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In this paper, biodegradable red fluorescent protein (RFP) chromophore analogue DPFP-SS-FA nanoparticles were synthesized for hypoxic two-photon photodynamic therapy. The maximum emission wavelength of DPFP-SS-FA is in the red-to-near-infrared region at 674 nm. Interestingly, these DPFP-SS-FA nanoparticles remain stable under physiological conditions, but deplete glutathione and disintegrate into the RFP chromophore analogue monomer in the tumor microenvironment. Meanwhile, electron paramagnetic resonance data have shown that DPFP-SS-FA produced enhanced 1 O 2 /O 2 ˙ - signals after glutathione depletion causing an enhanced PDT effect. DPFP-SS-FA has negligible cell dark toxicity and high phototoxicity in hypoxic environments, indicating the outstanding hypoxia-overcoming ability of DPFP-SS-FA. In addition, due to its folic acid receptor and lysosome dual-targeting ability, DPFP-SS-FA is highly enriched in A-549 tumor cells. In particular, the hypoxic two-photon photodynamic therapy mediated by DPFP-SS-FA nanoparticles was validated in a zebrafish tumor model. Under 800 nm two-photon excitation, DPFP-SS-FA enabled bright two-photon fluorescence imaging and significantly inhibited the growth of tumor cells in zebrafish. The biodegradable DPFP-SS-FA nanoparticles reasonably constructed in this study can serve as excellent candidates for efficient hypoxic two-photon photosensitizers to treat deep tumor tissues.

Osteosarcoma (OS) is a prevalent and highly malignant bone tumor, characterized by its aggressive nature, invasiveness, and rapid progression, contributing to a high mortality rate, particularly among adolescents. Traditional treatment modalities, including surgical resection, radiotherapy, and chemotherapy, face significant challenges, especially in addressing chemotherapy resistance and managing postoperative recurrence and metastasis. Phototherapy (PT), encompassing photodynamic therapy (PDT) and photothermal therapy (PTT), offers unique advantages such as low toxicity, minimal drug resistance, selective destruction, and temporal control, making it a promising approach for the clinical treatment of various malignant tumors. Constructing multifunctional delivery systems presents an opportunity to effectively combine tumor PDT, PTT, and chemotherapy, creating a synergistic anti-tumor effect. This review aims to consolidate the progress in the application of novel delivery system-mediated phototherapy in osteosarcoma. By summarizing advancements in this field, the objective is to propose a rational combination therapy involving targeted delivery systems and phototherapy for tumors, thereby expanding treatment options and enhancing the prognosis for osteosarcoma patients. In conclusion, the integration of innovative delivery systems with phototherapy represents a promising avenue in osteosarcoma treatment, offering a comprehensive approach to overcome challenges associated with conventional treatments and improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

With its minimal invasiveness, photodynamic therapy (PDT) is considered one of the most elegant modalities in cancer treatment. In this study, a facile hybrid nanoparticle was developed, composed of upconversion nanoparticles and chlorin e6-bearing pullulan, which can serve as a photosensitizer activated by a near-infrared red laser. Cell death induction in cancer cells was achieved through energy transfer from the near-infrared red laser emitted by the upconversion nanoparticles to chlorin e6. The therapeutic efficacy of our hybrid system surpassed that of the clinically available photosensitizer, Photofrin, and hybrid liposomes comprising upconversion nanoparticles and chlorin e6 were employed as control. Accumulation of our system in tumor tissue in tumor xenograft mice was primarily achieved through the enhanced permeability and retention (EPR) effect. The administered hybrids were excreted from each organ within 21 days after administration, minimizing the risk of undesirable side effects. Notably, our system exhibited 400 times higher PDT activity in tumor-bearing mice compared to the control groups. It also effectively inhibited metastasis.

Ferroptosis primarily relies on reactive oxygen (ROS) production and lipid peroxide (LPO) accumulation, which opens up new opportunities for tumor therapy. However, a standalone ferroptosis process is insufficient in inhibiting tumor progression. Unlike previously reported Fe-based nanomaterials, we have engineered a novel nanoreactor named IR780/Ce@EGCG/APT, which uses metal-polyphenols network (Ce@EGCG) based on rare-earth cerium and epigallocatechin gallate (EGCG) to encapsulate IR780 and modified with the aptamer (AS1411). The intricately designed nanoreactor is specifically taken up by tumor cells, releasing Ce 3+ , EGCG, and IR780. On the one hand, Ce 3+ triggers ROS production via a Fenton-like reaction, inducing ferroptosis in tumor cells. On the other hand, IR780 accumulates in mitochondria and disrupts mitochondrial function upon laser irradiation, leading to tumor cell apoptosis. EGCG serves as a sensitizer, simultaneously enhancing the sensitivity of tumor cells to ferroptosis and photothermal therapy. After a single dose and three times of 808 nm laser irradiation for treatment, it has been observed that the nanoreactor induces dendritic cells (DCs) maturation, facilitates cytotoxic T lymphocyte infiltration, improves immunosuppressive microenvironment, activates the systemic immune system, and generates long-term immune memory., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Since the available treatments are not highly effective to combat cancer, therefore, the alternative strategies are unavoidable. Photodynamic therapy (PDT) is one of the emerging approaches which is target specific and minimally invasive. This study explores the successful development of Poly (D,L-lactide-co-glycolide) (PLGA) coated mesoporous silica nanoparticles (MSNs) and their augmented effects achieved by integrating curcumin (Cur) and cetyltrimethylammonium bromide (CTAB) in the polymeric layer and silica's pores, respectively. The synthesized nanocarriers (Cur-PLGA-cMSNs) have shown preferential targeting to the cellular organelles facilitated by CTAB's and Cur's affinity to mitochondria. CTAB and Cur-based PDT induced oxidative stress and generation of reactive oxygen species (ROS), resulting in dysfunctional mitochondria and triggered apoptotic pathways. PLGA coating has produced multifunctional effects, including; gatekeeping effects at pore openings, providing an extra loading site, enhancing the hemocompatibility of MSNs, and masking the free cur-related prolonged coagulation time. Cur-PLGA-cMSNs, as a multifaceted and combative approach with synergistic effects demonstrate promising potential to enhance outcomes in cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The purpose of this study is to investigate whether the iontophoresis-assisted riboflavin delivery to posterior sclera with less delivery time, can achieve the same riboflavin permeation efficiency as the passive soaking way, and its effect on the mechanical properties of posterior sclera for accelerated scleral collagen cross-linking (A-SXL). In this study, 0.1% riboflavin solution was applied into the posterior sclera of porcine eyes either by the iontophoresis-assisted or passive soaking method, with delivery time of 5, 7.5, 10, 12.5, 15, 17.5, and 20 min, respectively. The fluorescence intensity and the distribution of riboflavin concentration in the 10 μm frozen sections of the sclera were evaluated by fluorescence inverted microscope. The posterior sclera with riboflavin treatment through either the iontophoresis-assisted or the passive soaking method for different durations ranging from 5 to 20 min was treated with ultraviolet A (UVA) irradiation at an intensity of 10 mW/cm 2 for 9 min. The elastic modulus was determined at the physiological strain level using the uniaxial tensile test after ASXL. The results showed that the fluorescence intensity of riboflavin increased by prolonging the delivery time in both the iontophoresis and passive soaking groups, and the permeation depth of riboflavin remained constant over 15 min. The fluorescence intensity in the iontophoresis group was significantly higher than in the passive soaking group at 12.5 min and 15 min, respectively. The elastic modulus at 12.5 min in the iontophoresis group was significantly higher than in the passive soaking group at the same delivery time and showed no significant difference compared to the passive soaking group at 20 min. In conclusion, it indicated that iontophoresis-assisted delivery could not only shorten the surgery time but also achieve similar mechanical performance to the passive soaking method in ASXL., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

STING agonists can activate natural and adaptive immune responses, and are expected to become a new type of immunotherapy drug for tumor therapy. However, how to target deliver STING agonists to tumor tissues is a key factor affecting the efficacy of tumor treatment. Sonodynamic therapy (SDT) has become a research hotspot in the field of cancer treatment due to its non-invasive, spatiotemporally controllable, and high tissue penetration capabilities. Therefore, how to choose the appropriate drug delivery strategy, build a suitable drug delivery system to co-deliver photosensitizers and STING agonists, is a challenge faced in the tumor treatment. In this study, we developed an albumin-based nanodelivery system named FA-ICG&MnOx@HSA that co-loaded the sonosensitizers indocyanine green (ICG) and manganese oxide (MnOx). This approach achieved folate receptor-targeting mediated tumor delivery and tumor microenvironment (TME)-responsive release facilitated by high levels of glutathione (GSH) and hydrogen peroxide (H 2 O 2 ), which catalyze oxygen generation to potentiate SDT efficacy in killing tumors and inducing immunogenic cell death (ICD). Simultaneously, the released Mn 2+ acted as a STING agonist promoting dendritic cell maturation, IFN-β production, and proliferation of T cells. Ultimately, this albumin based co-loaded sonosensitizer and STING agonist demonstrated promising potential for advancing tumor treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although nearly 30 years have passed since the introduction of the first clinically approved photosensitizer for photodynamic therapy, progress in developing new pharmaceutical formulations remains unsatisfactory. This review highlights that despite years of research, many recurring challenges and issues remain unresolved. The paper includes an analysis of selected essential studies involving aminolevulinic acid and its derivatives, as well as other photosensitizers with potential for development as medical products. Among various possible vehicles, special attention is given to gelatin, alginates, poly(ethylene oxide), polyacrylic acid, and chitosan. The focus is particularly on infectious and cancerous diseases. Key aspects of developing new semi-solid drug forms should prioritize the creation of easily manufacturable and biocompatible preparations for clinical use. At the same time, new formulations should preserve the primary function of photosensitizers, which is the generation of reactive oxygen species capable of destroying pathogenic cells or tumors. Additionally, the use of adjuvant properties of carriers, which can enhance the effectiveness of macrocycles, is emphasized, especially in chitosan-based antibacterial formulations. Current research indicates that many promising dyes and macrocyclic compounds with high potential as photosensitizers in photodynamic therapy remain unexplored in formulation and development work. This review outlines potential new and previously explored pathways for advancing photosensitizers as active pharmaceutical ingredients (APIs)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O 2 , has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O 2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O 2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFR high cSCC but also to extend its applicability to other EGFR high malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Large, rapid extracellular oxygen transients (ΔpO 2 ) have been measured in vivo during ultra-high dose rate radiation therapy; however, it has been unclear if they match intracellular oxygen levels. Here, the endogenously produced protoporphyrin IX (PpIX) delayed fluorescence signal was measured as an intracellular in-vivo oxygen sensor to quantify these transients, with direct comparison to extracellular pO 2 . Intracellular ΔpO 2 is closer to the cellular DNA, the site of major radiobiological damage, and therefore should help elucidate radiochemical mechanisms of the FLASH effect and potentially be translated to human tissue measurement., Methods and Materials: PpIX was induced in mouse skin through intraperitoneal injection of 250 mg/kg of aminolevulinic acid. The animals were also administered a 50 µL intradermal injection of 10 µM oxyphor G4 (PdG4) for phosphorescence lifetime pO 2 measurement. Paired oxygen transients were quantified in leg or flank tissues while delivering 10 MeV electrons in 3 µs pulses at 360 Hz for a total dose of 10 to 28 Gy., Results: Transient reductions in pO 2 were quantifiable in both PpIX delayed fluorescence and oxyphor phosphorescence, corresponding to intracellular and extracellular pO 2 values, respectively. Reponses were quantified for 10, 22, and 28 Gy doses, with ΔpO 2 found to be proportional to the dose on average. The ΔpO 2 values were dependent on initial pO 2 in a logistic function. The average and standard deviations in ΔpO 2 per dose were 0.56 ± 0.18 mm Hg/Gy and 0.43 ± 0.06 mm Hg/Gy for PpIX and oxyphor, respectively, for initial pO 2 > 20 mm Hg. Although there was large variability in the individual animal measurements of ΔpO 2 , the average values demonstrated a direct and proportional correlation between intracellular and extracellular pO 2 changes, following a linear 1:1 relationship., Conclusions: A fundamentally new approach to measuring intracellular oxygen depletion in living tissue showed that ΔpO 2 transients seen during ultra-high dose rate radiation therapy matched those quantified using extracellular oxygen measurement. This approach could be translated to humans to quantify intracellular ΔpO 2 . The measurement of these transients could potentially allow the estimation of intracellular reactive oxygen species production., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Photodynamic priming (PDP) leverages the photobiological effects of subtherapeutic photodynamic therapy (PDT) regimens to modulate the tumor vasculature and stroma. PDP also sensitizes tumors to secondary therapies, such as immunotherapy by inducing a cascade of molecular events, including immunogenic cell death (ICD). We and others have shown that PDP improves the delivery of antibodies, among other theranostic agents. However, it is not known whether a single PDP protocol is capable of both inducing ICD in vivo and augmenting the delivery of immune checkpoint inhibitors. In this rapid communication, we show for the first time that a single PDP protocol using liposomal benzoporphyrin derivative (Lipo-BPD, 0.25 mg/kg) with 690 nm light (75 J/cm 2 , 100 mW/cm 2 ) simultaneously doubles the delivery of ⍺-PD-L1 antibodies in murine AT-84 head and neck tumors and induces ICD in vivo. ICD was observed as a 3-11 fold increase in tumor cell exposure of damage-associated molecular patterns (Calreticulin, HMGB1, and HSP70). These findings suggest that this single, highly translatable PDP protocol using clinically relevant Lipo-BPD holds potential for improving immunotherapy outcomes in head and neck cancer. It can do so by simultaneously overcoming physical barriers to the delivery of immune checkpoint inhibitors, and biochemical barriers that contribute to immunosuppression., (© 2023 American Society for Photobiology.)

Different types of photosensitizers (PSs) have different dynamics and intensities of accumulation, depending on the type of tumor or different areas within the same tumor. This determines the effectiveness of fluorescence diagnostics and photodynamic therapy (PDT). This paper studies the processes of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) and chlorin e6 (Ce6) accumulation in the central and border zones of a tumor after combined administration of two PSs into the patient's body. Fluorescence diagnostic methods have shown that sublingual administration of 5-ALA leads to the more intense accumulation of PpIX in a tumor compared to oral administration. Differences have been identified in the dynamics of 5-ALA-induced PpIX and Ce6 accumulation in the central and border zones of the tumor, as well as normal tissues. Ce6 accumulates mainly in the central zone of the tumor while PpIX accumulates in the border zone of the tumor. All patients with combined PDT experienced complete therapeutic pathomorphosis and relapse-free observation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

The skin is the first natural barrier of the human body. Bacterial infections severely hinder the healing process of skin wounds and pose a great threat to human health. Therefore, it is particularly urgent to develop new antimicrobial strategies for bacterial pathogen clearance and wound healing. In this study, a metal-organic framework (MOF), Fe-MIL88B-NH 2 , was incorporated with the photosensitizer indocyanine green (ICG) to construct composite nanoparticles (MOF@ICG NPs) with multiple antibacterial activities. Under mild near-infrared (NIR) irradiation, the photosensitizer ICG in the MOF@ICG NPs undergoes photothermal conversion (∼45 °C) and photodynamic reactions to generate heat and singlet oxygen ( 1 O 2 ). In addition, the Fenton reaction of the NPs with hydrogen peroxide (H 2 O 2 ) in the bacterial infection microenvironment resulted in the generation of hydroxyl radicals (˙OH), thus achieving the three-mode combination of low-temperature photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT). The in vitro experimental results showed that MOF@ICG MPs had excellent antibacterial properties and good cytocompatibility, with some ability to promote the migration of L-929 fibroblasts. Furthermore, under NIR irradiation, MOF@ICG NPs could significantly kill bacteria and promote skin wound healing according to the results of animal experiments. The wound healing rate reached 87.1% after 7 days of treatment. The research results break through the limitations of single-mode antibacterial technology and provide certain theoretical guidance and technical support for the research and development of new antibacterial materials.

Photodynamic therapy (PDT) is a promising cancer treatment approach. Indocyanine green (ICG) is a water-soluble tricarbocyanine dye with a peak absorption wavelength of around 800 nm and possesses the capacity to produce reactive oxygen species. FTIR spectroscopy is rarely used and offers insights into molecular changes in cancer studies. MCF-7 cells were injected into Nude mouse. Once the tumor had grown to a size of 3-4 mm, mice were randomized into the 12 PDT groups. After each mouse received 5 mg/kg of ICG, they were photo-irradiated with a diode laser emitting light at 809 nm, followed by waiting intervals of 0, 30, 60, and 90 min. Laser irradiation parameters were 150, 250, 500 mW/cm2 and irradiation duration was 1200s. The tumor size was measured every day for four days. The FTIR spectroscopy was used to perform spectral analysis on tumor tissue samples. Four distinct regions (3600-2800 cm-1, 1750-1550 cm-1, 1540-1450 cm-1, and 1700-1100 cm-1) were analyzed, and Hierarchical Cluster study was carried out. A decrease in tumor volume was observed with all PDT applications, except, increases in tumor volume was observed at 150mW 90-minute group. PDT administered after 90 min revealed variations in 150mW and 250mW laser powers in the 3600 cm-1-2800 cm-1 range. The 250mW and 500mW applications resulted in a considerable reduction in fibroadenoma and carcinoma tissues, according to an analysis comparing the A1695 / A1635 ratio. It is proposed that the ideal treatments for further investigation have a power output of 250 mW., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Cancer treatment continues to be a substantial problem due to tumor complexities and persistence, demanding novel therapeutic techniques. This review investigates the synergistic potential of combining photodynamic therapy (PDT) and tailored medication delivery technologies to increase mitochondrial toxicity and improve cancer outcomes. PDT induces selective cellular damage and death by activating photosensitizers (PS) with certain wavelengths of light. However, PDT's efficacy can be hampered by issues such as poor light penetration and a lack of selectivity. To overcome these challenges, targeted drug delivery systems have emerged as a promising technique for precisely delivering therapeutic medicines to tumor cells while avoiding off-target effects. We investigate how these technologies can improve mitochondrial targeting and damage, which is critical for causing cancer cell death. The combination method seeks to capitalize on the advantages of both modalities: selective PDT activation and specific targeted drug delivery. We review current preclinical and clinical evidence supporting the efficacy of this combination therapy, focusing on case studies and experimental models. This review also addresses issues such as safety, distribution efficiency, resistance mechanisms, and costs. The prospects of further research include advances in photodynamic agents and medication delivery technology, with a focus on personalized treatment. In conclusion, combining PDT with targeted drug delivery systems provides a promising frontier in cancer therapy, with the ability to overcome current treatment limits and open the way for more effective, personalized cancer treatments.

At present, chemotherapy combined with photodynamic therapy is exerting satisfactory therapeutic effects in the treatment of tumors. Chlorin e6 (Ce6) is a photosensitizer with high efficiency and low dark toxicity. At the same time, elemene (ELE) contains high-efficiency and low-toxicity anti-cancer active ingredients, which can effectively penetrate tumor tissue and inhibit its recovery and proliferation. Due to the poor water solubility of these two drugs, we prepared ELE/Ce6 co-loaded liposomes (Lipo-ELE/Ce6) to improve their water solubility, thereby enhancing the anti-tumor effect. The characterization of Lipo-ELE/Ce6 showed that Lipo-ELE/Ce6 had suitable encapsulation efficiency (EE), particle size, polydispersity (PDI), zeta potential, and good photo-controlled release properties. In vitro, Lipo-ELE/Ce6 effectively inhibited the growth of T24 cells and induced apoptosis, and more importantly, in vivo experiments showed that Lipo-ELE/Ce6 had significant anti-tumor effects, which was significantly better than free drugs. The above results suggest that Lipo-ELE/Ce6 can significantly enhance the induction of apoptosis of non-muscle invasive bladder cancer (NMIBC) by light-controlled release and ROS response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nanophotothermolysis (NPhT) effect is considered to be an approach for the development of highly selective modalities for anticancer treatment. Herein, we evaluated an antitumor efficacy of NPhT with intravenously injected zinc phthalocyanine particles (ZnPcPs) in murine subcutaneous syngeneic tumor models. In S37 sarcoma-bearing mice a biodistribution of ZnPcPs was studied and the high antitumor efficacy of ZnPcPs-mediated NPhT was shown, including a response of metastatic lesions. The morphological investigation showed the main role of a local NPhT-induced vascular damage in the tumor growth and tumor spread inhibition. Murine tumors of different histological origin were not equally sensitive to the treatment. The results demonstrate a potential of ZnPcPs-mediated NPhT for treatment of surface tumors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Oral 5-aminolevulinic acid for transurethral resection of bladder tumor reduces bladder cancer recurrence compared with standard white-light transurethral resection of bladder tumor. However, data regarding risks of adverse events with this drug are unclear. The aim of the present study was to identify risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis-transurethral resection of bladder tumor., Methods: We studied 104 cases of 5-aminolevulinic acid-photodynamic diagnosis-transurethral resection of bladder tumor from October 2021 to April 2023, administering 20 mg/kg 5-aminolevulinic acid orally at least 2 h pre-surgery. Four major adverse events associated with 5-aminolevulinic acid were selected to identify risk factors for their occurrence, including perioperative hypotension, nausea and/or vomiting, photosensitivity, and liver dysfunction. Univariate and multivariate analyses were conducted to identify the risk factors of those adverse events., Results: Perioperative hypotension (11.5 %), nausea and/or vomiting (37.5 %) photosensitivity (31.7 %), and liver dysfunction (51.9 %) were observed. Multivariate analyses revealed that spinal anesthesia was associated with hypotension (p = 0.02), whereas advanced age (p < 0.01) and higher body mass index (p < 0.01) were associated with nausea and/or vomiting. Also, male sex (p < 0.01) and longer operative time (p = 0.01) were associated with photosensitivity, and renin-angiotensin system inhibitors use was associated with postoperative liver dysfunction (p < 0.01)., Conclusions: For elderly male obese patients taking renin-angiotensin system inhibitors, particular attention is needed during the perioperative period of photodynamic diagnosis-transurethral resection of bladder tumor under spinal anesthesia due to the higher risk of onset of the adverse events involved in oral administration of 5-aminolevulinic acid., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG 8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Postoperative recurrence of tongue squamous cell carcinoma (TSCC) has always been a clinical problem for patients and doctors. Surgery and radiotherapy are the main treatment methods for TSCC, but reoperation often leads to functional impairment. Side effects of radiotherapy include mucosal gland damage, dry mouth, weakened or lost taste. Improved treatment is needed., Objective: To evaluate the clinical outcome of a patient with TSCC treated with Microdrop aminolevulinic acid (ALA) photodynamic treatment (PDT) twice., Methods: ALA was dissolved in 5 % lidocaine and the concentration of ALA was 20 % by Microdrop method. Then, the tumor tissue was expanded 1 cm outward, and the injection points were evenly distributed with an upper and lower left and right interval of 2-3 mm. The 1 ml syringe was used to perform the injection in the skin of the tumor area, and there was a small cuticle at each injection point. A pathologically confirmed patient with TSCC received twice Microdrop ALA-PDT treatments, which were evaluated at 1 month and 4 months later., Results: After 3 h of Microdrop ALA injection, the wavelength of semiconductor laser was set to 630 nm, and the energy of 300 mW /cm 2 was irradiated for 30 min. After two treatments, the lesions were not visible, and no recurrence occurred after 4 months of follow-up. The patient's tongue function was well preserved and the cosmetic effect was good., Conclusion: Microdrop ALA-PDT may be effective in the salvage treatment of select tongue squamous cell carcinoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: 5-Aminolevulinic acid hydrochloride (5-ALA), available under the trade name Gleolan, is an orally administered fluorophore drug used to enhance visual differentiation of cancerous tissue from healthy tissue, primarily during surgical resection of high-grade gliomas. Although given preoperatively, 5-ALA has important implications for anesthetic care throughout the perioperative period. This article reviews pharmacology, safety concerns, and perioperative considerations for patients who receive oral 5-ALA., Recent Findings: Although approved for clinical use by the United States Food and Drug Administration in 2017, studies and case reports published since then have further delineated side effects of this medication and its mechanisms and pharmacokinetics., Summary: Mitigating the possible side effects of 5-ALA requires an understanding of its basic mechanism as well as focused perioperative planning and communication. Administration of this medication may result in nausea, vomiting, photosensitivity, increase in serum concentration of liver enzymes, and hypotension. Patients who receive 5-ALA must be protected from prolonged light exposure during the first 48 h after consumption and administration of other photosensitizing agents should be avoided (Supplemental Video File/Video abstract)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The immunosuppressive tumor microenvironment (TME) in solid tumors often impedes the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs), as a promising cancer vaccine that can potently stimulate immune responses, have garnered interest as a potential platform for cancer therapy. However, the low yield of OMVs limits their utilization. To address this limitation, we developed a novel approach to synthesize OMV-like multifunctional synthetic bacterial vesicles (SBVs) by pretreating bacteria with ampicillin and lysing them through sonication. Compared to OMVs, the yield of SBVs increased by 40 times. Additionally, the unique synthesis process of SBVs allows for the encapsulation of bacterial intracellular contents, endowing SBVs with the capability of delivering catalase (CAT) for tumor hypoxia relief and activating the host cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. To overcome the toxicity of lipopolysaccharide (LPS) on the SBVs surface, we decorated SBVs with a biocompatible polydopamine (PDA) shell, which allowed TME reprogramming using SBVs to be conducted without adverse side effects. Additionally, the photosensitizer indocyanine green (ICG) was loaded into the PDA shell to induce immunogenic cell death and further improve the efficacy of immunotherapy. In summary, the SBVs-based therapeutic platform SBV@PDA/ICG (SBV@P/I) can synergistically elicit safe and potent tumor-specific antitumor responses through combined immunotherapy and phototherapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG., Methods: 7 patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity as an adverse effect associated with 5-ALA and TS was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: Tumor-specific fluorescence intensity was strong in 4 cases and weak in 3. Photosensitivity occurred in only 1 patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and 1 patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up., Conclusions: The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Clinical guidelines for infectious keratitis treatment require that anti-inflammatory drugs can only be used after infection elimination, which causes irreversible inflammatory damage to the cornea. In this work, photodynamic metal organic frameworks (PCN-224) were used as drug carrier to load Pt NPs with catalase-like activity and anti-inflammatory drug (Dexamethasone, DXMS) for endogenous oxygen generation and reduced corneal damage, respectively. The photodynamic therapy (PDT) effect was greatly enhanced in bacteria elimination and bacterial biofilms removal through catalysis of overexpressed hydrogen peroxide (H 2 O 2 , ∼8.0 and 31.0 μM in bacterial solution and biofilms, respectively) into oxygen by Pt NPs. More importantly, the cationic liposome modified PCN-224@Pt@DXMS@Liposomes (PPDL NPs) greatly enhanced the adhesion to negatively charged ocular surface and penetration into corneal barrier and bacterial biofilms. Both in vitro cell viability test and in vivo eye irritation tests proved good biocompatibility of PPDL NPs under 660 nm laser irradiation. Furthermore, PDT of PPDL NPs in rapid bacteria killing was verified through infectious keratitis animal model. The superior bactericidal effect of antibacterial materials could largely replace the bactericidal effect of the immune system. It is worth mentioning that this simultaneous sterilization and anti-inflammation treatment mode is a new exploration against the clinical treatment guidelines., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is a photochemical therapeutic modality used clinically for dermatological, ophthalmological and oncological applications. Pheo a was used as a model photosensitizer, either in its free form or encapsulated within poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-PCL) polymer micelles. Block copolymer micelles are water-soluble biocompatible nanocontainers with great potential for delivering hydrophobic drugs. Empty PEO-PCL micelles were also tested throughout the experiments. The goal was to conduct an in vitro investigation into human colorectal tumor HCT-116 cellular responses induced by free and encapsulated Pheo a in terms of cell architecture, plasma membrane exchanges, mitochondrial function, and metabolic disturbances. In a calibrated PDT protocol, encapsulation enhanced Pheo a penetration (flow cytometry, confocal microscopy) and cell death (Prestoblue assay), causing massive changes to cell morphology (SEM) and cytoskeleton organization (confocal), mitochondrial dysfunction and loss of integrity (TEM), rapid and massive ion fluxes across the plasma membrane (ICP-OES, ion chromatography), and metabolic alterations, including increased levels of amino acids and choline derivatives ( 1 H NMR). The detailed investigation provides insights into the multifaceted effects of encapsulated Pheo-PDT, emphasizing the importance of considering both the photosensitizer and its delivery system in understanding therapeutic outcomes. The study also raises questions as to the broader impact of empty nanovectors per se, and encourages a more comprehensive exploration of their biological effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cold tumors lack T cells infiltration and have low immunogenicity, resulting insufficient immunotherapy response. Therefore, how to realize the transformation from cold tumor to hot tumor is an urgent problem to be solved. Photodynamic therapy can induce immunogenic death of tumor cells (ICD) and activate T lymphocytes to produce tumor immune response. However, hypoxia in the cold tumor microenvironment limits the effectiveness of photodynamic therapy. So in this article, MET-HMME/CAT-HMME@Nlip as a functional co-delivery nanoliposomes was constructed based on overcoming the above problems. Firstly, the oxygen-deficient state could be improved by the following two ways, one is catalase loaded in CAT-HMME@Nlip can decompose high concentration hydrogen peroxide to produce oxygen, and the other is metformin loaded in MET-HMME@Nlip can decrease oxygen consumption by inhibiting of mitochondrial respiration. And then with the increase of substrate oxygen concentration, the sensitivity of photodynamic therapy can be greatly improved and the anti-tumor immune response by PDT-induced ICD can also be enhanced obviously. In addition, metformin could act as a small molecule immune checkpoint inhibitor to reduce the expression of PD-L1 on the surface of tumor cells, thereby effectively improving the specific killing ability of cytotoxic T cells to tumor cells which could not only erasing the primary tumor, but also inhibiting the growth of simulated distant tumors through the immune memory function. This study provides a new idea for improving the clinical treatment effect of hypoxic cold tumors, especially for tumors that could not benefit from immunotherapy due to low or no expression of PD-L1 protein on the surface of tumor cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) has emerged as a promising treatment for malignant tumours in recent decades due to its impressive spatiotemporal selectivity, minimal invasiveness, and few adverse effects. Despite these advancements, there remain significant challenges in effectively delivering photosensitizers to tumours and overcoming tumour hypoxia to maximize the therapeutic benefits of PDT. Ongoing research efforts are focused on developing innovative strategies to overcome the above-mentioned challenges, such as nanoplatforms and combination therapy approaches. Hence, reactive oxygen species (ROS)-responsive polymeric micelles are promising candidates to enhance the distribution and retention of photosensitizers within tumours. Additionally, efforts to alleviate tumour hypoxia may further improve the anti-tumour effects of PDT. In this study, we designed ROS-responsive polymeric micelles (TC@PTP) co-loaded with a Tapp-COF, a porphyrin derivative, and capsaicin for PDT of melanoma. These ROS-responsive nanocarriers, constructed from thioketal (TK)-linked amphiphilic di-block copolymers (PEG5K-TK-PLGA5K), could accumulate in the tumor microenvironment and release drugs under the action of ROS. Capsaicin, acting as a biogenic respiratory inhibitor, suppressed mitochondrial respiration and the hypoxia-inducible factor 1 (HIF-1) signaling pathway, thereby increasing oxygen levels at the tumour site. These PDT-triggered ROS-responsive nanoparticles effectively alleviated the tumour hypoxic microenvironment and enhanced anti-tumour efficacy. With superior biocompatibility and tumour-targeting abilities, the platform holds great promise for advancing anti-tumour combination therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has many characteristics including high metastatic rates, poor overall survival, and low response to traditional chemotherapy. Photodynamic therapy (PDT), emerging as a precise treatment modality, has shown promise in improving the antitumor response. However, it still faces challenges such as limited light penetration depth, rapid oxygen consumption, and inadequate targeting ability. In this study, we developed Rose Bengal (RB, photosensitizer) and oxygen co-loaded CREKA-modified UCNP-based nanoliposomes (CLIP-RB-PFOB@UCNP) for tumor targeting and near-infrared (NIR)-triggered deep and long-lasting PDT. Our results demonstrated that CLIP-RB-PFOB@UCNP effectively targeted and accumulated in tumor tissue through the interaction between CREKA and fibronectin, which is overexpressed in tumor cells. Under NIR irradiation, CLIP-RB-PFOB@UCNP exhibited significant destruction of orthotopic tumors, reduced the level of HIF-1α, and efficiently suppressed lung metastasis in a metastatic TNBC model. In conclusion, this study offers new avenues for improving the therapeutic outcomes of PDT for clinical TNBC treatment.

The treatment of unresectable locally advanced triple-negative breast cancer (TNBC) and TNBC with metastasis is challenging. Many anticancer drugs, such as doxorubicin, still hinder positive therapeutic outcomes due to severe side effects. Photodynamic therapy (PDT) has an anticancer effect, and combining PDT with chemotherapy may improve breast cancer therapy. The use of cargo-loaded biomimetic PEGylated liposomes for cancer therapy may enhance efficacy and reduce side effects. In this study, liposomes were formulated to accommodate doxorubicin (Dox) and IR780. Breast cancer cells (4T1 cells) and macrophage cell membranes were isolated and camouflaged onto the PEGylated liposomes, creating a new biomimetic platform called Dox-IR780@Lip@Ms. The Dox-IR780@Lip@Ms platform was characterized and tested in vitro and in vivo . The results showed that the Dox-IR780@Lip@Ms had an ovoid shape with a double lamina structure, monodispersity, and uniform distribution. The size was 132.37 ± 1.22 nm, the PDI was 0.044 ± 0.067, and the zeta potential was -9.67 ± 1.08 mV. The encapsulation efficiency of Dox and IR780 in Dox-IR780@Lip@Ms was 89.36% ± 3.07% and 92.34% ± 0.66%, respectively. The release rate of Dox from Dox-IR780@Lip@Ms was good after laser irradiation. At pH 7.4, the release rate of Dox was 23.85% ± 0.62% at 3 h without laser irradiation and 36.62% ± 1.32% at 3.5 h with laser irradiation. At pH 6.5, the release rate of Dox was 32.54% ± 0.32% at 3 h without laser irradiation and 62.79% ± 2.15% at 3.5 h with laser irradiation. The cytotoxicity of IR780@Lip@Ms was lower than that of Dox-IR780@Lip@Ms. The cell uptake and generation of reactive oxygen species of Dox-IR780@Lip@Ms were significant. Dox-IR780@Lip@Ms exhibited immune escaping ability in vitro , homotypic targeting ability to cancer cells, high capability to kill cancer cells after laser irradiation, minimal cardiotoxicity, increased accumulation of Dox and IR780 in the tumor, and an increased anticancer effect in a tumor-bearing animal model. In conclusion, hybrid cell membranes of breast cancer and macrophages camouflaging PEGylated liposomes loaded with Dox and IR780 can significantly improve breast cancer therapy after laser irradiation in murine models.

Introduction: Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors., Materials and Methods: PMOF@HA was synthesized by the coordination of transition metal iron (Zr 4+ ) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O 2 and 1 O 2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively., Results: Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H 2 O 2 into O 2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O 2 self-supply and PDT efficacy., Conclusion: This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Background: Photodynamic therapy (PDT) has been strongly recommended as an excellent alternative treatment for Bowen disease (BD). However, reported data on 5-aminolaevulinic acid-mediated PDT (ALA-PDT) with red-light irradiation are limited and the long-term effectiveness remains to be determined, especially in dark-skinned populations., Objectives: We aimed to review routine clinical practice in the field of BD treatment with ALA-PDT over an extended study period (2011-2021), calculate the overall clearance rate, and explore and evaluate factors that might affect the effectiveness of therapy in a real-world setting., Methods: The medical records of patients with BD who received ALA-PDT with red-light irradiation between February 2011 and June 2021 were reviewed and summarized. Univariate and multivariate analyses of clinically relevant variables that may affect treatment outcomes were conducted to identify risk predictors., Results: The overall clearance rate of 122 BD lesions was 89.3% with a median follow-up time of 36 months. The correlation between the effectiveness and fluorescence intensity of pre-PDT or PDT sessions was statistically significant after eliminating the interference of confounding factors. All recurrences occurred in the first 2 years following ALA-PDT., Conclusions: ALA-PDT is an effective treatment for BD in patients with darker-coloured skin. Well-executed operations and effective pretreatment are the determinants of effectiveness. Fluorescence intensity of pre-PDT appeared to be a significant predictor of final effectiveness. In addition, 2 years of follow-up is necessary following ALA-PDT., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The combination of nanoplatform-based chemotherapy and photodynamic therapy (PDT) is a promising way to treat cancer. Celastrol (Cela) exhibits highly effective anti-hepatoma activity with low water solubility, poor bioavailability, non-tumor targeting, and toxic side effects. The combination of Cela-based chemotherapy and PDT via hepatoma-targeting and reactive oxygen species (ROS)-responsive polymeric micelles (PMs) could solve the application problem of Cela and further enhance antitumor efficacy., Methods: In this study, Cela and photosensitizer chlorin e6 (Ce6) co-loaded glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) PMs (Cela/Ce6/GCTR PMs) were prepared and characterized. The safety, ROS-sensitive drug release, and intracellular ROS production were evaluated. Furthermore, the in vitro anti-hepatoma effect and cellular uptaken in HepG2 and BEL-7402 cells, and in vivo pharmacokinetic, tissue distribution, and antitumor efficacy of Cela/Ce6/GCTR PMs in H22 tumor-bearing mice were then investigated., Results: Cela/Ce6/GCTR PMs were successfully prepared with nanometer-scale particle size, favorable drug loading capacity, and encapsulation efficiency. Cela/Ce6/GCTR PMs exhibited a strong safety profile and better hemocompatibility, exhibiting less damage to normal tissues. Compared with Cela-loaded GCTR PMs, the ROS-responsiveness of Cela/Ce6/GCTR PMs was increased, and the release of Cela was accelerated after combination with PDT. Cela/Ce6/GCTR PMs can efficiently target liver tumor cells by uptake and have a high cell-killing effect in response to ROS. The combination of GCTR PM-based chemotherapy and PDT resulted in increased bioavailability of Cela and Ce6, improved liver tumor targeting, and better anti-hepatoma effects in vivo., Conclusion: Hepatoma-targeting and ROS-responsive GCTR PMs co-loaded with Cela and Ce6 combined with PDT exhibited improved primary hepatic carcinoma therapeutic effects with lower toxicity to normal tissues, overcoming the limitations of monotherapy and providing new strategies for tumor treatment., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Xu et al.)

Nanomedicines that combine reactive oxygen species (ROS)-responsive polyprodrug and photodynamic therapy have shown great potential for improving treatment efficacy. However, the consumption of ROS by overexpressed glutathione in tumor cells is a major obstacle for achieving effective ROS amplification and prodrug activation. Herein, we report a polyprodrug-based nanoparticle that can realize ROS amplification and cascaded drug release. The nanoparticle can respond to the high level of hydrogen peroxide in tumor microenvironment, achieving self-destruction and release of quinone methide. The quinone methide depletes intracellular glutathione and thus decreases the antioxidant capacity of cancer cells. Under laser irradiation, a large amount of ROS will be generated to induce cell damage and prodrug activation. Therefore, the glutathione-depleting polyprodrug nanoparticles can efficiently inhibit tumor growth by enhanced photodynamic therapy and cascaded locoregional chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy., Methods: The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody., Results: QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors., Conclusion: QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Darier disease and Hailey-Hailey disease are rare autosomal dominant genodermatoses that negatively impact patient quality of life. In addition, they pose challenges to dermatologists who manage these diseases. There is currently no treatment that reliably induces remission for either disease, leaving patients dependent on symptom management. Oral and topical retinoids are the most commonly used therapies but have numerous side effects that often lead to discontinuation or inability to tolerate long-term treatment (Burge and Wilkinson in J Am Acad Dermatol 27:40-50, 1992). Due to the rarity of these diseases, there are no clinical trials investigating treatment options for the persistent flares patients experience. In light of this, dermatologists have tried various methods used in the management of other inflammatory disorders including photodynamic therapy (PDT). A systematic review was conducted to investigate this treatment option which yielded a total of 12 studies that had reported the use of photodynamic therapy (PDT) as a treatment option for Darier or Hailey-Hailey disease. Though results showed that PDT can induce disease remission for up to several months or years, there are many unanswered questions that need to be addressed before adopting PDT as a leading treatment option for those genodermatoses. In particular, cost, tolerability, and efficacy and safety in patients who are skin of color need to be further studied. Lastly, recommendations on treatment duration, number of sessions, photosensitizing agents, lasers, and continuation or discontinuation of topical and systemic medications need to be appraised before formal recommendations can be made., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (∼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo, the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Drug-loaded polymeric micelles have proven to be highly effective carrier systems for the efficient delivery of hydrophobic photosensitizers (PSs) in photodynamic therapy (PDT). This study introduces the micellization potential of poly(oligoethylene glycol methyl ether methacrylate) (pOEGMA) as a novel approach, utilizing the hydrophobic methacrylate segments of pOEGMA to interact with highly hydrophobic zinc phthalocyanine (ZnPc), thereby forming a potential micellar drug carrier system. The ZnPc molecule was synthesized from phthalonitrile derivatives and its fluorescence, photodegradation, and singlet oxygen quantum yields were determined in various solvents. In solvents such as tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide, the ZnPc compound exhibited the requisite photophysical and photochemical properties for PDT applications. The pOEGMA homopolymer was synthesized via reversible addition-fragmentation chain-transfer polymerization, while ZnPc-loaded pOEGMA micelles were prepared using the nanoprecipitation method. Characterization of the pOEGMA, ZnPc, and micelles was conducted using FTIR, 1 H-NMR, dynamic light scattering, matrix-assisted laser desorption/ionization time-of-flight mass spectrometries, gel permeation chromatography, and transmission electron microscopy. The critical micelle concentration was determined to be 0.027 mg ml -1 using fluorescence spectrometry. The drug loading and encapsulation efficiencies of the ZnPc-loaded micelles were calculated to be 0.67% and 0.47%, respectively. Additionally, the release performance of ZnPc from pOEGMA micelles was monitored over a period of nearly 10 d, while the lyophilized micelles exhibited stability for 3 months. Lastly, the ZnPc-loaded micelles were more biocompatible than ZnPc on L929 cell line. The results suggest that the pOEGMA homopolymer possesses the capability to micellize through its methacrylate segments when interacting with highly hydrophobic molecules, presenting a promising avenue for enhancing the delivery efficiency of hydrophobic PSs in PDT. Moreover, it was also deciphered that obtained formulations were highly biocompatible according to cytotoxicity results and could be safely employed as drug delivery systems in further applications., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Introduction: High incidence and fatality rates of cancer remain a global challenge. The success of conventional treatment modalities is being questioned on account of adverse effects. Photodynamic therapy (PDT) is a potential alternative. It utilizes a combination of photosensitizer (PS), light and oxygen to target the tissues locally, thereby minimizing the damage to neighboring healthy tissues. Conventional PSs suffer from poor selectivity, high hydrophobicity and sub-optimal yield of active radicals. Graphene nanomaterials (GNs) exhibit interesting particulate and photophysical properties in the context of their use in PDT., Area Covered: We focus on describing the mechanistic aspects of PDT-mediated elimination of cancer cells and the subsequent development of adaptive immunity. After covering up-to-date literature on the significant enhancement of PDT capability with GNs, we have discussed the probability of combining PDT with chemo-, immuno-, and photothermal therapy to make the treatment more effective., Expert Opinion: GNs can be synthesized in various size ranges, and their biocompatibility can be improved through surface functionalization and doping. These can be used as PS to generate ROS or conjugated with other PS molecules for treating deep-seated tumors. With increasing evidence on biosafety, such materials offer hope as antitumor therapeutics.

Background: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome. Only a few studies have reported the treatment of PPV, including a case using photodynamic therapy (PDT) to treat PPV-associated port-wine stains (PWS)., Objective: To investigating the efficacy and adverse effects of hemoporfin-PDT in PPV-associated PWS., Methods: The efficacy and adverse effects in patients with PPV who underwent two sessions of hemoporfin-PDT from January 2019 to December 2022 were retrospectively analyzed., Results: Twenty patients were included (13 females, 7 males, age range: 2-31 years; mean: 8.20 ± 8.92 years). Two, nine, seven, and two patients had PPV types Ia, IIa, IIb, and IIIa, respectively. After two treatments, the visual evaluation indicated the color of the PWS in 4, 5, 6, and 5 patients showed poor, fair, good, and excellent improvements, respectively. The combined good and excellent improvement rates in patients with PWS and pigmentary nevus overlapping in the same treatment area and in patients with PWS in the treatment areas only were 33.3% versus 87.5%, respectively, and were significantly different (p = 0.02). Minor side effects, such as edema, scabbing, hyperpigmentation, and blistering, were observed in some patients after PDT., Conclusion: Hemoporfin-PDT is an effective treatment for PPV-associated PWS. Patients with PWS and pigmentary nevus overlapping in the same treatment area showed poorer efficacy than patients with PWS in the treatment areas only., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host's immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the "cold" properties of tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Phototherapy utilizing bacterial carriers has demonstrated efficacy in anti-tumor therapy, while the poor delivery of phototherapeutic agents and immunogenicity of microbial substances remain problematic. Herein, we develop a nanocoated bacterial delivery system (IF-S.T) that in situ forms the efficient photothermal agents via biomineralization and improves the intracellular oxygenation, thus triggering the self-enhanced photothermal therapy (PTT) and photodynamic therapy (PDT) on tumor. We densely coat self-assembled IF (ICG-Fe 2+ ) nanocomplex onto the surface of LT2, weakly virulent strain of Salmonella typhimurium (S.T), by bioadaptive nanocoating techniques, masking bacterial virulence factors and reducing the potential immune adverse effects. Upon penetrating into the tumor environment, IF-S.T responds to H 2 O 2 to trigger the removal of the IF coating, where S.T produces excess hydrogen sulfide (H 2 S). H 2 S reacts with Fe 2+ , yielding ferrous sulfide (FeS) for PTT, and inhibits mitochondrial respiration to enhance tumor cell oxygenation for PDT. Consequently, IF-S.T plus laser irradiation exhibits direct tumor cells killing and elicits robust antitumor immune responses, leading to the complete tumor elimination. Thus, IF-S.T represents a promising platform for effective tumor delivery of photoactive agents for improved PTT/PDT efficacy., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Here, we disclose the synthesis of poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels incorporating a squaraine dye (Sq) as a chemical crosslinker, viz. Sq@PHEMA. Photothermal and photodynamic features of Sq@PHEMA hydrogels are evaluated in detail. It is noteworthy that Sq@PHEMA induces hyperthermia upon irradiation with an 808 nm laser. Furthermore, Sq@PHEMA enables the generation of reactive oxygen species (ROS) upon irradiation with red light. To our delight, Sq@PHEMA hydrogels can be used as efficient dual photosensitizers pertinent to both PDT and PTT simultaneously. Finally, the hydrogels are loaded with methotrexate (MTX) to investigate controlled drug release behavior. It is noted that Sq@PHEMA hydrogels are promising candidates as drug delivery systems since on-demand MTX release is feasible upon irradiation. In summary, we effectively demonstrate that hydrogel cross-linker engineering allows for synergistic photodynamic and photothermal therapy. Furthermore, drug delivery is also feasible with the Sq@PHEMA core., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.

Background: Conventional topical psoriasis treatments suffer from limited delivery to affected areas and skin irritation due to high local drug concentration., Purpose: This study aims to prepare hypericin (HYP) loaded nanostructured lipid carriers (NLCs) and their application in psoriasis treatment through intradermal administration using hollow microneedles assisted by photodynamic therapy., Methods: The colloidal characteristics of NLCs, entrapment efficiency and morphology were evaluated. An ex-vivo skin distribution study was conducted along with testing the in vivo antipsoriatic activity in mice with the imiquimod-induced psoriasis model., Results: The particle size and zeta potential of HYP-NLCs were 167.70 nm and -18.1, respectively. The ex-vivo skin distribution study demonstrated the superior distribution of HYP-NLCs to a depth of 1480 µm within the skin layers relative to only 750 µm for free HYP. In vivo studies revealed that the levels of NF-KB, IL 6, MMP1, GSH, and catalase in the group treated with HYP-NLCs in the presence of light were comparable to the negative control., Conclusions: The histopathological inspection of dissected skin samples reflected the superiority of HYP-NLCs over HYP ointment. This could be ascribed to the effect of nanoencapsulation on improving HYP properties besides the ability of hollow microneedles to ensure effective HYP delivery to the affected psoriatic area.

This systematic review evaluated the efficacy and safety of photodynamic therapy (PDT) in the management of cutaneous leishmaniasis (CL). The electronic search for identification of relevant studies, adhered to the PICOS (Population, Intervention, Comparator, Outcomes and Study type) framework, was conducted through PubMed, Google scholar, Dimensions, X-mol, and Semantic Scholar till December 2023. All types of studies reporting PDT in the management of CL with no language restriction were included. Methodological quality appraised of the selected studies was performed using Jadad index. Of the 317 identified studies, 21 reported PDT for the treatment of CL lesions, consisting of two randomized controlled trials (RCTs), four single-center open study, one case series and 14 case reports. Collectively, these studies presented a total of 304 patients with ages ranging from 1 to 82 years, undergoing varying number of PDT sessions (3-28) and follow-up durations spanning 4 weeks to 24 months. The CL lesions predominantly manifested on the exposed body areas, such as face, limbs, neck, ear and nose, and characterized with the use of clinical variables, such as plaques, papules, erythema and ulceration. PDT protocols differed in the photosensitizer type, incubation time, light source characteristics (e.g., wavelength, output power, and energy density), duration of light illumination, number of PDT sessions and their respective frequencies. Treatment response was assessed through the clinical presentation (i.e., at the baseline and after PDT completion) or by the absence of Leishmania parasites. Adverse effects comprised of pain, burning and tingling sensation experienced during PDT, followed by erythema, pigmentation changes and edema post-treatment. This systematic review revealed that PDT is an efficacious and safe modality for the treatment of CL, with mild and transient side effects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

X-ray-excited photodynamic therapy (X-PDT) employs X-rays as an energy source, overcoming the light penetration limitations of traditional photodynamic therapy (PDT) but is constrained by high-energy radiation and the hypoxic tumor microenvironment. Low-dose X-ray-excited photodynamic therapy and reduction of mitochondrial oxygen consumption can serve as significant breakthroughs in overcoming these barriers. In this study, NaLuF 4 :Tb/Gd (15%/5%)@NaYF 4 (ScNP) nanoparticles adsorbing the photosensitizer MC540 and loaded with α-(nitrate ester) acid (NEAA) were prepared as low X-ray dose triggered nano-scintillators. The final product obtained was NaLuF 4 :Tb/Gd (15%/5%)@NaYF 4 @mSiO 2 @MC540@NEAA (ScNP-MS@MC540@NEAA) nanocomposites, which exhibited intense green luminescence. X-PDT generates cytotoxic reactive oxygen species (ROS) with minimal ionizing radiation damage. Simultaneously, NEAA reacts with glutathione (GSH) to generate nitric oxide (NO) for gaseous treatment of the damaged mitochondrial respiratory chain to reduce oxygen consumption and alleviate hypoxia, enhancing the X-PDT efficacy and realizing a closed-loop treatment. The superoxide ions (˙O 2 - ) can rapidly react with NO produced to form the highly cytotoxic reactive nitrogen species (RNS) peroxynitrite anion (ONOO - ), which exhibits higher cytotoxicity compared to ROS. Furthermore, GSH scavenges toxic ROS and maintains the physiological function of tumor cells. It can induce cancer cell overoxidation and nitrosative stress. This work describes a low-dose X-ray-triggered X-PDT system with total radiation of 50 mGy, which involves GSH consumption, self-supplied NO, mitochondrial damage alleviation, and hypoxia relief to generate ROS and RNS, forming a closed-loop anti-hypoxia dual-mode system with synergistically enhanced anti-tumor effects, without significant biological side effects. It provides a promising platform for deep-seated tumor X-PDT with considerable application prospects.

Objectives: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) using oral 5-aminolevulinic acid hydrochloride reduced residual tumors in high-risk non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD-TURBT for intravesical recurrence after a second transurethral resection for high-risk NMIBC., Methods: High-risk NMIBC patients initially treated with PDD-TURBT (PDD group) were prospectively registered between 2018 and 2020. High-risk patients with NMIBC who were initially treated with white-light TURBT (WL group) were retrospectively registered. Intravesical recurrence-free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis., Results: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25-0.77). In subgroup analysis, PDD-TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14-0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16-0.86), and no postoperative intravesical Bacillus Calmette-Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13-0.58)., Conclusions: PDD-TURBT may reduce short-term intravesical recurrence in patients with high-risk NMIBC., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)