Therapeutic Effect Of Photodynamic Therapy Research Articles

Nanoengineered M1 macrophages enhance photodynamic therapy of melanoma through oxygen production and subsequent antitumor immunity

Photodynamic therapy (PDT) is an emerging treatment for melanoma stimulating antitumor immune responses. However, oxygen consumption by PDT exacerbates hypoxia and immunosuppression in the tumor microenvironment. This issue could potentially be addressed by M1 macrophages with high hydrogen peroxide concentrations, which can be catalyzed to oxygen, thereby increasing oxygen level and enhancing intrinsic immune response of M1 macrophages and their ability to stimulate adaptive immunity. Herein, biocompatible photosensitizer-containing nanoparticles were designed by combining bovine serum albumin and manganese dioxide (BMB). These nanoparticles were internalized by M1 macrophages in vitro to form nanoengineered macrophages (BMB@M1). BMB@M1 demonstrated various ways to transfer nanoparticles in melanoma with high tumor site accumulation. Within the tumor microenvironment characterized by hydrogen peroxide and acidity, BMB underwent Mn2+ transformation and generated oxygen. The paramagnetic property of Mn2+ was used for magnetic resonance imaging, enabling visualization of the melanoma enrichment process of BMB@M1. Oxygen supplementation enhanced the therapeutic effect of PDT and stimulated the secretion of IL-12 and IFN-γ by macrophages, synergistically promoting the infiltration of T cells and dendritic cells into the tumor. These findings showed that nanoengineered M1 macrophage could be used as a delivery system to enhance immune effects of PDT.

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer.

Hypoxia is a pervasive feature of solid tumors, which significantly limits the therapeutic effect of photodynamic therapy (PDT) and further influences the immunotherapy efficiency in breast cancer. However, the transient alleviation of tumor hypoxia fails to address the underlying issue of increased oxygen consumption, resulting from the rapid proliferation of tumor cells. At present, studies have found that the reduction of the oxygen consumption rate (OCR) by cytochrome C oxidase (COX) inhibition that induced oxidative phosphorylation (OXHPOS) suppression was able to solve the proposed problem. Herein, we developed a specific mitochondrial-targeting nanotrapper (I@MSN-Im-PEG), which exhibited good copper chelating ability to inhibit COX for reducing the OCR. The results proved that the nanotrapper significantly alleviated the hypoxic tumor microenvironment by copper chelation in mitochondria and enhanced the PDT effect in vitro and in vivo. Meanwhile, the nanotrapper improved photoimmunotherapy through both enhancing PDT-induced immunogenetic cell death (ICD) effects and reversing Treg-mediated immune suppression on 4T1 tumor-bearing mice. The mitochondrial-targeting nanotrapper provided a novel and efficacious strategy to enhance the PDT effect and amplify photoimmunotherapy in breast cancer.

Clinical case of successful application of photodynamic therapy in advanced vulvar cancer

A significant  therapeutic effect of photodynamic  therapy (PDT) is shown in a patient with extensive vulvar cancer after ineffective surgical and chemoradiotherapy. During the year, three courses of local PDT with a photosensitizer based on chlorin e6 were carried out. The photosensitizer was administered intravenously three hours before irradiation at a dose of 1.2 mg/kg. For laser irradiation (662 nm) of the vulvar tumor, a light guide for external irradiation was used: the power density was 0.2 W/cm2, the light dose was from 100 to 250 J/cm2. As a result of treatment, tumor regression and stable remission are observed. The patient remains under observation.

A dual donor–acceptor fluorescent probe with viscosity response and lipid droplets targeting to initiate oxidative stress for tumor elimination

A dual donor–acceptor photosensitizer TCN-2 prepared based on single donor–acceptor could fulfil lipid droplets targeting to trigger apoptosis and tumor growth arrest. Meanwhile, all of experiments both in phosphate buffer solution and intracellular surroundings have demonstrated that TCN-2 catalyzed the production of type I as well as type II reactive oxygen species, forming a hybrid reactive oxygen species pattern, indicating that TCN-2 could be applied to initiate a series of biological responses triggered by oxidative stress within most high-viscosity solid tumors. In addition, TCN-2 also has the capability of fluorescence imaging, which could perfectly combine therapeutic imaging to achieve therapeutic effects while identifying cancerous lesions. Due to the structural design of double electron-absorbing groups, TCN-2 retained excellent lipophilicity while enhancing solubility in the biological environment. Terrific biocompatibility, minimal phototoxic damage to normal cells and tissues, and specific driving to prescriptive organelles to maximize therapeutic effects were used to enhance the therapeutic effect of photodynamic therapy to cease disease progression.

Thermally Managed, Injectable Optoelectronic Probe with Heat Dissipation Guide for Photodynamic Therapy.

The development of fabrication technologies and appearance of new materials has resulted in dramatic increase in the performance of electronic devices, while the overall size has decreased. Recent electronic devices made of micro/nano-size components show high efficiency and outstanding performance with compact size, but these devices have revealed several fatal problems. In particular, the isolated heat that is generated by numerous components concentrated in a limited small area at high density, such as bio-integrated devices, is an issue that needs to be urgently addressed, because it is closely related to the performance and lifetime of electronic devices. To solve these problems, the microscale light emitting diode (µLED)-based neural probe is introduced on an injectable heat dissipation guide. The heat dissipation guide is made of boron nitride (BN) nanomaterials with high thermal conductivity. The heat management noticeably improves the optical output performance of the µLEDs, in which BN effectively dissipates heat, and allows enhanced lighting from the LEDs to be transmitted through brain tissue without thermal damage. Moreover, it shows remarkable improvement in the therapeutic effect of photodynamic therapy of mouse cancer cells.

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We report on an attempt to increase the therapeutic effect of photodynamic therapy using a lipid nanoparticle (LNP). The findings indicate that the internal structure of the LNPs change depending on the amount of photosensitizer in the particle. The photoactivity and cell‐killing effect of photosensitizer also changed with increasing amount of cargo, suggesting that the internal structure of the LNP is an important factor that affect the therapeutic effect.Further details can be found in the article by Fumika Kubota, Satrialdi, Yuta Takano, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima, and Yuma Yamada (e202200119). image

Effectiveness of photodynamic therapy (PDT) in the management of symptomatic oral lichen planus -A systematic review.

Oral Lichen Planus (OLP) is a chronic mucocutaneous inflammatory disease of unknown aetiology characterized by T cell mediated autoimmune response which trigger apoptosis of basal cells of an oral epithelium. Corticosteroids are the primary therapeutic option for symptomatic OLP however treatment of lesions unresponsive to corticosteroids that tend to recur are becoming challenging for the clinicians. Currently photodynamic therapy (PDT) is being explored as a new curative option for reduction of pain and/or burning sensation associated with OLP lesions. The aim of this systematic review was to analyse studies from literature on the therapeutic effectiveness of PDT in management of symptomatic OLP unresponsive to corticosteroid therapy. The electronic retrieval systems and databases PUBMED [MEDLINE], EMBASE, SCOPUS, WEB OF SCIENCE, GOOGLE SCHOLAR, and SCIENCE DIRECT were searched independently by two authors for relevant articles from January 2015 till July 2021. Primary studies focussed on the role of PDT in treatment of symptomatic OLP and published in English were included. Out of the 370 articles, only ten studies met the selection criteria. Included studies demonstrated PDT as an effective alternative modality to treat symptomatic OLP with no drop outs. In all studies, with PDT reduction in lesion size and VAS score was observed during each follow up sessions and after treatment (approx. 12 weeks) when compared to pre-treatment level (p<0.001). Four studies noted PDT to be more effective than topical corticosteroids in reduction of signs and symptoms of OLP (p=0.001). In the future, long-term studies on larger population should be conducted to establish the clinical effectiveness in PDT in symptomatic OLP. Studies should take into consideration different sources of light and photosensitizers to determine the ideal parameters of PDT treatment for OLP. Wavelength is the most important factor in all types of photo therapies, so the most appropriate wavelength should be selected to obtain better outcome.

Oxygen-carrying acid-responsive Cu/ZIF-8 for photodynamic antibacterial therapy against cariogenic Streptococcus mutans infection.

Caries as a result of acid demineralization is the most common oral microbial infectious disease. Due to the small and complex intraoral operating space, it is challenging to completely remove Streptococcus mutans (S. mutans) and other cariogenic bacteria. As an intelligent acid-responsive photosensitive nanomaterial, O2-Cu/ZIF-8@Ce6/ZIF-8@HA (OCZCH) was chosen to adapt to the anaerobic and acidic microenvironment for inactivating S. mutans. In this work, OCZCH not only exhibits a regular nanomorphology in SEM and TEM images but also shows intelligent acid responsiveness as evidenced by the release of Ce6 and oxygen. When excited by near-infrared light at 650 nm, Ce6 releases reactive oxygen species (ROS) that act synergistically with internal oxygen to significantly enhance the antimicrobial therapeutic effect of photodynamic therapy (PDT). In vitro antimicrobial experiments showed that OCZCH could achieve an impressive sterilization effect against S. mutans and biofilm. Notably, the acid-producing ability of the bacteria was also significantly inhibited. With its oxygen-carrying photosensitizing properties, excellent responsiveness to acidic environments, and antimicrobial capacity under anaerobic conditions, OCZCH is considered an innovative candidate for clinical application in treating dental caries.

A protein-targeted photosensitizer for highly efficient cancer therapy

Photodynamic therapy typically employs photo-triggered photosensitizers to generate reactive oxygen species to destroy cancer cells. However, the therapeutic effect of photodynamic therapy is often limited owing to the ultrashort diffusion distance of reactive oxygen species and easy efflux of photosensitizers. Herein, we design and synthesize a protein-targeted molecular photosensitizer for highly efficient photodynamic therapy. The designed photosensitizer can covalently bind with the sulfhydryl groups of intracellular proteins to achieve the protein targeting. Under irradiated with near infrared laser, the photosensitizer was locally activated, and the produced reactive oxygen species directly destroy intracellular bioactive proteins, causing cell dysfunction and ultimately inducing cell apoptosis. Significantly, the leakage of molecular photosensitizer is effectually avoided due to the protein targeting. In vivo experimental results indicated that the effect of treatment was efficiently enhanced with the protein-targeted strategy. This work can offer new insights for designing protein-based therapeutic drugs.

Cellular Hypoxia Mitigation by Dandelion-like Nanoparticles for Synergistic Photodynamic Therapy of Oral Squamous Cell Carcinoma.

Hypoxia at the tumor site limits the therapeutic effects of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC), which is an oxygen-consumption process. Inhibiting cellular oxygen consumption and reducing cellular ATP production are expected to enhance PDT. In this study, we designed and constructed dandelion-like size-shrinkable nanoparticles for tumor-targeted delivery of hypoxia regulator resveratrol (RES) and photodynamic agent chlorine e6 (CE6). Both drugs were co-encapsulated in small-sized micelles modified with EGFR targeting ligand GE11, which was further conjugated on hyaluronic nanogel (NG) to afford RC-GMN. After targeted accumulation in tumors mediated by GE11 and enhanced penetration and retention (EPR) effects, RC-GMN was degraded by hyaluronidase (HAase) and resulted in small-sized micelles, allowing for deep penetration and dual-receptor-mediated cellular internalization. Resveratrol inhibited cellular oxygen consumption and provided sufficient oxygen for PDT, which consequently activated PDT to produce reactive oxygen species (ROS). Notably, we found that autophagy was overactivated in PDT, which was further strengthened by the hypoxia regulator resveratrol, elevating autophagic cell death. The synergistic effects of resveratrol and CE6 promoted autophagic cell death and apoptosis in the enhanced PDT, resulting in stronger antitumor effects in the orthotopic OSCC model. Therefore, the facilitated delivery of hypoxia regulator enhanced PDT efficacy by elevating oxygen content in tumor cells and inducing autophagic cell death and apoptosis, which offers an alternative strategy for enhancing the PDT effects against OSCC.

Intelligent Supramolecular Nanoprodrug Based on Anionic Water-Soluble [2]Biphenyl-Extended-Pillar[6]arenes for Combination Therapy.

An anionic water-soluble [2]biphenyl-extended-pillar[6]arenes modified with eight ammonium salt ions (AWBpP6) was successfully synthesized to establish a drug-drug conjugate supramolecular nanoprodrug (SNP) with a high drug-loading capacity. This SNP can generate a synergistic triple therapeutic effect of photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy (CT; i.e., PDT-PTT-CT) with excellent biocompatibility.

Oxygen-evolving hollow polydopamine alleviates tumour hypoxia for enhancing photodynamic therapy in cancer treatment.

Hypoxia, a characteristic hallmark of solid tumours, restricts the therapeutic effect of photodynamic therapy (PDT) for cancer treatment. To address this issue, a facile and nanosized oxygen (O2) bubble template is established by mixing oxygenated water and water-soluble solvents for guiding hollow polydopamine (HPDA) synthesis, and O2 is encapsulated in the cavity of HPDA. HPDA with abundant catechol is designed as a carrier for zinc phthalocyanine (ZnPc, a boronic acid modified photosensitizer) via borate ester bonds to fabricate nanomedicine (denoted as HZNPs). The in vitro and in vivo results indicate that O2-evolving HZNPs could alleviate tumour hypoxia and enhance PDT-anticancer efficiency. Melanin-like HPDA with a photothermal conversion rate (η) of 38.2% shows excellent synergistic photothermal therapy (PTT) efficiency in cancer treatment.

Recent Advances in Hypoxia-Overcoming Strategy of Aggregation-Induced Emission Photosensitizers for Efficient Photodynamic Therapy.

Hypoxia is an inherent physiologic barrier in the microenvironment of solid tumor and has badly restricted the therapeutic effect of photodynamic therapy (PDT). Meanwhile, the photosensitizer (PS) agents used for PDT applications regularly encounter the tiresome aggregation-caused quenching effect that seriously decreases the production efficiency of cytotoxic reactive oxygen species. The aggregation-induced emission (AIE) PSs with antiquenching characteristics in the aggregate state are considered as a promising tool for achieving highly efficient PDT applications, and plenty of studies have widely demonstrated their advantages in various diseases. Herein, the recent progress of AIE PSs in the battle of antitumor hypoxia issue is summarized and the practical molecular principles of hypoxia-overcoming AIE PSs are highlighted. According to the hypoxia-overcoming mechanism, these representative cases are divided into low O2 -dependent (type I PDT) and O2 -dependent tactics (mainly including O2 -enrichment type II PDT and combination therapy). Furthermore, the underlying challenges and prospects of AIE PSs in hypoxia-overcoming PDT are proposed and thus expect to promote the next development of AIE PSs.

Dual-Emission Carbonized Polymer Dots for Ratiometric pH Sensing, pH-Dependent Generation of Singlet Oxygen, and Imaging-Guided Dynamics Monitoring of Photodynamic Therapy.

The pH environment in cancer cells has been demonstrated to display vital influences on the therapeutic effect of photodynamic therapy (PDT). It is very interesting to develop pH-responsive probes for simultaneous pH sensing and dynamics monitoring of the effects of PDT, and therefore assessing the correlation between them. In this study, a multifunctional fluorescence probe, dual-emission carbonized polymer dot (CPD) in blue and red regions, which uses ethylene imine polymer (PEI) and 4,4',4″,4‴-(porphine-5, 10, 15, 20-tetrayl) tetrakis (benzoic acid) (TCPP) as precursors through a one-step hydrothermal amide reaction, has been designed for ratiometric pH sensing, generating pH-dependent 1O2 for PDT of cancer cells, and investigating the dynamics effects of PDT through pH-guided imaging. The prepared CPDs were successfully used for ratiometric pH response, pH-dependent generation of 1O2, and dynamics monitoring PDT in HeLa cells. This study may provide an alternative strategy to prepare CPD-based theranostic integrated nanoprobes for PDT through the rational design of precursors.

A Dual-Nanozyme-Catalyzed Cascade Reactor for Enhanced Photodynamic Oncotherapy against Tumor Hypoxia.

Tumor hypoxia is a typical characteristic of tumor microenvironment (TME), which seriously compromises the therapeutic effect of photodynamic therapy (PDT). The development of nanozymes with oxygen-generation ability is a promising strategy to overcome the oxygen-dependent of PDT but remained a great challenge. Herein, a dual-nanozymes based cascade reactor HAMF is proposed to alleviate tumor hypoxia for enhanced PDT. The hollow mesoporous silica nanoparticles (HMSNs) are constructed as an excellent nanocarrier to load ultra-small gold nanoparticles (Au NPs) and manganese dioxide (MnO2 ) shell via in situ reduction method, and further coordination with an efficient photosensitizer 4-DCF-MPYM (4-FM), a thermally activated delayed fluorescence (TADF) fluorescein derivative. With the response to TME, MnO2 can catalyze endogenous H2 O2 into O2 and subsequently accelerating glucose oxidation by Au NPs to produce additional H2 O2 , which is reversely used as the substrate for MnO2 -catalyzed reaction, thereby constantly producing singlet oxygen (1 O2 ) for enhanced PDT upon light irradiation. This work proposed a cascade reactor based on dual-nanozyme to relieve tumor hypoxia for effective tumor suppression, which may enrich the application of multi-nanozymes in biomedicine.

An All‐in‐One Organic Semiconductor for Targeted Photoxidation Catalysis in Hypoxic Tumor

AbstractTumor hypoxia severely limits the therapeutic effects of photodynamic therapy (PDT). Although many methods for oxygen generation exist, substantial safety concerns, spatiotenporal uncontrollability, limited efficacy, and complicated procedures have compromised their practical application. Here, we demonstrate a biocompatiable all‐in‐one organic semiconductor to provide a photoxidation catalysis mechanism of action. A facile method is developed to produce gram‐level C5N2 nanoparticles (NPs)‐based organic semiconductor. Under 650 nm laser irradiation, the semiconductor split water to generate O2 and simultaneously produce singlet oxygen (1O2), showing that the photocatalyst for O2 evolution and the photosensitizer (PS) for 1O2 generation could be synchronously achieved in one organic semiconductor. The inherent nucleus targeting capacity endows it with direct and efficient DNA photocleavage. These findings pave the way for developing organic semiconductor‐based cancer therapeutic agents.

An All-in-One Organic Semiconductor for Targeted Photoxidation Catalysis in Hypoxic Tumor.

Tumor hypoxia severely limits the therapeutic effects of photodynamic therapy (PDT). Although many methods for oxygen generation exist, substantial safety concerns, spatiotenporal uncontrollability, limited efficacy, and complicated procedures have compromised their practical application. Here, we demonstrate a biocompatiable all-in-one organic semiconductor to provide a photoxidation catalysis mechanism of action. A facile method is developed to produce gram-level C5 N2 nanoparticles (NPs)-based organic semiconductor. Under 650 nm laser irradiation, the semiconductor split water to generate O2 and simultaneously produce singlet oxygen (1 O2 ), showing that the photocatalyst for O2 evolution and the photosensitizer (PS) for 1 O2 generation could be synchronously achieved in one organic semiconductor. The inherent nucleus targeting capacity endows it with direct and efficient DNA photocleavage. These findings pave the way for developing organic semiconductor-based cancer therapeutic agents.

Comparison of actual and simulated tumoricidal effects induced by photodynamic therapy.

Numerous studies employ mathematical methods, such as Monte Carlo simulation, to predict the tumor killing effects of photodynamic therapy (PDT) by simulating optical propagation, photosensitizer distribution, and oxygen distribution. Whether these models faithfully reflect tumor killing is unknown, and model validation using tumor cross sections in these studies is usually insufficient to answer this question. To fill this gap in our knowledge, we employed a mouse model of breast cancer to determine the spatiotemporal effects of PDT using direct histopathological and biochemical analyses of whole tumors. We prepared approximately 700 5-μm-thick serial sections of breast tumors of syngeneic mice treated with PDT employing the photosensitizer photocarcinorin (PsD-007, a second-generation photosensitizer developed in China). Three adjoining sections were subjected to hematoxylin and eosin staining to assess necrosis, the TUNEL assay to evaluate apoptosis, and CD31 staining to detect angiogenesis, respectively. We then generated a three-dimensional (3D) reconstruction of the tumor to evaluate these processes. We simultaneously used the Monte Carlo method to develop a model of light distribution throughout the tumor to evaluate the actual and simulated tumor killing effects induced by PDT. Tumor necrosis decreased exponentially as a function of distance from the source of illumination, while the distributions of apoptosis and neovascularization were independent of light distribution. Most apoptosis occurred in the lower layers (3000-4000 μm) of the tumor where the light intensity was too low to excite the photosensitizer. Neovascularization occurred at depths ranging from 2500 to 3500 μm. These analyses provided a 3D view of how a tumor is destroyed using PDT. Although the optical distribution model predicted tumor necrosis caused by PDT, it was ineffective in predicting the sites of apoptosis and vascular destruction. Mathematical modeling is limited in its capabilities required to gain a comprehensive understanding of the spatiotemporal events associated with PDT. The mouse model developed here will serve as a platform for detailed direct histopathological, biochemical, and molecular genetic analyses of the effects of PDT, which will facilitate the development of optimized treatment strategies.

Assessment of choriocapillary blood flow changes in response to half-dose photodynamic therapy in chronic central serous chorioretinopathy using optical coherence tomography angiography

BackgroundOptical coherence tomography angiography (OCTA) is a newly developed imaging quantitative technique for analysis of choriocapillaris (CC) flow changes, thereby exploring the pathological mechanism of chronic central serous chorioretinopathy (CCSC) and the therapeutic effects of photodynamic therapy (PDT). In this study, we sought to quantify the blood flow changes in CC of CCSC patients receiving half-dose PDT using OCTA.MethodsA total of 28 affected eyes and 24 unaffected eyes of 26 CCSC patients receiving half-dose PDT, and 40 eyes of 20 healthy gender- and age-matched subjects were retrospectively enrolled in this study. The proportion of total areas of flow signal voids (FSV, %) in CC level of OCTA was assessed in both eyes of the CCSC patients at baseline and repeated in multiple sections at 1-week, 1-month, 3-month and 6-month intervals after PDT. In addition, the CC patterns in response to PDT at early stage and the subsequent morphologic changes were qualitatively documented using OCTA.ResultsFor affected eyes, FSV at 6-m follow-up was significantly lower than that at 1-m follow-up (p = 0.036). When compared to normal control eyes, FSV in affected eyes was significantly higher at 1-m, 3-m and 6-m follow-up (p < 0.05 for all), and FSV in unaffected eyes was significantly higher at baseline, 1-w, 1-m and 3-m follow-up (p < 0.05 for all). Three CC patterns of early response to PDT were identified, including signs of recovery with more even flow signals, transient appearance of worse ischemia and secondary neovascularization within CC level.ConclusionAbnormal CC flow attenuation remains in completely resolved eyes of CCSC patients treated with half-dose PDT.

Nanomaterials to relieve tumor hypoxia for enhanced photodynamic therapy

This review summarizes recent research progress in versatile nanomaterials for enhanced photodynamic therapy by relieving tumor hypoxia. • This review summarizes recent progress in nanomaterials for enhanced photodynamic therapy by relieving tumor hypoxia. • The methods for constructing these nanomaterials based on characteristic factors in tumor are discussed. • The limitations and prospects of nanomaterials for enhanced photodynamic therapy are also discussed. Photodynamic therapy (PDT) shows great potential for tumor treatment owing to its high spatiotemporal selectivity, minimal invasiveness and patient compliance. However, the therapeutic effect of PDT is seriously hindered by the tumor hypoxia in vivo. Hypoxia is a typical hallmark of the solid tumor microenvironment, which promotes the proliferation, invasion and metastasis of tumor cells. Additionally, the oxygen consumption during PDT will further aggravate the tumor hypoxia, resulting in multiple undesirable side-effects. To resolve these problems, many studies have been conducted to improve the efficacy of PDT by increasing oxygen concentration in tumor. Here, we focus on the current advances in nanomaterials-mediated tumor oxygenation via oxygen-carrying or oxygen-generating strategies to relieve tumor hypoxia. Based on the comprehensive overview, we hope these inspirations in hypoxia-associated anti-tumor therapy will provide perspectives in designing new oxygenation nanomaterials in this promising field.