Self-assembled nanoparticles of glycosylated AABB-type phthalocyanines for selective photodynamic therapy.

Target-activated selective photodynamic antibacterial therapy: In situ enhancing 1O2 yield of conjugated polyelectrolytes by E. coli surface.

Abstract BACKGROUND The infiltrative nature of malignant brain tumors, such as glioblastoma, complicates complete surgical resection and leads to high recurrence rates. We developed a novel microscope-guided photo-theranosis system to precisely identify and simultaneously treat tumor tissues while minimizing damage to surrounding normal tissue. This study provides a proof-of-concept for this innovative therapeutic strategy. METHODS Human U87MG and U87MG-GFP glioblastoma cells were used in cultures and spheroids. Diagnostic capability of the system was validated by detecting GFP fluorescence, while therapeutic efficacy was assessed by applying region-selective photodynamic therapy (PDT) with a 595 nm LED. Hypericin was used as a photosensitizer, with its delivery confirmed via fluorescence imaging. For in vivo studies, an orthotopic xenograft mouse model was established using U87MG-GFP cells. Following craniotomy, the exposed tumor underwent an intraoperative photo-theranosis procedure: 1) tumor scanning, 2) region of interest (ROI) selection, and 3) masked PDT on the selected ROI to evaluate its performance. RESULTS The system successfully identified tumor regions via GFP fluorescence and demonstrated the capability for selective PDT. In vitro, the PDT-treated group showed statistically significant inhibition of spheroid tumor growth compared to the non-PDT control group (mean relative volume: 1.089 ± 0.717 vs. 2.496 ± 0.992, respectively; p < 0.05). In the brain tumor animal model, the system effectively scanned the post-craniotomy tumor and enabled user-defined, ROI-specific PDT, thus validating its feasibility for intraoperative application. CONCLUSIONS The microscope-guided photo-theranosis system suggests a new paradigm for treating malignant brain tumors by enabling real-time, accurate diagnosis and concurrent therapy. This technology has the potential to become an innovative intraoperative strategy that maximizes tumor control while minimizing damage to healthy tissue, offering a significant advancement in neuro-oncological surgery.

Cancer remains a major global health challenge, necessitating the development of alternative therapies that minimize side effects and overcome drug resistance associated with conventional treatments. In this study, it reports the synthesis and characterization of a series of platinum(II) complexes based on azadipyrromethene (ADPM) ligands as novel photosensitizers for photodynamic therapy (PDT). These complexes are designed to enhance light absorption and photochemical activity through the incorporation of heavy atoms. Their photophysical properties—including absorption spectra, fluorescence emission, and singlet oxygen generation efficiency—are systematically investigated. The complexes exhibited strong absorption in the visible region and high singlet oxygen yields, indicating their suitability for PDT applications. In vitro assays using several cancer cell lines demonstrate low cytotoxicity under dark conditions, whereas light activation induces a significant cytotoxic response. Flow cytometry analysis further confirms that the treatment induces apoptotic cell death. These effects were found to be both light‐ and concentration‐dependent. Overall, this study's results demonstrate the potential of these platinum–ADPM complexes as effective and selective PDT agents, offering a promising strategy for the development of safer and more targeted cancer therapies.

Despite intensive worldwide research efforts and multiple available therapeutic schemes for cancer treatment, cancer still remains a challenge, rendering the need for the discovery of new therapeutic approaches imperative. Photodynamic therapy (PDT) is a novel, non-invasive anti-cancer treatment that relies on the generation of reactive oxygen species (ROS) that are cytotoxic to cancer cells. ROS are generated by the interaction between a photosensitizer (PS) drug, a light source (primarily a laser), and oxygen. Although PDT offers the advantage of using non-ionizing radiation and bears great therapeutic potential, it has not yet been widely adopted in clinical practice. This review summarizes the new developments in the use of PDT in combination with chemotherapy, immunotherapy, and radiotherapy, giving emphasis to the combination of PDT with a novel type of therapy that also takes into account the tumor microenvironment (TME) to enhance treatment efficacy. TME-targeting therapies include strategies like hypoxia modulation, vascular normalization, and immune cell reprogramming. Interestingly, when combined with PDT, these therapies can improve therapeutic outcomes while reducing side effects, and nanoparticle-based delivery systems have demonstrated the potential to enhance PDT selectivity and efficiency. This review highlights PDT's enormous potential in treating various cancer types and underscores the need for continued exploration of combination therapies to maximize its clinical impact.

Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, poses a significant therapeutic challenge due to its highly invasive nature and resistance to conventional therapies, including surgery, chemotherapy, and radiotherapy. Despite advances in standard treatments, patient survival remains limited, requiring the exploration of innovative strategies. Photodynamic therapy (PDT) has emerged as a promising approach, leveraging light-sensitive photosensitizers (PSs), molecular oxygen, and specific light wavelengths to generate reactive oxygen species (ROS) that selectively induce tumor cell death. Originally developed for skin cancer, PDT has evolved to target more complex malignancies, including GBM. The refinement of second- and third-generation PS, coupled with advancements in nanotechnology, has significantly improved PDT's selectivity, bioavailability, and therapeutic efficacy. Moreover, the combination of PDT with chemotherapy, targeted therapy, and immunotherapy, among other therapeutic modalities, has shown potential in enhancing therapeutic outcomes. This review provides a comprehensive analysis of the preclinical and clinical applications of PDT in GBM, detailing its mechanisms of action, the evolution of PS, and novel combinatory strategies that optimize treatment efficacy. However, several challenges remain, including overcoming GBM-associated hypoxia, enhancing PS delivery across the blood-brain barrier, and mitigating tumor resistance mechanisms. The integration of PDT with molecular and genetic insight, alongside cutting-edge nanotechnology-based delivery systems, may revolutionize GBM treatment, offering new prospects for improved patient survival and quality of life.

A water-soluble and heavy-atom-free hemicyanine photosensitizer, H-WBHcy, specifically activated by ˙OH (a tumor biomarker), was synthesized for the first time. H-WBHcy could sensitively respond to ˙OH (LOD = 8.7 nM), showing red-shifted absorption from 500 nm to 694/765 nm as well as fluorescence emission at 910 nm. Meanwhile, ˙OH was able to trigger the oxidized product of H-WBHcy to further produce 1O2 under 808 nm laser irradiation, which could significantly inhibit the growth of cancer cells. We believe this work provides a strategy for developing activatable near-infrared photosensitizers for precise photodynamic therapy.

Developing activatable photodynamic agents is becoming a promising mode for realizing selective photodynamic therapy (PDT) in cancer treatment. However, till now only a few H2S-activatable photodynamic agents have been involved in this field. Here, we fabricated H2S-activatable nano-assemblies (P@TPPCY) for the treatment of colon cancer containing high concentration H2S. The H2S-activatable photosensitizer (TPPCY) was synthesized by covalent conjugation between tetraphenylporphyrin (TPP) and heptamethine cyanine (Cy7), and then TPPCY was encapsulated by an amphiphilic polymer DSPE-mPEG to form P@TPPCY nano-assemblies. We demonstrated that the photosensitizing effect of TPP was efficiently quenched by Cy7 with strong absorption in the NIR region via fluorescence resonance energy transfer (FRET) effect. Interestingly, the FRET effect between Cy7 and TPP was attenuated by the decrease of absorption of Cy7 in the NIR region after the Cy7 reacted with H2S, and then the photosensitizing effect of TPP in P@TPPCY was activated. Strikingly, the P@TPPCY showed efficient H2S-activatable photodynamic therapy (PDT) in vitro against HCT116 cells (human colon carcinoma cell line), thus this work provides a new method for realizing accurate treatment of colon cancer in virtue of high H2S concentration microenvironment.

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.

Despite advances in Ir(III) and Ru(II) photosensitizers (PSs), their lack of selectivity for cancer cells has hindered their use in photodynamic therapy (PDT). We disclose the synthesis and characterization of two pairs of Ir(III) and Ru(II) polypyridyl complexes bearing two β-carboline ligands (N^N') functionalized with -COOMe (L1) or -COOH (L2), resulting in PSs of formulas [Ir(C^N)2(N^N')]Cl (Ir-Me: C^N = ppy, N^N' = L1; Ir-H: C^N = ppy, N^N' = L2) and [Ru(N^N)2(N^N')](Cl)2 (Ru-Me: N^N = bpy, N^N' = L1; Ru-H: N^N = bpy, N^N' = L2). To enhance their selectivity toward cancer cells, Ir-H and Ru-H were coupled to a bombesin derivative (BN3), resulting in the metallopeptides Ir-BN and Ru-BN. Ir(III) complexes showed higher anticancer activity than their Ru(II) counterparts, particularly upon blue light irradiation, but lacked cancer cell selectivity. In contrast, Ir-BN and Ru-BN exhibited selective photocytoxicity against prostate cancer cells, with a lower effect against nonmalignant fibroblasts. All compounds generated ROS and induced severe mitochondrial toxicity upon photoactivation, leading to apoptosis. Additionally, the ability of Ir-Me to oxidize NADH was demonstrated, suggesting a mechanism for mitochondrial damage. Our findings indicated that the conjugation of metal PSs with BN3 creates efficient PDT agents, achieving selectivity through targeting bombesin receptors and local photoactivation.

Herein, we report a novel flavin analogue as singular chemical component for lysosome bioimaging, and inherited photosensitizer capability of the flavin core was demonstrated as a promising candidate for photodynamic therapy (PDT) application. Fine-tuning the flavin core with the incorporation of methoxy naphthyl appendage provides an appropriate chemical design, thereby offering photostability, selectivity, and lysosomal colocalization, along with the aggregation-induced emissive nature, making it suitable for lysosomal bioimaging applications. Additionally, photosensitization capability of the flavin core with photostable nature of the synthesized analogue has shown remarkable capacity for generating reactive oxygen species (ROS) within cells, making it a promising candidate for photodynamic therapy (PDT) application.

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality employed for the treatment of various types of cancers, localized infections, and other diseases. Upon illumination, the photo-excited photosensitizer generates singlet oxygen and other reactive species, thereby inducing cytotoxicity in the target cells. The hypoxic tumour microenvironment (TME), however, poses a limitation on the supply of oxygen in tumour tissues. Moreover, under such conditions, tumour metastasis and drug resistance frequently occur, further compromising the efficacy of PDT in combating tumours. Traditionally, type I photosensitizers with lower oxygen consumption demonstrate significant potential in overcoming hypoxic environments and play a crucial role in determining the therapeutic efficacy of PDT because type I photosensitizers can generate highly cytotoxic free radicals. In comparison, type II photosensitizers exhibit high oxygen dependence. The rate of reactive oxygen species (ROS) generation in the type II process is significantly higher than that in the type I process. Thus, the efficiency and selectivity of PDT depend on the properties of the photosensitizer. Here, the recent development and application of type I and type II photosensitizers, mainly in the past year, are summarized. The design methods, electronic structures, photophysical properties, lipophilic properties, electric charge, and other molecular characteristics of these photosensitizers are discussed in detail. These modifications alter the microstructure of photosensitizers and directly impact the results of PDT. The main content of this paper will have a positive promoting and inspiring effect on the future development of PDT.

DNA nanomachines could initiate the cascade reaction in an autonomous mode under the drive of triggers, which achieve the signal amplification for the bioimaging of intracellular biomarkers. Compared with the "always-on" nanomachine that possibly produces false-positive signals, a controllable nanomachine with the on-site activation could be better for accurate tumor imaging and precise tumor therapy. Till now, the endogenous and exogenous triggers have been developed to design the controllable nanosensors. However, their combinations to develop feasible DNA nanomachines have been rarely studied. Herein, we constructed a near-infrared (NIR)-light-controlled DNA nanomachine that was first activated by the NIR light and then induced a target-triggered amplification process under the drive of an endogenous stimulus. Owing to adenosine-5'-triphosphate (ATP) having much higher concentration in cancer cells than that in healthy cells and the extracellular fluid, the obtained DNA nanomachine was selectively activated in cancer cells with inhibited interference signals from the surrounding healthy tissues. With obvious advantages including the exogenous NIR light initiation, the selective activation by the target microRNA, and the sensitive acceleration by the ATP-induced strand recycling reaction, the constructed nanomachine could be used to image the intracellular microRNA with increased sensitivity. Besides, after modifying the DNA sequence with the photosensitizer molecules, the obtained nanomachine could perform the selective photodynamic therapy on the tumor sections with the outstandingly decreased side effects. Thus, we hope the designed nanomachine could provide some important hints to design feasible nanomachines for accurate tumor diagnosis and precise tumor therapy.

Photodynamic therapy is known for its non-invasiveness to significantly reduce undesired side effects on patients. However, the infiltration and invasiveness of tumor growth are still beyond the specificity of traditional light-controlled photodynamic therapy (PDT), which lacks cellular-level accuracy to tumor cells, possibly leading to "off-target" damage to healthy tissues such as the skin or immune cells infiltrated. Here, upconversion nanoparticles (UCNPs) were co-encapsulated with manganese dioxide (MnO2) by amphiphilic polymers poly(styrene-co-methyl acrylate) (PSMA) and further coated with photosensitizer (riboflavin)-loaded mesoporous silica (C@S/V). The C@S/V nanoprobes exhibited shielded upconversion luminescence in normal conditions (pH 7.4, no hydroperoxide (H2O2)) under 980-nm irradiation and thus minimal reactive oxygen production from riboflavin. However, the excess H2O2 (1mM) and acidic environment (pH 5.5) could decompose the MnO2 within the C@S/V, resulting in remarkable enhancement of upconversion luminescence and a favorable hypoxia-relieving condition for PDT, providing a spatiotemporal signal for therapy initiation. The C@S/V nanoprobes were applied to the co-culture of normal cells (HEK293) and pancreatic cancer cells (Panc02) and performed a selective killing on Panc02 under the 980-nm irradiation. By using the "double-safety" strategy, a responsive C@S/V nanoprobe was designed by the selective activation of acidic and H2O2-rich conditions and 980-nm irradiation for spatiotemporally selective photodynamic therapy with cellular-level accuracy.

Periodontal diseases are global health concern since they affect almost 20-50% of global population and are widespread in both developed and developing countries. Periodontal disease develops as result of persistent infection caused by different periodontopathic bacteria and inflammation of tooth's supporting tissue. Traditional methods of periodontal care involve mechanical removal of biofilm and using antibiotics and antibacterial disinfectants as supplemental measure. However, in locations with restricted access, removal of plaque and decrease in quantity of pathogenic organisms may suffer. Furthermore, increased antibiotic resistance has led to development of newer therapeutic modalities, including photodynamic therapy (PDT). Application of PDT in periodontics, such as pocket debridement, gingivitis, and aggressive periodontitis, continues to develop into fully developed clinical therapeutic modality and is regarded as potential new strategy for eliminating pathogenic bacteria in periodontitis. Photosensitizer activated by light of certain wavelength in presence of O2 is used in PDT, potent laser-initiated photochemical reaction. Because traditional therapy, such as scaling and root planing, is ineffective at entirely eliminating periodontal infections, especially in deep periodontal pockets, antimicrobial PDT may be viewed as alternate therapeutic approach. Additionally, dual selectivity of PDT, which restricts damage to healthy tissues, gives it competitive advantage over alternative therapies. Purpose of this research is to review the available information about PDT and periodontal disease.

From cell membrane to mitochondria: Time-dependent AIE photosensitizer for fluorescence imaging and photodynamic anticancer therapy

Selective photodynamic therapy (PDT) for cancer cells is more efficient and much safer. Most selective PDTs are realized by antigene-biomarker or peptide-biomarker interactions. Here, we modified dextran with hydrophobic cholesterol as a photosensitizer carrier to selectively target cancer cells, including colon cancer cells, and fulfilled selective PDT. The photosensitizer was designed with regular Aggregation-Induced Emission (AIE) units, including triphenylamine and 2-(3-cyano-4,5,5-trimethylfuran-2-ylidene)propanedinitrile. The AIE units can help to decrease the quenching effect in the aggregate state. The efficiency of the photosensitizer is further improved via the heavy atom effect after bromination modification. We found that the obtained photosensitizer nanoparticles could selectively target and ablate cancer cells after encapsulation into the dextran-cholesterol carrier. This study indicates that the polysaccharide-based carrier may have potential for cancer-targeting therapy beyond expectations.

Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG2000 to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.

Special issue on enhanced photodynamic therapy: Part II

Targeted photodynamic therapy (TPDT) based on the photosensitizers responsive for tumor microenvironment is promising because of the better anti-tumor effect and less phototoxicity against normal tissue than the traditional PDT. Nanoparticle-based stimuli-responsive photosensitizers have been widely explored for TPDT. Based on the acidic microenvironments in solid tumors, an ultrasmall pH-responsive silicon phthalocyanine nanomicelle (PSN) (smaller than 10[Formula: see text]nm) was designed for selective PDT of tumor. PSN had high drug loading efficacy (more than 28%) and exhibited morphological transitions, enhanced fluorescence and improved singlet oxygen yield under acidic environments. PSN was renal clearable and could rapidly accumulate and be retained at tumor sites, achieving a tumor-inhibiting effect better than phthalocyanine micelle without pH response. Tumors of mice treated with PSN for PDT were completely ablated without recurrence. Thus, we have developed a phthalocyanine-based pH-responsive micelle with excellent tumor targeting ability, which is expected to realize the selective PDT of tumor.