Photodynamic Therapy Drug Research Articles

PH-sensitive phthalocyanine-loaded polymeric nanoparticles as a novel treatment strategy for breast cancer.

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.

Cyclic Ruthenium-Peptide Prodrugs Penetrate the Blood-Brain Barrier and Attack Glioblastoma upon Light Activation in Orthotopic Zebrafish Tumor Models.

The blood-brain barrier (BBB) presents one of the main obstacles to delivering anticancer drugs in glioblastoma. Herein, we investigated the potential of a series of cyclic ruthenium-peptide conjugates as photoactivated therapy candidates for the treatment of this aggressive tumor. The three compounds studied, Ru-p(HH), Ru-p(MH), and Ru-p(MM) ([Ru(Ph2phen)2 (Ac-X1RGDX2-NH2)]Cl2 with Ph2phen = 4,7-diphenyl-1,10-phenanthroline and X1, X2 = His or Met), include an integrin-targeted pentapeptide coordinated to a ruthenium warhead via two photoactivated ruthenium-X1,2 bonds. Their photochemistry, activation mechanism, tumor targeting, and antitumor activity were meticulously addressed. A combined in vitro and in vivo study revealed that the photoactivated cell-killing mechanism and their O2 dependence were strongly influenced by the nature of X1 and X2. Ru-p(MM) was shown to be a photoactivated chemotherapy (PACT) drug, while Ru-p(HH) behaved as a photodynamic therapy (PDT) drug. All conjugates, however, showed comparable antitumor targeting and efficacy toward human glioblastoma 3D spheroids and orthotopic glioblastoma tumor models in zebrafish embryos. Most importantly, in this model, all three compounds could effectively cross the BBB, resulting in excellent targeting of the tumors in the brain.

Preclinical Photodynamic Therapy Targeting Blood Vessels with AGuIX® Theranostic Nanoparticles.

Background: Glioblastoma multiforme (GBM) is the most common highly aggressive, primary malignant brain tumor in adults. Current experimental strategies include photodynamic therapy (PDT) and new drug delivery technologies such as nanoparticles, which could play a key role in the treatment, diagnosis, and imaging of brain tumors. Objectives: The purpose of this study was to test the efficacy of PDT using AGuIX-TPP, a polysiloxane-based nanoparticle (AGuIX) that contains TPP (5,10,15,20-tetraphenyl-21H,23H-porphine), in biological models of glioblastoma multiforme and to investigate the vascular mechanisms of action at multiple complexity levels. Methods: PDT effects were studied in monolayer and spheroid cell culture, as well as tumors in chicken chorioallantoic membranes (CAMs) and in mice were studied. Results: Treatment was effective in both endothelial ECRF and glioma U87 cells, as well as in the inhibition of growth of the glioma spheroids. PDT using AGuIX-TPP inhibited U87 tumors growing in CAM and destroyed their vascularization. The U87 tumors were also grown in nude mice. Their vascular network, as well as oxygen partial pressure, were assessed using ultrasound and EPR oximetry. The treatment damaged tumor vessels and slightly decreased oxygen levels. Conclusions: PDT with AGuIX-TPP was effective against glioma cells, spheroids, and tumors; however, in mice, its efficacy appeared to be strongly related to the presence of blood vessels in the tumor before the treatment.

Efficient Delivering of a Photodynamic Therapy Drug into Cellular Membranes Rationalized by Molecular Dynamics.

Photodynamic therapy (PDT) represents a most attractive therapeutic strategy to reduce side-effects of chemotherapy and improve the global quality of life of patients. Yet, many PDT drugs suffer from poor bioavailability and cellular intake, and thus, drug-delivering strategies are mandatory. In this article, we rationalize the behavior of a temoporfin-based PDT drug, commercialized under the name of Foscan, complexed by two β-cyclodextrin units, acting as drug carriers, in the presence of a lipid bilayer. Our all-atom simulations have unequivocally shown the internalization of the drug-delivering complex and suggest its possible spontaneous dissociation in the lipid bilayer core. The factors favoring penetration and dissociation have also been analyzed, together with membrane perturbation due to the interaction with the drug carrier complex. Our results confirm the suitability of this encapsulation strategy for PDT and rationalize the experimental results concerning its efficacy.

Glycosylated AIE‐active Red Light‐triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy

AbstractPhotocaging 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−⋅)‐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.

Glycosylated AIE-active Red Light-triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy.

Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggeredphotolysis 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-•)-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 simultaneouslygenerate 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.

Water-Soluble Rotaxane-Type Porphyrin Dyes as a Highly Membrane-Permeable and Durable Photosensitizer Suitable for Photodynamic Therapy.

Porphyrins have emerged as highly effective photosensitizers in the field of photodynamic therapy (PDT) because of their high singlet oxygen generation efficiency. However, most porphyrin derivatives do not have adequate water solubility and cell membrane permeability suitable for use in PDT. In addition, they frequently suffer from low durability under photoirradiation. Here, we propose rotaxane-type photosensitizers, in which a porphyrin axle is irreversibly encapsulated within cyclodextrins (CDs), to overcome the drawbacks of porphyrins for PDT. The rotaxane-type photosensitizers were synthesized in high yields by employing a cooperative capture strategy. The CD derivatives worked as a transparent shell to impart a porphyrin axle not only with water solubility but also with photostability. These rotaxanes showed higher cell membrane permeability and photoinduced cytotoxic abilities than talaporfin sodium, presently used as a clinical photosensitizer. The rotaxane-based photosensitizer could have potential for being ideal PDT drugs.

PREPARATION AND STANDARDIZATION OF EXPERIMENTAL BATCHES OF "PHOTORAN E6, LYOPHILIZATE FOR THE PREPARATION OF SOLUTION FOR INFUSIONS", A DRUG FOR PHOTODYNAMIC THERAPY USING HOGWEED LEAVES AS RAW MATERIALS

Introduction. In recent years, there has been a sharp increase in the number of oncological diseases associated with more frequent detection of malignant neoplasms, including in the early stages. Photosensitizers are widely used for the diagnosis and treatment of oncological diseases. Already at the beginning of the twentieth century, it was discovered that a cancer cell is able to accumulate and retain colored substances [1]. In Russia, the photosensitizer "Photoran E6, lyophilizate for the preparation of an infusion solution" is widely used for the diagnosis of malignant tumors. The sub-stance for its production is sodium chloride E6, obtained by chemical synthesis from methylpheophorbide A. which, according to the patent, is extract-ed from the biomass of the green microalgae Spirulina Platensis, native to Japan and California. In this regard, there is an urgent question of replacing imported intermediates with more affordable ones. For this purpose, Sosnowski's hogweed (Heraculum sosnowskyi) was chosen. In connection with the above, the aim of this study was to obtain and standardize in terms of quality the finished drug for photodynamic therapy "Pho-toran E6, lyophilizate for the preparation of an infusion solution" produced from sodium chloride E6, synthesized using a new type of raw material (leaves of borscht Sosnowski). Material and methods. The object of the study was three series of the finished medicine product (hereinafter referred to as GLS) "Photoran, lyophi-lizate for the preparation of an infusion solution", produced from an active pharmaceutical substance synthesized from methylpheophorbide a, ob-tained, in turn, from the leaves of borscht Sosnovsky as an alternative source of vegetable raw materials [2]. The quality indicators of the finished me-dicinal product were determined according to the methods described in the regulatory documentation in accordance with the Regulatory Documentation of the XIV and XV editions. Results. For the research, the aseptic production of three series of GLS was carried out from the previously produced active pharmaceutical sub-stance Sodium Chloride E6. AFS was synthesized from an intermediate obtained from the leaves of borscht Sosnowski. The standardization of the ob-tained series of the drug has been carried out. The possibility of using Sosnowski's hogweed as a plant raw material for the production of photosensi-tizers based on chlorophyll derivatives has been evaluated. Conclusion. In the course of the study, the technology of aseptic production of GLS "Photoran, lyophilizate for the preparation of solution for infusions" was implemented. The quality indicators of the three produced batches of the finished drug have been determined.

Multifunctional DNA Nanoflower Applied for High Specific Photodynamic Cancer Therapy In Vivo.

Photodynamic therapy (PDT) is a newly emerged strategy for disease treatment. One challenge of the application of PDT drugs is the side-effect caused by the non-specificity of the photosensitive molecules. Most of the photosensitizers may invade not only the pathogenic cells but also the normal cells. In recent, people tried to use special cargoes to deliver the drugs into target cells. DNA nanoflowers (NFs) are a kind of newly-emerged nanomaterial which constructed through DNA rolling cycle amplification (RCA) reaction. It is reported that the DNA NFs were suitable materials which have been widely applied as nanocargos for drug delivery in cancer chemotherapeutic treatment. In this paper, we have introduced a new multifunctional DNA NF which could be prepared through an one-pot RCA reaction. This proposed DNA NF contained a versatile AS1411 G-quadruplex moiety, which plays key roles not only for specific recognition of cancer cells but also for near-infrared ray based photodynamic therapy when conjugating with a special porphyrin molecule. We demonstrated that the DNA NF showed good selectivity toward cancer cells, leading to highly efficient photo-induced cytotoxicity. Moreover, the in vivo experiment results suggested this DNA NF is a promising nanomaterial for clinical PDT.

Graphene-Based Photodynamic Therapy and Overcoming Cancer Resistance Mechanisms: A Comprehensive Review.

Photodynamic therapy (PDT) is a non-invasive therapy that has made significant progress in treating different diseases, including cancer, by utilizing new nanotechnology products such as graphene and its derivatives. Graphene-based materials have large surface area and photothermal effects thereby making them suitable candidates for PDT or photo-active drug carriers. The remarkable photophysical properties of graphene derivates facilitate the efficient generation of reactive oxygen species (ROS) upon light irradiation, which destroys cancer cells. Surface functionalization of graphene and its materials can also enhance their biocompatibility and anticancer activity. The paper delves into the distinct roles played by graphene-based materials in PDT such as photosensitizers (PS) and drug carriers while at the same time considers how these materials could be used to circumvent cancer resistance. This will provide readers with an extensive discussion of various pathways contributing to PDT inefficiency. Consequently, this comprehensive review underscores the vital roles that graphene and its derivatives may play in emerging PDT strategies for cancer treatment and other medical purposes. With a better comprehension of the current state of research and the existing challenges, the integration of graphene-based materials in PDT holds great promise for developing targeted, effective, and personalized cancer treatments.

Fluorescence lifetime imaging and phasor analysis of intracellular porphyrinic photosensitizers applied with different polymeric formulations

The fluorescence lifetime of a porphyrinic photosensitizer (PS) is an important parameter to assess the aggregation state of the PS even in complex biological environments. Aggregation-induced quenching of the PS can significantly reduce the yield of singlet oxygen generation and thus its efficiency as a medical drug in photodynamic therapy (PDT) of diseased tissues. Hydrophobicity and the tendency to form aggregates pose challenges on the development of efficient PSs and often require carrier systems. A systematic study was performed to probe the impact of PS structure and encapsulation into polymeric carriers on the fluorescence lifetime in solution and in the intracellular environment. Five different porphyrinic PSs including chlorin e6 (Ce6) derivatives and tetrakis(m-hydroxyphenyl)-porphyrin and -chlorin were studied in free form and combined with polyvinylpyrrolidone (PVP) or micelles composed of triblock-copolymers or Cremophor. Following incubation of HeLa cells with these systems, fluorescence lifetime imaging combined with phasor analysis and image segmentation was applied to study the lifetime distribution in the intracellular surrounding. The data suggest that for free PSs, the structure-dependent cell uptake pathways determine their state and emission lifetimes. PS localization in the plasma membrane yielded mostly monomers with long fluorescence lifetimes whereas the endocytic pathway with subsequent lysosomal deposition adds a short-lived component for hydrophilic anionic PSs. Prolonged incubation times led to increasing contributions from short-lived components that derive from aggregates mainly localized in the cytoplasm. Encapsulation of PSs into polymeric carriers led to monomerization and mostly fluorescence emission decays with long fluorescence lifetimes in solution. However, the efficiency depended on the binding strength that was most pronounced for PVP. In the cellular environment, PVP was able to maintain monomeric long-lived species over prolonged incubation times. This was most pronounced for Ce6 derivatives with a logP value around 4.5. Micellar encapsulation led to faster release of the PSs resulting in multiple components with long and short fluorescence lifetimes. The hydrophilic hardly aggregating PS exhibited a mostly stable invariant lifetime distribution over time with both carriers. The presented data are expected to contribute to optimized PDT treatment protocols and improved PS-carrier design for preventing intracellular fluorescence quenching. In conclusion, amphiphilic and concurrent hydrophobic PSs with high membrane affinity as well as strong binding to the carrier have best prospects to maintain their photophysical properties in vivo and serve thus as efficient photodynamic diagnosis and PDT drugs.

Carrier-Free, Amorphous Verteporfin Nanodrug for Enhanced Photodynamic Cancer Therapy and Brain Drug Delivery.

Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure-drug nanoformulation of VP, termed "NanoVP", eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65-150nm) and 1500-fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2-fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP-PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5-aminolevulinic acid (5-ALA). Moreover, low-dose NanoVP-PDT can safely open the blood-brain barrier, increasing drug accumulation in rat brains by 5.5-fold compared to 5-ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM.

Enhanced photocytotoxicity induced by a triphenylphosphonium-appended platinum diimine complex

Photodynamic therapy (PDT) agents induce photodamage only where photosensitizers localize in tumor cells. Since apoptosis is a major pathway of PDT-mediated cell death in vivo, the therapeutic efficacy of PDT drugs against tumor cells may be improved by regulating intrinsic apoptosis. Mitochondria are the major intracellular organelles that regulate apoptosis, thus triphenylphosphonium, a well-known mitochondria-targeting molecule, was appended to a photoactive platinum diimine complex. The ability of the triphenylphosphonium-appended complex to generate singlet oxygen was assessed by fluorescence spectroscopy using 1,3-diphenylisobenzofuran as a probe. The photocytotoxicity towards HeLa cells (human cervical cancer cell line) or HL-7702 cells (human liver cell line) was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays. The platinum complex has moderate capability to generate singlet oxygen and it has more potent photocytotoxicity than its analogue Pt-CA. Both platinum diimine complexes studied are largely nontoxic to human liver cells either in the dark or after irradiation.

Dissolving Microneedle-Based Cascade-Activation Nanoplatform for Enhanced Photodynamic Therapy of Skin Cancer.

Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ). TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs). Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process. The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.

Combining photodynamic therapy and cascade chemotherapy for enhanced tumor cytotoxicity: the role of CTT2P@B nanoparticles.

The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this study, we devised a molecular prodrug named CTT2P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT2P within bovine serum albumin (BSA), resulting in the formulation known as CTT2P@B. The molecular prodrug CTT2P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh3), photosensitizer TPPOH2, ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH2, CTT2, CTT2P, and CTT2P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660nm with an intensity of 280mWcm-2. Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.

Singlet oxygen‐responsive hyaluronate dot clusters for tumor therapy

AbstractIn this study, we developed nanoclusters that respond to singlet oxygen and can be adjusted in size to enhance the efficacy of tumor therapy. Specifically, we engineered nanoclusters, denoted as dHAc‐PSDA‐Ce6, through the covalent conjugation of hyaluronate dots (dHA) with 3,3‐(propane‐2,2‐diylbis(sulfanediyl))dipropionic acid (PSDA) as a cleavable crosslinker mediated by singlet oxygen, and chlorin e6 (Ce6) as a representative model drug for photodynamic therapy. The hyaluronic acid (HA) component within dHAc‐PSDA‐Ce6 was harnessed for the specific targeting of CD44 receptors that are overexpressed on tumor cells. Upon subjecting the vicinity of tumor cells to light irradiation, the PSDA crosslinker within dHAc‐PSDA‐Ce6 undergoes cleavage, likely facilitated by the singlet oxygen generated by Ce6. This cleavage process leads to the formation of dHA‐Ce6 molecules. We hypothesized that a nanocluster, circulating safely within the bloodstream, would undergo a transformation into individual dHA‐Ce6 molecules upon light irradiation at the localized tumor site. This transformation, in turn, enhances the photodynamic antitumor effect. Our in vitro investigations have demonstrated the remarkable efficacy of dHAc‐PSDA‐Ce6 in inducing tumor cell death upon light irradiation. Furthermore, our in vivo biodistribution studies have revealed the substantial accumulation of these nanoclusters within the tumor site. We anticipate that this singlet oxygen‐responsive nanocluster harbors substantial promise for enhancing tumor accumulation and fortifying the effectiveness of tumor eradication.

Porphyrin Derivative with Binary Properties of Photodynamic Therapy and Water-Dependent Reversible Photoacidity Therapy for Treating Hypoxic Tumor.

Porphyrin photosensitizers are the classic drugs in clinical photodynamic therapy (PDT), but the hypoxia of tumor environment and the rapid oxygen consumption of PDT severely weaken their therapeutic effect. A recently reported water-dependent reversible photoacidity therapy (W-RPAT) is O2-independence, providing a solution for the treatment of hypoxic tumors. In this work, TPP-O-PEG5, a porphyrin derivative with binary properties of PDT and W-RPAT, is designed and synthesized for the first time. The nanoparticles (NPs) of TPP-O-PEG5 encapsulated with DSPE-mPEG2000, an amphiphilic polymer approved by Food and Drug Administration, can simultaneously produce reactive oxygen species and H+ under irradiation of a 660nm laser, and revert the H+ back under darkness, presenting strong phototoxicity to multiple tumor cell lines with no obvious difference between the IC50 values tested under normoxic (≈20% O2) and hypoxic (<0.5% O2) conditions. Excitingly, in vivo experiments show that the therapeutic effect of TPP-O-PEG5 NPs on large hypoxic tumors is better than that of NPe6, a clinical porphin PDT drug. This work provides a novel strategy for porphyrin photosensitizers to break through the limitation of hypoxic environment, and significantly improve the phototherapeutic effect on hypoxic tumors.

Successful Treatment of Erosive Lichen Planus With Tofacitinib: A Case Series and Review of the Literature.

Lichen planus (LP) is an inflammatory disease that affects the skin, hair, nails and mucous membranes. Erosive LP is a chronic and difficult-to-treat subtype of lichen planus, characterized by lesions on mucosal surfaces, particularly in the oral and genital areas. The prevalence of erosive LP has not been determined. To date, treatment has consisted of surgical intervention, photodynamic therapy, laser therapy, and systemic or topical drugs, including steroids and immunomodulatory agents. LP usually need longer periods of treatment and are known as precancerous lesions with a 0.4% to 12% conversion rate. In addition, nearly 25% of patients who develop erosive LP of the vulva are resistant to topical corticosteroids, which are the first choice of treatment. This study reports 6 cases with a mean age of 3.33 years, who were diagnosed with erosive LP lesions and previously failed in treatment with local, intralesional, and systemic steroids, and hydroxychloroquine. These patients were then treated with 10 mg of tofacitinib per day. Interestingly, with the new treatment, the patients' mean overall satisfaction score was 9.16 out of 10 (range: 8-10), the mean pain relief score was 9.16 out of 10 (range: 9-10) and patients' symptom improvement also began an average of 1.33 months after starting treatment (range: 1-2.5 months).

Nanomaterials for light-mediated therapeutics in deep tissue.

Light-mediated therapeutics, including photodynamic therapy, photothermal therapy and light-triggered drug delivery, have been widely studied due to their high specificity and effective therapy. However, conventional light-mediated therapies usually depend on the activation of light-sensitive molecules with UV or visible light, which have poor penetration in biological tissues. Over the past decade, efforts have been made to engineer nanosystems that can generate luminescence through excitation with near-infrared (NIR) light, ultrasound or X-ray. Certain nanosystems can even carry out light-mediated therapy through chemiluminescence, eliminating the need for external activation. Compared to UV or visible light, these 4 excitation modes penetrate more deeply into biological tissues, triggering light-mediated therapy in deeper tissues. In this review, we systematically report the design and mechanisms of different luminescent nanosystems excited by the 4 excitation sources, methods to enhance the generated luminescence, and recent applications of such nanosystems in deep tissue light-mediated therapeutics.

Endoplasmic reticulum and mitochondrial double-targeted NIR photosensitizer synergistically promote tumor cell death

The excessive production of reactive oxygen species (ROS) can damage the mitochondrial membrane and induce apoptosis, causing endoplasmic reticulum stress and triggering immunogenic cell death. Therefore, the combination of apoptosis and immunogenic death by the dual-targeted ROS generator has great potential to address inefficient cancer treatment. A near-infrared photosensitizer was developed for efficient ROS production and dual-targeted cancer treatment. Due to the modulation of electron structure, the reduced transition energy barrier affords TCy5-I-3F the highest efficiency to produce ROS. TCy5-I-3F has excellent mitochondrial and endoplasmic reticulum targeting ability, causing cell apoptosis and stress of the endoplasmic reticulum for destroying cancer cells. In the dual-targeted mode, high expression of GRP780, activation of heat shock protein (HSP70), the outflow of high mobility group protein B1, efflux of Calreticulin, and massive efflux of adenosine triphosphate are evaluated in the pharmacological experiments. In vivo experiments, the maturation of dendritic cells (DC, CD80+, CD86+), CD8+ T cells and CD3+ T cells also highlights the effectiveness. The tumors of mice treated with TCy5-I-3F and near-infrared (NIR) light are significantly inhibited. The multifunctional targeting design and corresponding mechanisms prove a new insight for exploring efficient photodynamic therapy drugs.