Two-photon photodynamic therapy (TP-PDT) provides a broad prospect for cancer treatment due to its deep penetration, minimal invasiveness and fewer side effects. In this work, a series of quasi-intrinsic photosensitizers (PSs) are proposed for TP-PDT based on the cytosine. To ensure the efficient intersystem crossing rates and strong absorption within the therapeutic window (600-900 nm), the ring-expansion and substitution of F and Cl halogen atoms are considered. Our calculations revealed that these C-analogues could maintain the fundamental pyrimidine skeleton with inherently planarity and possess relatively low logP values contributing to their enhanced cancer cell-targeting capability. More importantly, the modifications could bring significant red-shifted one-photon absorption and enlarged two-photon absorption cross-section that responsible for selective excitation during PDT. Following the vertical photoexcitation, the population in the long-lived triplet state are characterized by examining the deactivation rates and the corresponding decay lifetime. Additionally, the generation of reactive oxygen species for PDT is confirmed through calculations of ionization potential as well as electron affinity (type I mechanism), and the T1 energy (type II mechanism). Besides, the effects of base pairing on photosensitivity are investigated to evaluate the usefulness of proposed PSs in TP-PDT. These nucleobase derivatives are expected to contribute broader advancement of PDT and provide theoretical clues for enhancing cancer treatment efficacy with reduced cytotoxicity and improved biocompatibility.

Photodynamic therapy relies on the generation of cytotoxic effects triggered by the irradiation of a photosensitizer molecule, resulting in the production of reactive oxygen species at concentrations exceeding physiological levels. In this context, squaraine dyes, a prominent family of second-generation photosensitizers, have gained increasing attention for their remarkable properties, with their photobiological characteristics recently emerging as a key focus of in-depth research. Dansylpiperazine-bearing squaraine dyes exhibited strong absorption in the red visible spectral region, excellent photostability, and a predicted ability to interact with human serum albumin, potentially serving as a transport vehicle to target sites. Benzothiazole derivatives excelled in photodynamic activity, demonstrating 7- to 11-fold increased cytotoxicity upon irradiation against prostate adenocarcinoma PC-3 cells and tumor selectivity indices exceeding 10 when compared to normal NHDF cells. In contrast, the introduction of the dansylpiperazino group in indole-derived compounds unexpectedly declined their photodynamic activity. Concerning benzothiazole-based ones, multiple reactive oxygen species were shown to contribute to the photodynamic effects, with singlet oxygen playing a key role. Squaraine internalization was observed in various cytoplasmic organelles, including mitochondria, endoplasmic reticulum, and lysosomes, without clear evidence of preferential localization to any single organelle. Non-genotoxic in the dark, the squaraines induced cell death by apoptosis upon light activation, as evidenced by significant DNA fragmentation and increased caspase 3/7 activation, particularly for the dye with N-ethyl chains, at concentrations below 1.0 μM, underscoring their potency. Checkpoint arrests in G1 and G2/mitosis were observed for non-irradiated and irradiated conditions, respectively, highlighting the antiproliferative effects of these squaraine dyes.

Biotin is primarily taken up by cells through sodium-dependent multivitamin transporter, which is highly expressed in aggressive cancer cell lines, often at levels surpassing those of the folate receptor. This makes biotin an attractive ligand for tumor-targeted drug delivery. Building on this rationale, this study presents a series of six D-(+)-biotin-conjugated squaraine dyes derived from benzothiazole, indolenine, and benz[e]indole, with N-ethyl and N-hexyl chains. These compounds were thoroughly characterized in terms of their photophysical and photochemical properties, revealing strong absorption in the so-called "phototherapeutic window", notable fluorescence, especially the benzothiazole derivatives, aqueous stability, particularly the indolenine-based dyes, and moderate to high photostability. Computational studies further indicated a strong binding affinity to human serum albumin and avidin proteins. All dyes exhibited photodynamic activity, with indolenine derivatives showing remarkable tumor selectivity and benz[e]indole analogs evidencing superior photocytotoxicity. The most promising compounds preferentially accumulated in mitochondria, and both singlet oxygen and other reactive oxygen species were found to play a role in their photobiological effects. Additionally, they were non-genotoxic in the absence of irradiation, and apoptosis was the primary mechanism of cell death upon light activation. This was evidenced by preserved cytoplasmic membrane integrity, nuclear fragmentation, and caspase-3/7 activation, reinforcing the safety and potential of these compounds as phototherapeutic agents. Although cellular uptake via the sodium-dependent multivitamin transporter was not established, and diffusion is expected to be the predominant mechanism, the high predicted avidin-binding affinity of these dyes opens exciting new avenues for photodynamic therapy-combined strategies.

Background/Objectives: Primary cutaneous lymphomas (CLs) are a group of skin-limited lymphoproliferative disorders, including cutaneous T-cell (CTCLs) and B-cell lymphomas (CBCLs). Photodynamic therapy (PDT), a non-invasive, light-activated treatment, has gained attention as a skin-directed therapy for early-stage CLs due to its selectivity and favorable safety profile. This systematic review evaluates the current evidence on the clinical use of PDT in managing CLs. Methods: A systematic literature search was conducted in PubMed, Scopus, and Embase through 1 September 2024 following PRISMA guidelines. Search terms included "primary cutaneous skin lymphoma", "CTCL", "CBCL", "mycosis fungoides", "lymphomatoid papulosis", and "photodynamic therapy". After screening 1033 records, 30 studies were included. Data were extracted and categorized by lymphoma subtype and clinical outcomes. Results: Of the included studies, 23 focused on mycosis fungoides (MF), 5 on lymphomatoid papulosis (LyP), and 2 on CBCL. PDT demonstrated notable clinical efficacy in early-stage and localized disease, particularly MF, using methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA) as photosensitizers. Adjunctive techniques like microneedling and laser-assisted delivery improved treatment outcomes. PDT was generally well tolerated, with mild, transient side effects; rare complications such as localized neuropathy were reported. Conclusions: PDT is a promising, non-invasive treatment for early-stage CLs, especially MF and indolent CBCL variants. While current evidence supports its safety and effectiveness, further comparative and prospective studies are needed to refine protocols, evaluate long-term efficacy, and compare different photosensitizers.

With all diagnostic and therapeutic advances, such as surgery, radiation- and chemo-therapy, cervical cancer (CC) is still ranked fourth among the most frequent cancers in women globally. New biomarkers and therapeutic targets are warranted to be discovered for the early detection, treatment, and prognosis of CC. As component of the non-coding RNA's family, microRNAs (miRNAs) participate in several cellular functions such as cell proliferation, gene expression, many signaling cascades, apoptosis, angiogenesis, etc. MiRNAs can suppress or induce programmed cell death (PCD) pathways by altering their regulatory genes. Besides, abnormal expression of miRNAs weakens or promotes various signaling pathways associated with PCD, resulting in the development of human diseases such as CC. For that reason, understanding the effects that miRNAs exert on the various modes of tumor PCD, and evaluating the potential of miRNAs to serve as targets for induction of cell death and reappearance of chemotherapy. The current study aims to define the effect that miRNAs exert on cell apoptosis, autophagy, pyroptosis, ferroptosis, and anoikis in cervical cancer to investigate possible targets for cervical cancer therapy. Manipulating the PCD pathways by miRNAs could be considered a primary therapeutic strategy for cervical cancer.

Photodynamic therapy (PDT) is a targeted cancer treatment offering precise tumor ablation with minimal systemic toxicity. However, its clinical application is constrained by poor solubility, rapid clearance, and inadequate tumor accumulation of photosensitizers (PS). This study presents an innovative liquid metal nanoparticle (LMNP) platform, composed of gallium-indium eutectic alloy (EGaIn), engineered to address these drug delivery challenges in PDT. Using a one-step sonication process, EGaIn nanoparticles are synthesized and functionalized with folic acid (FA) for tumor-specific targeting, beta cyclodextrin (β-CD) for enhanced drug encapsulation, and benzoporphyrin derivative (BPD) as a PS. The inclusion of β-CD significantly improves the BPD loading capacity, achieving a three-fold enhancement (52% vs. 18%) while ensuring nanoparticle stability and sustained drug release. Covalent binding of FA and β-CD to the gallium oxide surface enables effective targeting and biocompatibility. In vitro analyses demonstrate potent PDT efficacy, even with reduced cellular uptake, underscoring the platform's ability to overcome intracellular delivery barriers. This LMNP-based nanoplatform addresses critical PDT limitations, such as suboptimal drug delivery and systemic toxicity, leveraging the unique chemical and physical properties of EGaIn nanoparticles. Its multifunctional design integrates targeted delivery, controlled release, and precise therapeutic activation, representing a promising advancement in the development of effective, personalized cancer treatment strategies.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are light-activated cancer treatments. PDT involves the administration of a photosensitizing agent, which is activated by light of a specific wavelength to generate reactive oxygen species. Alternatively, PTT involves the use of photothermal agents, which are materials that absorb light and convert it into heat. Gold nanoparticles are often used as photothermal agents owing to their localized surface plasmon resonance (LSPR), a key optical property, which allows them to efficiently absorb light and convert it into heat. Graphene, which is a 2D material with extraordinary optical and physical properties and a large surface area, shows great promise both in PDT and PTT as an intrinsic nanoheater or a versatile platform for the immobilization of gold nanoparticles and other functional molecules, including photosensitizers. Moreover, graphene-based derivatives, i.e. graphene oxide (GO) and reduced graphene oxide (rGO), exhibit intrinsic optical/spectroscopic signals, which can be used in fluorescence, Raman and thermal imaging. By combining gold nanoparticles with graphene derivatives, a higher increase in temperature can be achieved under light irradiation owing to the synergistic effect of these two materials and the drug delivery efficiency and multimodal imaging techniques can be enhanced. This review provides insights into graphene-based nanoplatforms, focusing on multimodal therapy and imaging techniques. Furthermore, future perspectives in the field of graphene-based- and hybrid-nanoplatforms are suggested.

Metal coordination compounds are currently a focus of research in developing new photosensitizers for materials and medicinal applications. As an abundant element in the earth's crust aluminum is a suitable target element. However, only limited studies are available on its use in photoactive systems. We now report the facile preparation of a library of homoleptic tris(dipyrrinato)aluminum(III) [AL(DIPY)3] complexes. The majority of complexes was characterized by single crystal X-ray analysis and their photophysical properties upon photoexcitation and their tendency to react with the molecular oxygen of the microenvironment and generate singlet oxygen - in polar and non-polar environment was investigated. These studies are complemented by density functional theory (DFT) calculations to assess the possible electronic distribution on the frontier molecular orbitals within the complexes. As a result of charge transfer states, long-lived triplet excited states were formed and allowed for singlet oxygen generation. An initial screening of the AL(DIPY)3 complexes via in vitro phototoxicity studies against a mouse colon carcinoma cell line (CT26) was promising as these complexes were able to trigger cell death upon irradiation at nanomolar and micromolar concentrations. The results highlight the potential of aluminum dipyrrin complexes as a broadly applicable class of photosensitizers.

The special case of far-red vision of mesopelagic dragonfish Malacosteus niger facilitated by the presence in the rod outer segment of photosensitizer chlorin e6 from diet has drawn considerable attention both in vision research and in photodynamic action. Rhodopsin binding of Ce6 from either the extracellular or intracellular loops may exert different effects. Theoretical works predict that the extracellularly bound Ce6 upon absorption of red light produces a singlet oxygen, which could via an oxygen tunnel reach the Lys-tethered 11-cis-retinal, by way of peroxy-dioxetane intermediates, to enhance 11-cis- to all-trans-retinal isomerization, therefore triggering the ultrafast phototransduction process. Recent works on the permanent photodynamic activation of some A-class G protein-coupled receptors suggest that the singlet oxygen generated by Ce6 photodynamic action might also oxidize the scotopsin moiety of rhodopsin, leading to direct oxidative rhodopsin activation. More attention needs to be paid to the latter respects of the far-red vision process of the deep-sea dragonfish, with potential translational values.

Different from reversible agonist-stimulated receptor activation, singlet oxygen oxidation activates permanently G protein-coupled receptor (GPCR) cholecystokinin 1 (CCK1R) in type II photodynamic action, with soluble photosensitizer dyes (sulphonated aluminum phthalocyanine, λmax 675 nm) or genetically encoded protein photosensitizers (KillerRed λmax 585 nm; mini singlet oxygen generator λmax 450 nm), together with a pulse of light (37 mW/cm2, 1-2 minutes). Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen (GPCR-ABSO): (1) CCK1R is quantitatively converted from dimer to monomer; (2) Transmembrane domain 3, a pharmacophore for permanent photodynamic CCK1R activation, can be transplanted to non-susceptible M3 acetylcholine receptor; and (3) Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation. GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs, but show some clear advantages: Enhanced selectivity (double selectivity of localized photosensitizer and light illumination), long-lasting activation with no need for repeated drug administration, antagonist-binding site remains intact when needed, ease to apply to multiple GPCR. This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.

In the treatment of cancer, the physical and mental stress on patients and the potential for strong side effects are serious problems; therefore, reliable delivery of drugs into cancer tissue cells is required. We have developed a near-infrared (NIR) photosensitizing dye, Zn6PTPc, for NIR-photochemical internalization (PCI) to achieve gentle and efficient endosomal escape and delivery of antibody drugs, which are known to have high targeting ability but low intracellular activity, into target cancer cells. Zn6PTPc allowed longer wavelengths to be used to achieve higher singlet oxygen generation efficiency by the molecular design based on a distorted π-electron system. The system effectively introduced immunotoxins into cells to significantly inhibit tumor tissue growth. The developed potent NIR photosensitizers facilitated NIR-PCI with high tumor-targeting ability.

Oral Squamous Cell Carcinoma (OSCC) is the most common type of head and neck cancer worldwide. Currently, the most common treatment for OSCC includes a combination of surgery, radiation, and chemotherapy. However, despite the advances made in therapeutic strategies, the prognosis for patients diagnosed with OSCC remains poor, especially at later stages, which emphasizes the need for a novel treatment approach. Photodynamic therapy (PDT) has been employed as stand-alone or adjuvant therapy for OSCC.

This study investigated the potential of using salivary proteins such as histatin-5 (Hst5) or derived peptides (RR14, DR9/RR14) to perform histatin-mediated PDT. The current literature has shown that histatins have the capacity to increase cellular membrane permeability, which indicates a potential synergistic effect when combined with a photosensitive agent. Toluidine Blue O (TBO) was used as the photosensitizer (PS) singularly combined with salivary peptides RR14, DR9/RR14, and Hst5 protein, and experiments were conducted to assess its biocompatibility and photodynamic effects on human gingival fibroblasts (FGH) and oral squamous cell carcinoma (SCC-25) cell lines.

The results showed that TBO concentrations below 4 μg/mL were non-cytotoxic to FGH cells, whereas concentrations up to 8 μg/mL were non-cytotoxic to SCC-25 cells. Also, the presence of histatins did not modify the absorption spectrum or photobleaching of TBO, enabling consistent production of reactive oxygen species (ROS) over time and rendering it as a stable and suitable PS for PDT. Further experiments also showed that when TBO was combined with Hst5, the ROS production increased by 186% compared to TBO alone.

Results suggest that the use of histatin-enhanced PS offer a promising alternative to conventional PDT, potentially improving its outcomes.

Novel pH-sensitive polymeric photosensitizer carriers from the phthalocyanine (Pc) group were investigated as potential photodynamic therapy drugs for the treatment of breast cancer. Their high antiproliferative activity was confirmed by photocytotoxicity studies, which indicated their high efficacy and specificity toward the SK-BR-3 cell line. Importantly, the Pcs encapsulated in the polymeric nanoparticle (NP) carrier exhibited a much better penetration into the acidic environment of tumor cells than their free form. The investigated Pc4-NPs and TT1-NPs exhibited a high selectivity to healthy fibroblasts as well as non-toxicity without irradiation. This paper describes the detailed mechanism of action of the evaluated compounds by measuring reactive oxygen species (ROS), including singlet oxygen; imaging cellular localization; and analyzing key signaling pathway proteins. An additional advantage of the evaluated compounds is their ability to inhibit the Akt protein expression, including its phosphorylation, which the Western blot test confirmed. This is particularly important because breast cancers often overexpress the HER-2 receptor-related signaling proteins. Moreover, an analysis of proteins such as GLUT-1, HO-1, phospho-p42/44, and BID revealed the significant involvement of ROS in disrupting cellular homeostasis, thereby leading to the induction of oxidative stress and resulting in apoptotic cell death.

Leveraging functional materials to develop advanced personal protective equipment is of significant importance for cutting off the propagation of infectious diseases, yet faces ongoing challenges owing to the unsatisfied antimicrobial efficiency. Herein a hierarchically porous cerium metal-organic framework (Ce-MOF) boosting the antimicrobial performance by intensifying catalytic reactive oxygen species (ROS) generation and bacterial entrapment simultaneously is reported. This Ce-MOF presents dendritic surface topography and hierarchical pore channels where the Lewis acid Ce sites are dispersedly anchored. Attributing to this sophisticated nanoarchitecture rendering the catalytic Ce sites highly accessible, it shows a ca. 1800-fold activity enhancement for the catalytic conversion of atmospheric oxygen to highly toxic ROS compared to traditional CeO2. Additionally, the dendritic and negative-charged surface engineered in this Ce-MOF substantially enhances the binding affinity toward positive-charged bacteria, enabling the spatial proximity between the bacteria and the short-lived ROS and therefore maximizing the utilization of highly toxic ROS to inactivate bacteria. It is demonstrated that this Ce-MOF-integrated face mask displays almost 100% antimicrobial efficacy even in insufficient light and dark scenarios. This work provides important insights into the design of antibacterial MOF materials by a pore- and surface-engineering strategy and sheds new light on the development of advanced self-antimicrobial devices.

The effectiveness of photodynamic therapy (PDT) for cancer treatment relies on the generation of cytotoxic singlet oxygen (1O2) in type II PDT. Hence, monitoring of 1O2 generation during PDT enables optimal treatment delivery to the tumor target with reduced off-target effects. Direct 1O2 observation by measuring its luminescence at 1270 nm remains challenging due to the very weak signal. This study presents 1O2 luminescence measurements using a time-resolved singlet oxygen luminescence detection system (TSOLD) applied to protoporphyrin IX (PpIX) in different solvents (ethanol and acetone) and biological media (bovine serum albumin and agarose-based solid phantom). The compact experimental setup includes a nanosecond diode laser with a function generator, a cuvette with photosensitizer solution, optical filtering and mirrors, an InGaAs single-photon avalanche diode detector, and time-tagger electronics. Increasing the concentration of PpIX in these media from 1 to 10 µg/g resulted in a 3-5 × increase in the 1O2 luminescence signal. Furthermore, increasing light scattering in the sample using Intralipid from 0.1 to 1% led to a decrease in the 1O2 luminescence signal and lifetime. These results confirm the marked effect of the microenvironment on the 1O2 signal and, hence, on the photodynamic efficacy.

Toluidine blue O (TBO) is a type I-type II photosensitizer that has shown good efficacy and selectivity in antimicrobial and anticancer photodynamic therapy applications. However, its complex photochemistry with multiple photoproducts hinders its application as a photosensitizer. We have previously described the mechanism for photooxidative demethylation of TBO which in acetonitrile yields two main products: demethylated-TBO (d-TBO) and double-demethylated-TBO (dd-TBO). In the current work, we describe the photophysical properties of these two photoproducts. In acetonitrile and phosphate buffer, demethylation induces an hypsochromic shift in the absorption and fluorescence emission maxima. Fluorescence quantum yields increase slightly for the demethylated photoproducts, in agreement with the lengthening of the fluorescence lifetimes. Triplet excited states lifetimes in the presence of oxygen decreased slightly upon demethylation. However, the singlet oxygen quantum yield increased significantly reaching unity for the dd-TBO photoproduct. These results are interpreted in terms of the competing pathways of TBO photochemistry. For TBO, demethylation is the main pathway for deactivation of the excited state, while for d-TBO, demethylation and singlet oxygen generation are significant. For dd-TBO, singlet oxygen generation is the main deactivation pathway. Overall, TBO demethylated photoproducts demonstrate good potential as candidates for photodynamic therapy applications.

The amphiphilic and asymmetric structure of porphyrins, when used as photosensitizers (PSs) for photodynamic therapy (PDT), has been shown through numerous previous studies to be a very important property that facilitates their entry into cells, which improves their efficiency in PDT. In this work, two groups of cationic AB3 pyridiniumporphyrins, free-base and chelated with Zn(II), both substituted with alkyl chains of various lengths, were studied in PDT on melanoma cell lines. The aim was to investigate the impact of hydrophilic-lipophilic balance and Zn(II) chelation, and the importance of matching the irradiation wavelength to the optical properties of the PS on in vitro PDT efficiency. Therefore, spectroscopic studies, singlet oxygen production and lipophilicity as well as cellular uptake, localization and cytotoxicity studies of the two series of porphyrins were performed. In both series of porphyrins, the longest alkyl chain (17 C-atoms long) enables the greatest internalization of the PS. Chelation with Zn(II) resulted in better physicochemical properties, but slower cellular internalization. As expected, free-base porphyrins were more PDT efficient than their Zn(II) complexes after 30-min photoactivation by low-fluence (2 mW/cm2) red light (643 nm). However the use of orange light (606 nm) with the same fluence rate was more suitable for Zn(II) porphyrins and resulted in similar overall toxicity to their free-base analogues with similar lipophilicity. Although the highest phototoxicity was achieved with the PSs carrying the longest alkyl chain, TMPyP3-C13H27 and Zn(II)-TMPyP3-C13H27 proved to be the most promising candidates for use in PDT as they exhibit high phototoxicity, but also greater selectivity towards melanoma cell lines (MeWo and A375) compared to fibroblasts (HDF).

Gliomas are aggressive intracranial tumors of the central nervous system with a poor prognosis, high risk of recurrence, and low survival rates. Radiation, surgery, and chemotherapy are traditional cancer therapies. It is very challenging to accurately image and differentiate the malignancy grade of gliomas due to their heterogeneous and infiltrating nature and the obstruction of the blood-brain barrier. Imaging plays a crucial role in gliomas which significantly plays an important role in the accuracy of the diagnosis followed by any subsequent surgery or therapy. Other diagnostic methods (such as biopsies or surgery) are often very invasive. Preoperative imaging and intraoperative image-guided surgery perform the most significant safe resection. In recent years, the rapid growth of nanotechnology has opened up new avenues for glioma diagnosis and treatment. For better therapeutic efficacy, developing microenvironment-responsive nanoplatforms, including novel nanotherapeutic platforms of sonodynamic therapy, photodynamic therapy, and photothermal treatments, are employed for improved patient survival and better clinical control outcome. In this review recent advancement of multifunctional nanoplatforms leading toward treatment of glioma is discussed.

P-glycoprotein (P-gp, ABCB1) is a well-researched ATP-binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P-gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non-toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub-cytotoxic photodynamic therapy process, can inhibit P-gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL-MDA-MB-231) and chemosensitive (MDA-MB-231) triple-negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P-gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL-MDA-MB-231 cells, but not in chemosensitive MDA-MB-231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P-gp in VBL-MDA-MB-231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P-gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR.

Photodynamic Therapy (PDT) has emerged as a highly efficient and non-invasive cancer treatment, which is crucial considering the significant global mortality rates associated with cancer. The effectiveness of PDT primarily relies on the quality of the photosensitizers employed. When exposed to appropriate light irradiation, these photosensitizers absorb energy and transition to an excited state, eventually transferring energy to nearby molecules and generating Reactive Oxygen Species (ROS), including singlet oxygen [1O2]. The ability to absorb light in visible and nearinfrared wavelengths makes porphyrins and derivatives useful photosensitizers for PDT. Chemically, Porphyrins, composed of tetra-pyrrole structures connected by four methylene groups, represent the typical photosensitizers. The limited water solubility and bio-stability of porphyrin photosensitizers and their non-specific tumor-targeting properties hinder PDT effectiveness and clinical applications. Therefore, a wide range of modification and functionalization techniques have been used to maximize PDT efficiency and develop multidimensional porphyrin-based functional materials. Recent progress in porphyrin-based functional materials has been investigated in this review paper, focusing on two main aspects including the development of porphyrinic amphiphiles that improve water solubility and biocompatibility, and the design of porphyrin-based polymers, including block copolymers with covalent bonds and supramolecular polymers with noncovalent bonds, which provide versatile platforms for PDT applications. The development of porphyrin-based functional materials will allow researchers to significantly expand PDT applications for cancer therapy by opening up new opportunities. With these innovations, porphyrins will overcome their limitations and push PDT to the forefront of cancer treatment options.

Previous research has revealed that mitochondria are an important target for photodynamic therapy (PDT), which might be employed as a therapeutic approach for several malignancies, including hepatocellular carcinoma (HCC). In this study, we investigated both intrinsic toxicity and photodynamic effects of the photosensitizer (PS) aluminum chloride phthalocyanine (AlClPc) on mitochondrial functions. Several aspects of mitochondrial bioenergetics, structure, and oxidative state were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation. Additionally, experiments were conducted to demonstrate the intrinsic and photodynamic effects of AlClPc on the viability of HepG2 cells. AlClPc interacted with mitochondria regardless of photostimulation; however, at the maximum utilized concentration (40 μM), photostimulation reduced its interaction with mitochondria. Although AlClPc hindered catalase (CAT) and glutathione reductase (GR) activities intrinsically, it had no discernable capacity to generate oxidative stress or impact bioenergetics in mitochondria without photostimulation, as one would anticipate from an ideal PS. When exposed to light, however, AlClPc had a substantially unfavorable influence on mitochondrial function, strengthening its intrinsic inhibitory action on CAT, producing oxidative stress, and jeopardizing mitochondrial bioenergetics. In terms of oxidative stress parameters, AlClPc induced lipid peroxidation and decreased the level of reduced glutathione (GSH) in mitochondria. Regarding bioenergetics, AlClPc promoted oxidative phosphorylation uncoupling and photodynamic inactivation of complex I, complex II, and the FoF1-ATP synthase complex, lowering mitochondrial ATP production. Lastly, AlClPc exhibited a concentration-dependent decrease in the viability of HepG2 cells, regardless of the presence or absence of photostimulation. While the harmful photodynamic effects of AlClPc on mitochondrial bioenergetics hold promise for treating HCC and other malignancies, the inherent toxic impacts on HepG2 cells underscore the need for caution in its application for this purpose.

Nanoparticles have become versatile assets in the medical field, providing notable benefits across diverse medical arenas including controlled drug delivery, imaging, and immunological assays. Among these, non-lamellar lipid nanoparticles, notably cubosomes and hexosomes, showcase remarkable biocompatibility and stability, rendering them as optimal choices for theranostic applications. Particularly, incorporating edge activators like sodium taurocholate enhances the potential of these nanoparticles for dermal and transdermal drug delivery, overcoming the stratum corneum, a first line of defense in our skin. This study reports on the formulation of monoolein-based cubosomes and hexosomes incorporating taurocholate and stabilized by Span 80 and co-encapsulating Chlorin e6 and coenzyme QH for photodynamic therapy in skin metastatic melanoma. The formulations were optimized using small-angle X-ray scattering, and cryo-transmission electron microscopy confirmed the presence of cubosomes or hexosomes, depending on the ratio between taurocholate and Span 80. Furthermore, the co-loaded nanoparticles exhibited high encapsulation efficiencies for both Ce6 and the coenzyme QH. In vitro studies on human melanoma cells (Me45) demonstrated the biocompatibility and photodynamic activity of the loaded formulations. These findings show the possibility of formulating more biocompatible cubosomes and hexosomes for photodynamic therapy in skin cancer treatment.

High concentrations of reactive oxygen species (ROS) can disrupt cell structure and induce apoptosis and necrosis of tumor cells. Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are two cancer treatments mediated by reactive oxygen species. Oxygen molecules (O2) are one of the indispensable factors in PDT and hypoxic tumor sites limit its application. However, another ROS-mediated method, CDT, can generate •OH and O2in situ by Fenton reaction or Fenton-like reaction. Synergistic PDT/CDT therapy is a strategy to overcome the limitations of tumor microenvironment therapy. In this review, PDT and CDT therapies are briefly introduced, with an emphasis on metal-basrd porphyrin nanoparticles constructed in different ways for PDT/CDT dual-mode therapy. By introducing the history and latest design schemes of the treatment model, it provides ideas for researchers engaged in ROS-mediated cancer therapies.

Ultrasound has gained prominence in biomedical applications due to its noninvasive nature and ability to penetrate deep tissue with spatial and temporal resolution. The burgeoning field of ultrasound-responsive prodrug systems exploits the mechanical and chemical effects of ultrasonication for the controlled activation of prodrugs. In polymer mechanochemistry, materials scientists exploit the sonomechanical effect of acoustic cavitation to mechanochemically activate force-sensitive prodrugs. On the other hand, researchers in the field of sonodynamic therapy adopt fundamentally distinct methodologies, utilizing the sonochemical effect (e.g., generation of reactive oxygen species) of ultrasound in the presence of sonosensitizers to induce chemical transformations that activate prodrugs. This cross-disciplinary review comprehensively examines these two divergent yet interrelated approaches, both of which originated from acoustic cavitation. It highlights molecular and materials design strategies and potential applications in diverse therapeutic contexts, from chemotherapy to immunotherapy and gene therapy methods, and discusses future directions in this rapidly advancing domain.

Cyanine-based near-infrared (NIR) fluorescent probes have played vital roles in biological application due to their low interference from background fluorescence, deep tissue penetration, high sensitivity, and minimal photodamage to biological samples. They are widely utilized in molecular recognition, medical diagnosis, biomolecular detection, and biological imaging. Herein, we provide a review of recent advancements in cyanine-based NIR fluorescent probes for the detection of pH, cells, tumor as well as their application in photothermal therapy (PTT) and photodynamic therapy (PDT).

Cancer immunotherapy using immune checkpoint blockades has emerged as a promising therapeutic approach. However, immunotherapy faces challenges such as low response rates in solid tumors, necessitating strategies to remodel the immune-suppressive tumor microenvironment (TME) into an immune-activated state. One of the primary approaches to achieve this transformation is through the induction of immunogenic cell death (ICD). Herein, we discussed strategies to maximize ICD induction using nanoparticles. In particular, this review highlighted various studies integrating chemotherapy, radiation therapy (RT), photodynamic therapy (PDT), and photothermal therapy (PTT) with nanoparticle-based immunotherapy. The research covered in this review aims to provide valuable insights for future studies on nanoparticle-assisted immunotherapy.

Effective cancer treatment relies on the precise deployment of clinical imaging techniques to accurately treat tumors. One highly representative technology among these is multi-imaging guided phototherapy. This work introduces a new and innovative theranostic drug that combines near-infrared (NIR) irradiation-induced photodynamic therapy (PDT) and photothermal therapy (PTT) to treat malignancies. Moreover, it can be utilized as a contrasting substance for X-ray computed tomography (CT) imaging and contrast-enhanced ultrasound (CEUS) to aid in the administration of therapy.

Cesium tungsten bronze nanobubbles (CsxWO3@NBs) were constructed via a water-controlled solvothermal synthesis and thin film hydration of phospholipid. Various methods, including dynamic light scattering, transmission electron microscopy, and X-ray photoelectron spectroscopy, were used to analyze and describe the size, shape, and chemical characteristics of the nanoparticles. In this study, hepatoma cell lines HepG2 and HUH7 were employed in vitro, and xenotransplantation mouse models were used to assess their antitumor effects. A series of in vitro and in vivo trials were conducted to assess the effectiveness of combining photodynamic and photothermal therapies, as well as using CEUS and CT imaging.

The CsxWO3@NBs exhibit photothermal effects and the generation of reactive oxygen species (ROS) under laser irradiation, thereby enabling effective photothermal and photodynamic combinatorial therapy. Following combined treatment, the activity and invasive capacity of hepatocellular carcinoma cells were markedly diminished, the development rate of the tumor was noticeably reduced, and the level of biological toxicity was low. Additionally, CsxWO3@NBs possess the capacity to serve as both a CT imaging agent and a contrast-enhanced ultrasound agent.

CsxWO3@NBs represent a promising theranostic agent for image-guided cancer therapy.

An excellent agreement for simulated and measured absorption and emission spectra is found for four donor-acceptor aromatic molecules (tetraphenylpyrazine, tetraphenylethene, distirylanthracene and hexaphenylsilole) whose derivatives serve as solid state photosensitizers. After comparing several hybrid TDDFT functionals, EOM-CCSD, and experiments, the best agreement was found with TD-B3LYP and double zeta basis sets (6-31G** and def2-SVP) for one molecule in gas phase. A full characterisation of twelve to twenty electronic excited states was performed in every system. Symmetry-forbidden bands are found in the absorption spectra by sampling fifty to hundred geometries from a Wigner distribution. The density of states in the region 2-6 eV was also analysed, showing a very packed region of excited states and suggesting that dark electronic states may play a role in the dynamics of some of the photoexcited systems. Further calculations were done with QM/xTB at geometries extracted from previously published X-ray data to evaluate the influence of the environment on the excitations of the four aggregated molecular crystals.

Microwave (MW) therapy is an emerging therapy with high efficiency and deep penetration to combat the crisis of bacterial resistance. However, as the energy of MW is too low to induce electron transition, the mechanism of MW catalytic effect remains ambiguous. Herein, a cerium-based metal-organic framework (MOF) is fabricated and used in MW therapy. The MW-catalytic performance of CeTCPP is largely dependent on the ions in the liquid environment, and the electron transition is achieved through a "tribovoltaic effect" between water molecules and CeTCPP. By this way, CeTCPP can generate reactive oxygen species (ROS) in saline under pulsed MW irradiation, showing 99.9995 ± 0.0002% antibacterial ratio against Staphylococcus aureus (S. aureus) upon two cycles of MW irradiation. Bacterial metabolomics further demonstrates that the diffusion of ROS into bacteria led to the bacterial metabolic disorders. The bacteria are finally killed due to "amino acid starvation". In order to improve the applicability of CeTCPP, It is incorporated into alginate-based hydrogel, which maintains good MW catalytic antibacterial efficiency and also good biocompatibility. Therefore, this work provides a comprehensive instruction of using CeTCPP in MW therapy, from mechanism to application. This work also provides new perspectives for the design of antibacterial composite hydrogel.

Neurological disorders such as neurodegenerative diseases and nervous system tumours affect more than one billion people throughout the globe. The physiological sensitivity of the nervous tissue limits the application of invasive therapies and leads to poor treatment and prognosis. One promising solution that has generated attention is Photodynamic therapy (PDT), which can potentially revolutionise the treatment landscape for neurological disorders. PDT attracted substantial recognition for anticancer efficacy and drug conjugation for targeted drug delivery. This review thoroughly explained the basic principles of PDT, scientific interventions and advances in PDT, and their complicated mechanism in treating brain-related pathologies. Furthermore, the merits and demerits of PDT in the context of neurological disorders offer a well-rounded perspective on its feasibility and challenges. In conclusion, this review encapsulates the significant potential of PDT in transforming the treatment landscape for neurological disorders, emphasising its role as a non-invasive, targeted therapeutic approach with multifaceted applications.

Treating brain tumors requires a nuanced understanding of the brain, a vital and delicate organ. Location, size, tumor type, and surrounding tissue health are crucial in developing treatment plans. This review comprehensively summarizes various treatment options that are available or could be potentially available for brain tumors, including physical therapies (radiotherapy, ablation therapy, photodynamic therapy, tumor-treating field therapy, and cold atmospheric plasma therapy) and non-physical therapies (surgical resection, chemotherapy, targeted therapy, and immunotherapy). Mechanisms of action, potential side effects, indications, and latest developments, as well as their limitations, are highlighted. Furthermore, the requirements for personalized, multi-modal treatment approaches in this rapidly evolving field are discussed, emphasizing the balance between efficacy and patient safety.

The use of 5-aminolevulinic acid (ALA) as a precursor for protoporphyrin IX (PpIX) is an established photosensitization strategy for photodynamic therapy (PDT) and fluorescence guided surgery. Ongoing studies are focused on identifying approaches to enhance PpIX accumulation as well as to identify tumor sub-types associated with high PpIX accumulation. In this study, we investigated PpIX accumulation and PDT treatment response with respect to nodule size in 3D cultures of pancreatic cancer cells (Panc1) and a derivative subline (Panc1OR), which has acquired drug resistance and exhibits increased epithelial mesenchymal transition. In monolayer and 3D culture dose response studies the Panc1OR cells exhibit significantly a higher level of photokilling at lower light doses than the drug naïve cells. Panc1OR also exhibits increased PpIX accumulation. Further analysis of cell killing efficiency per molecule of intracellular PpIX indicates that the drug resistant cells are intrinsically more responsive to PDT. Additional investigation using exogenous delivery of PpIX also shows higher cell killing in drug resistant cells, under conditions which achieve approximately the same intracellular PpIX. Overall these results are significant as they demonstrate that this example of drug-resistant cells associated with aggressive disease progression and poor clinical outcomes, show increased sensitivity to ALA-PDT.

Photodynamic therapy (PDT) relies on the interactions between light, photosensitizers, and tissue oxygen to produce cytotoxic reactive oxygen species (ROS), primarily singlet oxygen (1O2) through Type II photochemical reactions, along with superoxide anion radicals (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH) through Type I mechanisms. Accurate dosimetry, accounting for all three components, is crucial for predicting and optimizing PDT outcomes. Conventional dosimetry tracks only light fluence rate and photosensitizer concentration, neglecting the role of tissue oxygenation. Reactive oxygen species explicit dosimetry (ROSED) quantifies the reacted oxygen species concentration ([ROS]rx) by explicit measurements of light fluence (rate), photosensitizer concentration, and tissue oxygen concentration. Here we determine tissue oxygenation from non-invasive diffuse correlation spectroscopy (DCS) measurement of tumor blood flow using a conversion factor established preclinically. In this study, we have enrolled 24 pleural PDT patients into the study. Of these patients, we are able to obtain data on 20. Explicit dosimetry of light fluence, Photofrin concentration, and tissue oxygenation concentrations were integrated into the ROSED model to calculate [ROS]rx across multiple sites inside the pleural cavity and among different patients. Large inter- and intra-patient heterogeneities in [ROS]rx were observed, despite identical 60 J/cm2 light doses, with mean [ROS]rx,meas of 0.56 ± 0.26 mM for 13 patients with 21 sites, and [ROS]rx,calc1 of 0.48 ± 0.23 mM for 20 patients with 76 sites. This study presented the first comprehensive analysis of clinical ROSED in pleural mesothelioma patients, providing valuable data on future ROSED based pleural PDT that can potentially produce uniform ROS and thus improve the PDT efficacy for Photofrin-mediated pleural PDT.

A nucleus is crucial for both sonodynamic therapy (SDT) and antitumor immunity. However, how to burst ROS generation in situ, accurately damage a nucleus, and meanwhile activate a cGAS-STING pathway-induced innate immune response are still a great challenge. Here, we present TBzT-CPi, a small molecule with a D-A-π-A1 structure that simultaneously amplifies nucleus-targeted SDT and cGAS-STING pathway-dependent immune stimulation. TBzT-CPi could accumulate in the nucleus upon ultrasound irradiation and generate ROS in situ, which damages DNA and simultaneously triggers immunogenic cell death (ICD). Stirringly, nucleus-targeting SDT not only efficiently induces apoptosis in tumor cells but also modifies the immunosuppressive tumor microenvironment by activating cytotoxic T lymphocytes, maturing dendritic cells, and secreting cytokines. These findings pave the way for developing nucleus-targeting sonosensitizers for sonodynamic immunotherapy of cancer.

The issue of antimicrobial resistance is an escalating concern within the scope of global health. It is predicted that the existence of antibiotic-resistant bacteria might result in an estimated annual death of up to 10 million by 2050, along with possible economic losses ranging from 100 to 210 trillion. This study reports the production of poly[2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] nanoparticles (PCPDTBT-NPs) by nanoprecipitation as an alternative to tackle this problem. The size, shape, and optical features of these conjugated polymer NPs were analyzed. Their efficacy as photosensitizers against nonresistant (ATCC) and multidrug-resistant mcr-1-positive Escherichia coli was assessed under white light doses of 250 and 375 J·cm-2. PCPDTBT-NPs inactivated both E. coli strains exposed to white light at an intensity of 375 J·cm-2, while no antimicrobial effect was observed in the group not exposed to white light. Reactive oxygen species and singlet oxygen were detected using DCFH-DA and DPBF probes, allowing the investigation of the photoinactivation pathways. This work showcases PCPDTBT-NPs as photosensitizers to eliminate multidrug-resistant bacteria through photodynamic inactivation employing visible light.

Antimicrobial resistance remains an enduring global health issue, manifested when microorganisms, such as bacteria, lack responsiveness to antimicrobial treatments. Photodynamic inactivation (PDI) of microorganisms arises as a noninvasive, nontoxic, and repeatable alternative for the inactivation of a broad range of pathogens. So, this study reports the synthesis, structural characterization, and photophysical properties of a new tetra-β-substituted pyridinium-pyrazolyl zinc(II) phthalocyanine (ZnPc 1a) that was compared with two previously described pyridinium-pyrazolyl ZnPcs 2a and 3a. The PDI efficacy of these three ZnPcs (1a-3a) against a drug-resistant Gram-positive bacterium (as Staphylococcus aureus) and a Gram-negative bacterium (as Escherichia coli) is also reported. The PDI efficacy toward these bacteria was examined with ZnPcs 1a-3a in the 5.0-10.0 μM range using a white light source with an irradiance of 150 mW/cm2. All ZnPcs displayed a significant PDI activity against S. aureus, with reductions superior to 3 Log CFU/mL. Increasing the treatment time, the E. coli was inactivated until the detection limit of the method (>6.3 Log CFU/mL) using the quaternized ZnPcs 1a-3a (10.0 μM, 120 min) being the inactivation time was reduced when added the KI for ZnPcs 1a and 3a. These findings demonstrate the effective PDI performance of pyridinium-pyrazolyl group-bearing PSs, indicating their potential use as a versatile antimicrobial agent for managing infections induced by Gram-negative and Gram-positive bacteria.

Despite the fundamental importance of cell membrane microviscosity, changes in this biophysical parameter of membranes during photodynamic therapy (PDT) have not been fully understood.

In this work, changes in the microviscosity of membranes of live HeLa Kyoto tumor cells were studied during PDT with KillerRed, a genetically encoded photosensitizer, in different cellular localizations. Membrane microviscosity was visualized using fluorescence lifetime imaging microscopy (FLIM) with a viscosity-sensitive BODIPY2 rotor.

Depending on the localization of the phototoxic protein, different effects on membrane microviscosity were observed. With nuclear localization of KillerRed, a gradual decrease in microviscosity was detected throughout the entire observation period, while for membrane localization of KillerRed, a dramatic increase in microviscosity was observed in the first minutes after PDT, and then a significant decrease at later stages of monitoring. The obtained data on cell monolayers are in good agreement with the data obtained for 3D tumor spheroids.

These results indicate the involvement of membrane microviscosity in the response of tumor cells to PDT, which strongly depends on the localization of reactive oxygen species attack via targeting of a genetically encoded photosensitizer.

Conjunctival melanoma (CJM) is a rare malignant ocular surface tumor, which often leads to local recurrences and metastases. In murine models of subcutaneous tumors, treatment with a novel virus-like drug conjugate (VDC; Bel-sar) showed a dual mechanism of action with direct tumor cell killing as well as stimulation of an antitumoral immune response. Bel-sar is currently being evaluated for the treatment of primary uveal melanoma and indeterminate nevi in a phase III clinical trial. We determined whether Bel-sar also has direct antitumor efficiency and a potential immunostimulatory capacity in CJM cells.

Three human tumor-derived CJM lines were used. Bel-sar's subcellular and intracellular locations were determined with tracers. Following light activation of Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were assessed. Treated tumor cells were co-cultured with THP-1 derived macrophages to assess tumor-cell phagocytosis.

Bel-sar was bound and internalized by CJM cells and subsequently found in the cell membrane, lysosome, Golgi apparatus, and mitochondria. Bel-sar activation induced near complete cell death with half-maximal inhibitory concentration (IC50) values between 30 pM and 60 pM. Finally, light-activated Bel-sar enhanced exposure of DAMPs, including calreticulin, heat shock protein 90, and stimulated phagocytosis by macrophages.

Treatment with a novel VDC (Bel-sar) induced pro-immunogenic cell death in all three CJM cell lines. The in vitro cytotoxicity was accompanied by exposure of DAMPs, suggesting Bel-sar is a potential treatment for CJM by a dual mechanism of action. This dual mechanism may provide a targeted and direct killing of tumor cells and induce an immune response which might decrease local recurrences and metastasis.