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While numerous methods exist for diagnosing tumors through the detection of miRNA within tumor cells, few can simultaneously achieve both tumor diagnosis and treatment. In this study, a novel graphene oxide (GO)-based DNA nanodevice (DND), initiated by miRNA, was developed for fluorescence signal amplification imaging and photodynamic therapy in tumor cells. After entering the cells, tumor-associated miRNA drives DND to Catalyzed hairpin self-assembly (CHA). The CHA reaction generated a multitude of DNA Y-type structures, resulting in a substantial amplification of Ce6 fluorescence release and the generation of numerous singlet oxygen (1O2) species induced by laser irradiation, consequently inducing cell apoptosis. In solution, DND exhibited high selectivity and sensitivity to miRNA-21, with a detection limit of 11.47 pM. Furthermore, DND discriminated between normal and tumor cells via fluorescence imaging and specifically generated O21 species in tumor cells upon laser irradiation, resulting in tumor cells apoptosis. The DND offer a new approach for the early diagnosis and timely treatment of malignant tumors.
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ADN , Grafito , MicroARNs , Fotoquimioterapia , Nanomedicina Teranóstica , Fotoquimioterapia/métodos , Humanos , MicroARNs/análisis , Grafito/química , Nanomedicina Teranóstica/métodos , ADN/química , Apoptosis/efectos de los fármacos , Imagen Óptica , Línea Celular Tumoral , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagenRESUMEN
Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.
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Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Microambiente Tumoral , Fotoquimioterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Animales , Nanopartículas/química , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Humanos , Ratones , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Transferencia de Energía , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ratones Endogámicos BALB C , Luz , Ratones Desnudos , Óxido Nítrico/metabolismoRESUMEN
Although nearly 30â¯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).
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Three novel polypyridyl-Co(III)-vitamin B6 complexes viz., [Co(CF3-phtpy)(SBVB6)]Cl (Co1), [Co(anthracene-tpy)(SBVB6)]Cl (Co2), [Co(NMe2-phtpy)(SBVB6)]Cl (Co3), where 4'-(4-(trifluoromethyl)phenyl)-2,2':6',2''-terpyridine = CF3-phtpy, 4'-(anthracen-9-yl)-2,2':6',2''-terpyridine = anthracene-tpy;, 4-([2,2':6',2''-terpyridin]-4'-yl)-N,N-dimethylaniline = NMe2-phtpy, (E)-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-3-ol = H2SBVB6 was successfully developed for aPDT (antibacterial photodynamic therapy) applications. Co1-Co3 exhibited an intense absorption band at ca. 435-485 nm, which is attributed to ligand-to-metal charge transfer and was beneficial for antibacterial photodynamic therapy. The distorted octahedral geometry of the complexes with CoIIIN4O2 core was evident from the DFT study. The visible light absorption ability and good photo-stability of Co1-Co3 made them good photosensitizers for aPDT. Co1-Co3 displayed significant antibacterial responses against gram-positive (S. aureus) and gram-negative (E. coli) bacteria upon light exposure (10 J cm-2, 400-700 nm) and showed MIC values between 0.01-0.005 µg mL-1. The aPDT activities of these complexes were due to their ability to damage bacterial cell membranes via ROS generation. Overall, this study shows the photo-triggered ROS-mediated bacteria-killing potential of Co(III) complexes.
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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.
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Enfermedad de Darier , Pénfigo Familiar Benigno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Pénfigo Familiar Benigno/tratamiento farmacológico , Fotoquimioterapia/métodos , Fotoquimioterapia/efectos adversos , Enfermedad de Darier/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/efectos adversos , Resultado del Tratamiento , Calidad de VidaRESUMEN
Lipid droplets (LDs) serve as vital subcellular organelles, crucial for the maintenance of lipid and energy homeostasis within cells. Their visualization is of significant value for elucidating the intricate interactions between LDs and other cellular organelles. Despite the importance of LDs, the literature on the utilization of phthalocyanine-based photosensitizers for targeted LD imaging and two-photon imaging-guided photodynamic therapy (PDT) remains sparse. In this study, we have designed and synthesized trifluoromethyl-pyrrolidone silicon phthalocyanine (PyCF3SiPc). To enhance the water solubility of PyCF3SiPc and improve its tumor cells accumulation, we employed 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-mPEG2000) as a nanocarrier, thereby formulating DSPE@PyCF3SiPc nanoparticles. Our in vitro experiments in MCF-7 cells demonstrated that DSPE@PyCF3SiPc selectively targets and visualizes LDs, offering a reliable tool for tracking their dynamic movement. Moreover, DSPE@PyCF3SiPc demonstrates considerable phototoxicity against MCF-7 cells subjected to PDT underscoring its potential as an effective therapeutic agent. In conclusion, DSPE@PyCF3SiPc presents itself as a promising novel probe for the dual purpose of monitoring the dynamic movement of LDs and guiding imaging-assisted PDT. The development of this nanoparticle system not only advances our understanding of LD biology but also paves the way for innovative therapeutic strategies in oncology.
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As a typical natural photosensitizer, hypocrellin B (HB) offers the advantages of high molar extinction coefficient, high phototoxicity, low dark toxicity, and fast metabolism in vivo. However, the lack of tumor specificity hinders its clinical applications. Herein, we designed and synthesized a glutathione (GSH) responsive photosensitizer based on HB. The 7 - nitro - 2,1,3 - benzoxadiazole (NBD) covalently connected to HB not only served as a fluorescence quenching group but also as a GSH activating group. The photosensitizer HB-NBD showed almost no fluorescence and singlet oxygen generation as a result of the photoinduced electron transfer between HB and NBD. The designed photosensitizer HB-NBD can be activated by GSH in solutions and cancer cells, and then obtain recuperative fluorescence and photosensitive activity.
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Near-infrared (NIR) fluorescent probes with aggregation-induced emission (AIE) properties are of great significance in cell imaging and cancer therapy. However, the complexity of its synthesis, poor photostabilities, and expensive raw materials still pose some obstacles to their practical application. This study reported an AIE luminescent material with red emission and its application in in vitro imaging and photodynamic therapy (PDT) study. This material has the characteristics of simple synthesis, large Stokes shift, good photostabilities, and excellent lipid droplets-specific testing ability. Interestingly, this red-emitting material can effectively produce reactive oxygen species (ROS) under white light irradiation, further achieving PDT-mediated killing of cancer cells. In conclusion, this study demonstrates a simple approach to synthesize NIR AIE probes with both imaging and therapeutic effects, providing an ideal architecture for constructing long-wavelength emission AIE materials.
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Colorantes Fluorescentes , Rayos Infrarrojos , Gotas Lipídicas , Fotoquimioterapia , Especies Reactivas de Oxígeno , Humanos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Gotas Lipídicas/química , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Supervivencia Celular/efectos de los fármacos , Imagen Óptica , Estructura Molecular , Células HeLaRESUMEN
Introduction and importance: Near-infrared photoimmunotherapy (NIR-PIT, Alluminox) uses an antibody-photoabsorber conjugate and light excitation, requiring precise illumination. Mixed reality (MR) technology can enhance medical procedures through advanced visualization and planning. Case presentation: An 86-year-old man with recurrent oropharyngeal cancer and right cervical metastasis received NIR-PIT. Three-dimensional models from computed tomography (CT) and FDG-PET/CT images were used as holograms on a head-mounted display (HMD) for precise light targeting. Clinical discussion: HMD-MR technology was utilized for preoperative simulation and guided ideal light direction during surgery. This improved the effectiveness of NIR-PIT. Conclusion: Three months post-treatment, no residual lesion was observed, demonstrating the utility of HMD-MR technology in optimizing NIR-PIT outcomes.
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Two monocarbonyl dimethylamino curcuminoids, one derived from acetone (C3) and the second one from cyclohexane (C6), were synthesized aiming to study their photophysical properties and anticancer photodynamic potential. Compound C6 exhibited lower absorbance and fluorescence than C3. Photobleaching studies showed that C3 and C6 photostability behavior in DMSO differ significantly. C3 was completely photoconverted into a new species absorbing at lower wavelength than the parent compound, whereas, C6, upon a 30 min irradiation at λ = 440 nm with 15 mW/cm2 reached a photostationary phase where a smaller amount of the initial compound coexists with some photoproducts of higher and lower absorbance. Both compounds were able to generate significant amounts of ROS upon irradiation in an aqueous environment and exhibited successful intracellular localization in skin cancer cells (A431 cells). After dark cytotoxicity studies the concentrations of 5 µM and 1 µM for C3 and C6, respectively, were selected for the PDT assessment. C3 presented light dose-dependent photodynamic activity against A431 cells, resulting in 40 % cell viability after 12 min of light irradiation (440 nm, 15 mW/cm2). On the other side, C6 showed a biphasic light dose PDT effect with cell viability gradually decreasing up to 50 % after 5 min of light exposure, and then increasing again after 8 and 12 min of light exposure. The photodynamic performance of C6 may provide a new insight into the development of PSs with reduced prolonged photosensitivity.
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BACKGROUND/AIM: This experimental study aimed to examine the effectiveness of transdermal antimicrobial photodynamic therapy (APDT) with and without antimicrobial lock therapy (ALT), on catheter biofilms. METHODS: S. epidermidis and C. orthopsilosis biofilms were formed within peripheral venous catheters positioned in the marginal ear veins of New Zealand white rabbits. Biofilm formation was confirmed with scanning electron microscopy in two catheters. 24 catheters with staphylococcal biofilms and 24 with fungal biofilms were treated with APDT, ALT or "APDT plus ALT" for five days. Six catheters were separated as controls. APDT was applied with a red colored LED lamp and methylene blue as the photosensitizer. Vancomycin lock solutions were used as ALT for staphylococcal biofilms and amphotericin B for fungal biofilms. The effect of treatment procedures was evaluated by intraluminal biofilm viability testing based on spectrophotometric evaluation, and a quantitative (OD) value was obtained for each catheter. RESULTS: The mean OD values obtained by 600 nm spectrophotometric reading at 24 h (biofilm viability) after "ALT", "APDT" and "ALT plus APDT" procedures were 0.363, 0.151 and 0.128 for S. epidermidis and 0.092, 0.104 and 0.227 for C. orthopsilosis, respectively. All these OD values obtained after treatment procedures were lower than controls for both S. epidermidis (OD: 0,802) and C. orthopsilosis (OD: 0,315), although there were large fluctuations in our results. CONCLUSIONS: Our results suggest that transdermal APDT may be an effective method for treating staphylococcal and candida biofilms formed within intravenous catheters in our rabbit ear model. The combined use of APDT and ALT might be beneficial in these staphylococcal biofilms.
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INTRODUCTION: A local microneedle patch loaded with 5-aminolevulinic acid (ALA) was constructed to improve the efficiency of ALA photodynamic treatment of oral leukoplakia, reduce local photosensitivity reactions, and promote the healing of lesions. METHODS: The microneedle patch loaded with ALA was constructed with the hyaluronic acid (HA) solution (ALA-HAMN), and its morphology, strength, mucosal penetration, and biocompatibility were tested. RESULTS: In vivo safety and permeability tests confirmed that ALA-HAMN had good biocompatibility and could penetrate the mucosal barrier and quickly dissolve and release ALA for in situ transdermal administration. The 4-nitroquinoline oxide (NQO) rat model experiment showed that ALA-HAMN can significantly improve photodynamic therapy (PDT) efficiency and has no damage to mucosal tissue compared with the commonly used ALA cotton ball dressing. CONCLUSIONS: The ALA-loaded microneedle patch was successfully constructed for the photodynamic treatment of oral leukoplakia, and the photodynamic efficiency and comfort of oral leukoplakia were improved, which provided an effective delivery mode to improve clinical ALA-PDT treatment of oral leukoplakia (OLK).
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Near-infrared (NIR) organic materials have been widely developed for tumor phototherapy due to their deep tumor penetration, good biodegradability, and high photothermal conversion (PCE). However, most of the NIR organic dyes are easily destroyed by photooxidation due to their big and long conjugated structures, such as cyanine dyes. Under light irradiation, the reactive oxygen species (ROS) produced by these NIR dyes can easily break their conjugated skeleton, resulting in a dramatic decrease in phototherapeutic efficiency. Herein, an NIR organic dye cyanine dye (CyS) and a photosensitizer methylene blue (MB) were chosen to prepare nanocarrier CMTNPs by facile self-assembling with a natural antioxidant, tannic acid (TA). TA can greatly enhance the stability of NIR cyanine dyes by scavenging ROS. Furthermore, CMTNPs have a character of pH/thermal dual response, allowing for controlled release of MB in the slightly acidic tumor environment during photothermal therapy. The released MB can turn on both fluorescence and photodynamic therapy effects. In vitro and in vivo experiments demonstrated the remarkable tumor ablation ability of CMTNPs. Thus, our study provided an antiphotobleaching and controlled release photosensitizer strategy through the introduction of antioxidant TA into the nanocarrier for efficient collaborative photothermal/photodynamic therapy.
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Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggered photolysis process of current photocage is largely singlet oxygen (1O2)-dependent and lack of compatibility with other reactive oxygen species (ROS)-activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT-LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY-TPE fluorophore via the superoxide anion radical (O2-â¢)-cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT-LRC could be self-assembled into aggregation-induced emission (AIE)-active nanoparticles (BT-LRCs) owing to the regulation of carbohydrate-carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT-LRCs could simultaneously generate abundant O2-⢠through the aggregation modulated by lactose interactions, and DNA-damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor-bearing mice. Furthermore, the inherent AIE property of BT-LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real-time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.
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Numerous barriers hinder the entry of drugs into cells, limiting the effectiveness of tumor pharmacotherapy. Effective penetration into tumor tissue and facilitated cellular uptake are crucial for the efficacy of nanotherapeutics. Photodynamic therapy (PDT) is a promising approach for tumor suppression. In this study, we developed a size-adjustable porphyrin-based covalent organic framework (COF), further modified with hyaluronic acid (HA), to sequentially deliver drugs for combined chemo-photodynamic tumor therapy. A larger COF (P-COF, approximately 500 nm) was loaded with the antifibrotic drug losartan (LST) to create LST/P-COF@HA (LCH), which accumulates at tumor sites. After injection, LCH releases LST, downregulating tumor extracellular matrix (ECM) component levels and decreasing collagen density, thus reducing tumor solid stress. Additionally, the reactive oxygen species (ROS) generated from LCH under 660 nm laser irradiation induce lipid peroxidation of cell membranes. Owing to its larger particle size, LCH primarily functions extracellularly, paving the way for subsequent treatments. Following intravenous administration, the smaller COF (p-COF, approximately 200 nm) loaded with doxorubicin (DOX) and modified with HA (DOX/p-COF@HA, DCH) readily enters cells in the altered microenvironment. Within tumor cells, ROS generated from DCH facilitates PDT, while the released DOX targets cancer cells via chemotherapy, triggered by disulfide bond cleavage in the presence of elevated glutathione (GSH) levels. This depletion of GSH further enhances the PDT effect. Leveraging the size-tunable properties of the porphyrin COF, this platform achieves a multifunctional delivery system that overcomes specific barriers at optimal times, leading to improved outcomes in chemo-photodynamic multimodal tumor therapy in vivo.
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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-O2, has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O2 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-O2 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 EGFRhigh cSCC but also to extend its applicability to other EGFRhigh malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies.
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BACKGROUND: Acne is a chronic inflammatory skin disease. Photodynamic therapy (PDT) is a highly effective and safe drug-device combination treatment, typically using red and blue light. However, direct comparisons of aminolevulinic acid (ALA)-based PDT using these two light sources are lacking. Therefore, we compared the efficacy and adverse effects of ALA-based 450 nm blue laser-mediated PDT (BL-PDT) and 630 ± 10 nm red light-emitting diode-mediated PDT (RL-PDT) in the treatment of moderate-to-severe acne vulgaris, including analyses of different lesion types. METHODS: Sixteen patients with moderate-to-severe acne vulgaris were recruited. All patients underwent BL-PDT on the left side of the face and RL-PDT on the right side. Treatments were administered thrice at 2-week intervals, and follow-up continued for 2 weeks after the final treatment. The average rates of improvement in inflammatory and non-inflammatory acne lesions, IGA (Investigator's Global Assessment) scales, and IGA success rates were calculated. In addition, adverse effects during and after each treatment were recorded. RESULTS: At the 2-week follow-up after the final treatment, the average rates of improvement in total acne, inflammatory, and non-inflammatory lesions were 48.0%, 63.0%, and 30.0% in the BL-PDT group and 42.2%, 58.1%, and 27.5% in the RL-PDT group, respectively. The IGA scores for the two groups decreased by 1.8 and 1.7 points, respectively, and the IGA success rate was 53.3% in both groups. There were no significant differences between the BL-PDT and RL-PDT groups in any measure of effectiveness. However, the BL-PDT group exhibited more severe adverse effects, especially pain and hyperpigmentation. CONCLUSIONS: BL-PDT and RL-PDT have similar efficacies in moderate-to-severe acne vulgaris and are particularly effective for inflammatory acne lesions. RL-PDT benefits from milder adverse effects than those of BL-PDT.
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Tumor vaccines have become a promising approach for cancer treatment by triggering antigen-specific responses against tumors. However, autophagy and immunosuppressive tumor microenvironment (TME) reduce antigen exposure and immunogenicity, which limit the effect of tumor vaccines. Here, we develop fucoidan (Fuc) based chlorin e6 (Ce6)-chloroquine (CQ) self-assembly hydrogels (CCFG) as in situ vaccines. Ce6 triggers immune response in situ by photodynamic therapy (PDT) induced immunogenic cell death (ICD) effect, which is further enhanced by macrophage polarization of Fuc and autophagy inhibition of CQ. In vivo studies show that CCFG effectively enhances antigen presentation under laser irradiation, which induces a powerful in situ vaccine effect and significantly inhibits tumor metastasis and recurrence. Our study provides a novel approach for enhancing tumor immunotherapy and inhibiting tumor recurrence and metastasis.
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Autofagia , Vacunas contra el Cáncer , Clorofilidas , Cloroquina , Hidrogeles , Inmunoterapia , Macrófagos , Fotoquimioterapia , Polisacáridos , Porfirinas , Animales , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Vacunas contra el Cáncer/farmacología , Vacunas contra el Cáncer/inmunología , Porfirinas/química , Porfirinas/farmacología , Porfirinas/uso terapéutico , Autofagia/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Cloroquina/farmacología , Ratones Endogámicos C57BL , Microambiente Tumoral/efectos de los fármacos , Células RAW 264.7 , Línea Celular Tumoral , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Ratones Endogámicos BALB C , FemeninoRESUMEN
Photodynamic therapy (PDT) is an emerging clinical modality for diverse disease conditions, including cancer. This technique involves, the generation of cytotoxic reactive oxygen species by a photosensitizer in the presence of light and oxygen. Methylene blue (MB) is a cationic dye with an ability to act as photosensitizing and bioimaging agent. The direct utilization of MB as photosensitizer for biological applications has often been impeded by its poor photostability and unwanted tissue interactions. Nanocarriers such as mesoporous silica nanoparticles (MSNs) provide an effective means of overcoming these limitations. However, the mere physical adsorption of the dye within the MSN can result in leakage, compromising the effectiveness of PDT. Therefore, in this work, we report the conjugation of MB into MSNs using novel MB-silane derivatives, namely MBS1 and MBS2, to create dye-doped and amine-functionalized MSNs (MBS1-AMSN and MBS2-AMSN). The PDT efficacy and bioimaging capability of these nanoparticles were compared with those of MSNs in which MB was non-covalently encapsulated (MB@AMSN). The synthesized nanoparticles, ultra-small in size (≤ 35 ± 4â¯nm) with monodispersity, exhibited enhanced fluorescence quantum yields. MBS1-AMSN demonstrated 70-fold increase, while MBS2-AMSN showed 33-fold improvement in fluorescence quantum yields compared to MB@AMSN at the same concentration. Covalent conjugation resulted in a 2-fold enhancement in the singlet oxygen quantum yield of the dye in MBS1-AMSN and 1.2-fold improvement in MBS2-AMSN, compared to non-covalent encapsulation. Assessment on RAW 264.7 macrophages revealed superior fluorescence in cell imaging for MBS1-AMSN, establishing it as a more efficient PDT agent compared to MBS2-AMSN and MB@AMSN. These findings suggest that MBS1-AMSN holds significant potential as a theranostic nanoplatform for image-guided PDT.
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Pharmacological activation of the immunogenic cell death (ICD) pathway by endoplasmic reticulum (ER) targeted photosensitizer (PS) has become a promising strategy for tumor immunotherapy. Despite a clear demand for ER-targeted PS, the sluggish intersystem crossing (ISC) process, unstable excited state, insufficient ROS production, and immunosuppressive tumor microenvironment (ITME) combined to cause the high-efficiency agents are still limited. Herein, three groups commonly used in thermally activated delayed fluorescence (TADF) molecular design are used to modify the excited state characteristics of xanthene-based cyanine PS (obtained the XCy-based PS). The electronic and geometric modulation effectively optimize the excited state characteristics, facilitating the ISC process and prolonging the excited state life for boosting ROS generation. Among them, car-XCy showed 100 times longer excited state life and 225% higher ROS yield than that of original XCy. The satisfactory ROS production and ER-targeted ability of car-XCy arouse intense ER stress to activate the ICD. Adequate antigen presentation promotes the dendritic cell maturation and infiltration of cytotoxic T lymphocytes (CTLs), ultimately reversing the ITME to realize efficient immunotherapy. As a result, significant inhibition is observed in both primary and distant tumors, underscoring the efficacy of this TADF-guiding excited state characteristics modulation strategy for developing photodynamic immunotherapy drugs.