co-culture model of HMEC-1 endothelial cells and foam cells to study the affinity of ALA dendrimers for the foam cells. In this work it was proposed an in vitro model of atheromatous plaque, the aim was to study the selectivity of an ALA dendrimer for the foam cells as compared to the endothelial cells in a co-culture system and the type of cell death triggered by the photodynamic treatment. The ALA dendrimer 6m-ALA showed selectivity PDT response for foam cells against endothelial cells. A light dose of 1 J/cm2 eliminate foam cells, whereas less than 50% of HMEC-1 is killed, and apoptosis cell death is involved in this process, and no necrosis is present. We propose the use of ALA dendrimers as pro-photosensitisers to be employed in photoangioplasty to aid in the treatment of obstructive cardiovascular diseases, and these molecules can also be employed as a theranostic agent.
The preliminary data suggest that red-light whole-bladder photodynamic therapy is safe and effective in the treatment of Tis and may be useful in the prophylactic management of superficial bladder cancer. Theoretically, whole-bladder photodynamic therapy has the advantage of higher efficacy after a single treatment than most conventional modalities for superficial bladder cancer. In patients with Tis, the complete response rate is 88%, and 25% have recurrences during a mean follow-up of 20 months (range 12–60). In patients undergoing prophylaxis, the recurrence rate is 31% and the median time to recurrence is 18 months. Importantly, none of the high-risk patients treated with whole-bladder photodynamic therapy has developed disease progression in stage or grade at the time of recurrences. Whole-bladder therapy also has the potential advantage of repeat treatment without increased tumor resistance or increased morbidity. Data from the present phase II-III clinical trials involving a large number of patients will define the role of photodynamic therapy in the management of superficial bladder cancer.
With the development of phototherapy, which is a type of light-induced cancer treatment, various biomaterials have been well designed as photoabsorbing/sensitizing agents or effective carriers to enhance the therapeutic efficacy and evade the side effects of phototherapy. In recent years, the immunological responses induced by phototherapy have been widely explored, which are mainly triggered by the tumor associated antigens (TAAs) released from the dying cancer cells after phototherapy, together with the secretion of damage associated molecular patterns (DAMPs) and various pro-inflammatory cytokines/factors. To amplify these immunological responses induced by phototherapy, various adjuvant nano/micromaterials are introduced to boost the immune system to recognize and kill cancer cells. Moreover, such immune responses are further demonstrated to work in synergy with other immunotherapies such as immune checkpoint blockade (ICB), chimeric antigen receptor (CAR)-T cell and cytokine therapy, achieving significantly increased immune response rates and successful therapeutic outcomes. Here, this minireview will focus on the recent progress in engineering biomaterials for enhanced photoimmunotherapy and discuss the challenges, opportunities and future prospects in this field.
Dr. Thomas Dougherty and his Oncology Foundation of Buffalo were the first to support my (S.O.G.) research into the effects of photodynamic therapy (PDT) on the host immune system. The small grant I was awarded in 2002 launched my career as an independent researcher; at the time there were few studies on the importance of the immune response on the efficacy of PDT and no studies demonstrating the ability of PDT to enhance anti‐tumor immunity. Over the last decades the interest in PDT as an enhancer of anti‐tumor immunity and our understanding of the mechanisms by which PDT enhances anti‐tumor immunity have dramatically increased. In this review article, we look back on the studies that laid the foundation for our understanding and provide an update on current advances and therapies that take advantage of PDT enhancement of immunity.
Background:
5-Aminolevulinic acid (5-ALA) induces the accumulation of a large amount of protoporphyrin IX (PpIX) in tumors, which has been used in the treatment of several cancers. 5-ALA is commonly used for fluorescence-guided tumor resection in clinical neurosurgery and for photodynamic therapy based on the generation of cytotoxic oxygen.
Objective:
The purpose of this study was to identify the mechanisms of 5-ALA-induced immune response in macrophages in malignant glioma.
Methods:
Intracellular levels of 5-ALA-induced PpIX in C3H/HeN murine peritoneal macrophages were measured by the median fluorescence intensity using flow cytometry and confocal laser scanning microscopy. Macrophages were cultured in vitro with or without 0.5 mM 5-ALA, 0.1 μg/mL lipopolysaccharide, and 20% glioma-conditioned medium. Levels of immunosuppressive prostaglandin E2 (PGE2), interleukin-10, and transforming growth factor β were measured using enzyme immunoassay in the culture supernatant. In addition, macrophages and RSV-M mouse glioma cells were co-cultured in vitro with cell culture inserts with or without 5-ALA (0.1 and 0.5 mM) and lipopolysaccharide (0.1 μg/mL).
Results:
We found that 5-ALA-induced PpIX accumulated in macrophages and significantly suppressed PGE2 production and expression of both cyclooxygenase-2 and microsomal prostaglandin E synthase-1. 5-ALA treatment also suppressed PGE2 production by glioma-conditioned medium. 5-ALA suppressed RSV-M glioma cell proliferation in a concentration-dependent manner.
Conclusions:
These results indicate that 5-ALA suppressed PGE2 production by macrophages via the downregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression levels. This is a novel mechanism to induce effective immune response against glioma in macrophages.
The in vitro and in vivo anti-cancer activity of iodinated photosensitizers (PS) with and without erlotinib moiety was investigated in UMUC-3 [epidermal growth factor (EGFR) positive], T24 (EGFR low) cell lines, and tumored mice. Both the erlotinib conjugated PS 3 and 5 showed EGFR target specificity, but the position-3 erlotinib-PS conjugate 3 demonstrated lower photodynamic therapy (PDT) efficacy than the corresponding non-erlotinib analog 1, whereas the conjugate 5 containing an erlotinib moiety at position-17 of the PS gave higher tumor-uptake and long-term tumor cure (SCID mice bearing UMUC-3 tumors). PS-erlotinib conjugates in the absence of light were ineffective in vitro and in vivo, but robust apoptotic and necrotic cell death was observed in bladder cancer cells after exposing them with a laser light at 665 nm. In contrast to 18F-fluorodeoxyglucose (FDG), a positron emission tomography (PET) agent, the position-17 erlotinib conjugate (124I- analog 6) showed enhanced UMUC3 tumor contrast even at a low imaging dose of 15Ci/mouse
The monocyte/macrophage cell lineage reveals an enormous plasticity, which is required for tissue homeostasis, but is also undermined in various disease states, leading to a functional involvement of macrophages in major human diseases such as atherosclerosis and cancer. We recently generated in vivo evidence that crystalline, nonfluorescent nanoparticles of the hydrophobic porphyrin-related photosensitizer Aluminum phthalocyanine are selectively dissolved and thus may be used for specific fluorescent labelling of rejected, but not of accepted xenotransplants. This led us to hypothesize that nanoparticles made of planar photosensitizers such as porphyrins and chlorins were preferentially taken up and dissolved by macrophages, which was verified by in vitro studies. Here, using an in vitro system for macrophage differentiation/polarization of the human monocyte THP-1 cell line, we demonstrate differential uptake/dissolution of Temoporfin-derived nanoparticles in polarized macrophages, which resulted in differential photosensitivity. More importantly, low dose photodynamic sensitization using Temoporfin nanoparticles can be used to trigger M1 re-polarization of THP-1 cells previously polarized to the M2 state. Thus, sublethal photodynamic treatment using Temoporfin nanoparticles might be applied to induce a phenotypic shift of tumor-associated macrophages for the correction of an immunosuppressive microenvironment in the treatment of cancer, which may synergize with immune checkpoint inhibition.
La photodégradation de l'hématoporphyrine dérivée (HpD) est caractérisée par une modification du spectre d'absorption, une diminution de l'intensité de fluorescence, ainsi qu'une altération du pouvoir de photoinactivation cellulaire. A partir de ces trois critères, seront évaluées les constantes de photodégradation de l'HpD dans deux environnements biologiques différents. In vitro : sur solutions d'HpD supplémentées de sérum (2%). Le taux de photodégradation le plus important est obtenu à partir des essais de cytotoxicité cellulaire (test au MIT) suggérant que le système biologique d'estimation du photoblanchiment est le plus sensible. In vivo : sur tumeurs HT29 greffées sur souris et exposées à différentes fluences en lumière bleue ou en lumière rouge. Malgré sa faible profondeur de pénétration dans les tissus, la lumière bleue induit un taux de photodégradation supérieur à celui de la lumière rouge et elle semble par ailleurs réagir selon un processus radicalaire qui gagnerait tout le volume tumorale. L'HpD étant proposée en thérapie photodynamique (PDT) pour le diagnostic et le traitement des néoplasies, notre second objectif est de démontrer in vitro et in vivo si l'illumination de l'HpD à visée de diagnostic (?<415 nm) peut altérer l'efficacité de l'étape thérapeutique successive (?=630 nm). In vitro : les essais sur culture de cellules ont démontré que l'exposition séquentielle aux deux lumières diminuait la cytotoxicité. Cette interaction négative peut être modifiée par la production de photoproduits avec une faible activité photodynamique dont l'existence a été confirmée par la détection de nouveaux pics d'absorption et de fluorescence. In vivo : l'évolution du volume tumoral après exposition séquentielle aux deux lumières est plus rapide que celle des témoins exposés à une seule photoirradiation. Aucune relation directe ne permet de lier l'altération de l'activité photodynamique aux résultats obtenus par les autres méthodes d'évaluation du photoblanchiment. Seule l'évaluation des conséquences biologiques peut fournir une réponse objective.
Irreversible electroporation (IRE) may result in a form of immunogenic tumor cell death that converts the tumor microenvironment from immune suppressive to immune permissive. The resulting influx of pro-inflammatory innate immune cells and subsequent uptake of apoptotic cell fragments could ultimately result in the priming of tumor-specific killer T cells in the lymph nodes directly draining the tumor ablation site. These T cells in turn will recirculate through peripheral blood and may thus provide systemic protection against the outgrowth of distant metastases. Local tumor ablation through IRE may thus be translated into a systemic antitumor treatment by virtue of secondarily induced T cell priming. These processes may be further facilitated by the primarily nonthermal mechanism of action of IRE, resulting in the conservation of the intra- and peritumoral vasculature and the preserved chemical structure of damage-associated molecular patterns (DAMPs) that are vital for proper immune activation. In this chapter, different clinically explored local tumor ablation techniques are reviewed in relation to their ability to prime or boost an antitumor immune response. Evidence for similar antitumor immune effects of IRE are discussed, as well as ways in which this antitumor immune efficacy may be enhanced through combination treatment with immune modulatory regimens.
Photodynamic therapy (PDT) has become widely accepted and utilized for tumor therapy. Considering the natural shortcomings (e.g., lack of an ideal photosensitizer and limited light penetration depth), lanthanide doped upconversion nanoparticles (Ln-doped UCNP), which can be excited with near-infrared light (NIR) for UV/visible/NIR upconversion luminescence (UCL) emissions, show great potential for augmenting biological treatment with PDT for solid tumors and for visual bioimaging of disease lesions. This review summarizes the basic concepts and important influence factors on PDT, the optimized construction of UCNP-based photosensitizer (UCNP-PS) systems, and some representative examples of UCNP-based PDT (UC-PDT) applications in combination with other traditional therapy methods, such as chemotherapy, radiotherapy, photothermal therapy (PTT) and gene therapy. This review will provide guidance for the design and fabrication of future new UCNP-based nanocomposites for synergistic UC-PDT therapy.
According to the American Academy of Implant Dentistry, 3 million Americans have dental implants, and this number is growing by 500,000 each year. Proportionally, the number of biological complications is also increasing. Among them, peri-implant disease is considered the most common cause of implant loss after osseointegration. In this context, microorganisms residing on the surfaces of implants and their prosthetic components are considered to be the primary etiologic factor for peri-implantitis. Some research groups have proposed combining surgical and non-surgical therapies with systemic antibiotics. The major problem associated with the use of antibiotics to treat peri-implantitis is that microorganisms replicate very quickly. Moreover, inappropriate prescription of antibiotics is not only associated with potential resistance but also and most importantly with the development of superinfections that are difficult to eradicate. Although antimicrobial photodynamic therapy (aPDT) was discovered several years ago, aPDT has only recently emerged as a possible alternative therapy against different oral pathogens causing peri-implantitis. The mechanism of action of aPDT is based on a combination of a photosensitizer drug and light of a specific wavelength in the presence of oxygen. The reaction between light and oxygen produces toxic forms of oxygen species that can kill microbial cells. This mechanism is crucial to the efficacy of aPDT. To help us understand conflicting data, it is necessary to know all the particularities of the etiology of peri-implantitis and the aPDT compounds. We believe that this review will draw attention to new insights regarding the impact of aPDT on peri-implant disease.
APPLICATIONS OF MULTISPECTRAL AUTOFLUORESCENCE IMAGING OF MALIGNANT TUMORS
Papayan GV1,2, Petrishchev NN1,2, Kim SV3, Kim Hyung Ho3, Berezin VB4, Kang Uk4
1Center of Laser Medicine, First I.P. Pavlov Federal Medical University of St. Petersburg,
St. Petersburg
2Federal Almazov Medical Research Centre, St. Petersburg
3Seoul National University Bundang Hospital (SNUH), Seoul, Korea
4Korea Electrotechnology Research Institute (KERI), Seoul, Korea
The applications of multispectral autofluorescence imaging of malignant tumor was shown in in vitro and in vivo experiments.Using ТС-1 mouse tumor model it was demonstrated that the location of tumor formation can be clearly identified as early as 2 days after injection of tumor cells. Among observed effects the new one is an unusually active angiogenesis at early stage of tumor formation accompanied by atypical tortuous vessels with growth rate up to 3 mm/day. Two-wave excitation simultaneous laser with excitation on wavelength of 390 nm and 635 nm is shown to be promising for autofluorescence diagnosis along with single-wave excitation which is conventionally performed in the violet-blue region of the spectrum. This mode of excitation allows detecting the increased level of protoporphyrin IX even at early stage of carcinogenesis. The fluorescence due to active synthesis of protoporphyrin IX was shown to correlate with density of vessels. Increase of this fluorescence is observed also for aseptic inflammation but it has diffuse pattern which allows differentiating it from local fluorescence image at the site of tumor formation.The possibility of successful achievement of high-quality image using multispectral imaging and also optimization of registration settings were demonstrated in the experiment. The study of surgical specimen showed capabilities of imaging and measurement of autofluorescence in tumor tissue. The obtained results are intended to help in the development of endoscopic methods of imaging and devices for diagnosis of early tumors.
Die PDT ist ein nicht-thermisches, photochemisches, zweistufiges Behandlungsverfahren mit einer relativ selektiven Wirksamkeit gegenüber vaskularisierten Zielstrukturen.
The photosensitizing and pharmacokinetic properties of porphyrin-type compounds have been investigated for nearly a century. In the last decade, two porphyrin derivatives were approved in the U.S.A. and in several other countries for the photodynamic treatment of various lesions. An overview of the different mechanisms for preferential porphyrinoid localization in malignant tumors is presented herein. Several uptake pathways are possible for each photosensitizer, which are determined by its structure, mode of delivery and tumor type. Comparisons of the different mechanisms and correlations with the structure of the sensitizer are presented. Current delivery systems for porphyrin sensitizers are described, as well as recent strategies for enhancing their tumor-specificity, including conjugation to a carrier system that selectively targets a tumor-associated receptor or antigen. Copyright (C) 2002 Society of Porphyrins & Phthalocyanines.
We carried out the first investigation to establish rat tumor M-1 by laser irradiation of the large blood vessel zone in the inguinal triangle in conjunction with photosensitinogen growth inhibition. Relatively small-size metastases to the lymph nodes and liver (stage III-IV) were identified after the blood was exposed to laser radiation in combination with intravenous injection of photosensitinogen under clinical conditions.
Photodynamic therapy (PDT) with verteporfin has significantly improved functional outcome in the treatment of choroidal neovascularization (CNV) in various clinical disorders [86]. While CNV due to age-related macular degeneration [4, 53, 76-80, 84] and pathologic myopia [83, 85] was the primary focus, several studies showed that the treatment effects of PDT were not only restricted to these two underlying disorders. Recently, several clinical studies observed PDT as a treatment modality of CNV due to ocular histoplasmosis syndrome [52, 55, 68], choroiditis [71, 89], angioid streaks [31, 37, 68], Stargardt's disease [81], symptomatic choroidal hemangioma [30, 61, 82] and other causes [15, 72]. While PDT has become an established treatment modality for various choroidal disorders, its role in the treatment of retinal diseases remains to be determined.
Resistance to cell death and the ability to overrule immunosurveillance represent two hallmarks of tumour cells. The optimal cancer treatment should combine the induction of cell death and immunostimulatory effects based on immune cells activation consequent to the immunogenic characteristics of dead cells and their removal. The dynamic interplay between dead cell and phagocytes leading to efficient phagocytosis is divided in four steps: 1) attraction and accumulation of phagocytes to the site of apoptotic cells, 2) recognition and tethering, 3) internalization and 4) processing of dead cells within the phagocytes avoiding phlogosis. Apoptotic cells secrete chemotactic signals attracting phagocytes and expose on plasma membrane ligands mediating receptor-specific physical contact with phagocytes. Indeed, the subsequent internalization steps and outcomes, i.e. immunotolerance or immunomodulation, profoundly depend on the phagocytic receptors involved. PhotoDynamic Therapy (PDT), a promising new cancer treatment, is based on the synergic action of photosensitizing drugs (PS) and light irradiation that allow to kill the cells respectively via chemical and physical stress. Highly Reactive Oxygen Species (ROS), formed by the transfer of energy absorbed by PS upon irradiation to molecular oxygen, mediate the destruction of target cells. The best feature of PDT is the ROS damage directionality, depending on PS localization that in turn is mediated by its hydrophilicity/hydrophobicity, and the precise delivery of light to the treated sites. Multiple advantages characterize PDT as cancer treatment modality and make it potentially capable to meet many currently unmet medical needs. Particularly, PDT elicits a strong acute inflammation, orchestrated by both the innate and adaptive immune system, ensuring a protective effect by containing the disruption of tissue homeostasis and removal of damaged cells. The acute inflammatory response depends on photosensitized dead cells. Indeed, PDT not only induces apoptosis, autophagy and necrosis in the tumour cells, but it is also effective to rapidly generate an abundance of alarm/danger signals, called Damage-Associated Molecular Patterns (DAMPs), detected by the innate immunity alert elements. These, recruited to the sites of dead cells, eliminate injured and dead cells by phagocytosis and trigger the antitumour immunity by maturation and activation of dendritic cells (DCs). Here we will discuss whether the multiple PDT-induced cell death types can result in an immune response, linked to the exposure and/or release of signals by dying cells, ending in the phagocytosis by the immune cells.
Photodynamic therapy refers to a new form of phototherapy in which non-psoralen photosensitizing drugs are administered systemically or topically to an individual. The drugs alone are inactive, but once activated by high-intensity light usually from a laser, they are exceptionally effective at inhibiting the growth of hyperproliferative tissues. PDT was originally designed for the treatment of malignancies because of the unique property of several photosensitizers to localize preferentially within tumors. Porfimer sodium (Photofrin), a first generation PDT photosensitizer, has already received regulatory approval in the USA, Canada, Japan, and Europe for the management of bladder, esophageal, and lung cancers. Although PDT has not been formally approved for dermatological malignancies, its efficacy in the treatment of superficial skin cancer has been demonstrated in several clinical studies [23, 38, 43, 85, 103, 125, 151, 163, 185]. Clinical trials are currently being conducted for this indication, and approval is likely within the next few years. Because of the accessibility of the skin, there is increasing interest in using this novel form of therapy for psoriasis and other benign cutaneous disorders as well.
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