Tumor Stimulus-Activatable Pretheranostic Agent: One Key to Three Locks.

The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of tumor-specific systems is highly desirable. In this work, a general design of tumor stimulus-activatable pretheranostic agents was put forward via a series of structures-tunable triphenylamine derivatives (TPA-2T-FSQ, TPA-2T-BSZ, and TPA-2T-ML) with phenothiazine, benzothiazine, and thiomorpholine as identifying groups of hypochlorite (HClO), respectively. Notably, the sulfur atom in phenothiazine of TPA-2T-FSQ was more easily oxidized to sulfoxide groups by HClO, transforming into an electron acceptor to form an excellent push-pull electronic system, which was beneficial to a large redshift of absorbance and emission wavelengths. Based on this, TPA-2T-FSQ resorted to a key of overexpressed HClO in the tumor to open "three locks", viz, NIR fluorescence, photothermal, and photoacoustic signals for multimodal diagnostic and treatment of the tumor. This study provided an elegant design to adopt tumor stimulus-triggerable pretheranostic for improving theranostic accuracy and efficiency, which was regarded as a promising candidate for precision medicine.

Near-infrared light activated photosensitizer with specific imaging of lipid droplets enables two-photon excited photodynamic therapy.

Two-photon excited phototherapy has attracted considerable attention due to its advantages such as deeper penetration depth and higher spatial resolution. The lack of a high-performance photosensitizer with large two-photon absorption cross-sections and specific targeting ability makes the efficacy of phototherapy in the treatment of cancer unsatisfactory. Here, a new BODIPY-derived photosensitizer 6DBF2 is designed with two-photon photosensitization for two-photon excited photodynamic therapy in vivo. 6DBF2 possesses good two-photon absorption and efficient 1O2 generation upon near-infrared laser excitation. Excellent targeting specificities to lipid droplets of 6DBF2 without any encapsulation or modification at a low working concentration of 0.1 µM is in favor of efficient photodynamic therapy. In vitro cancer cell ablation and in vivo tumor ablation inside mice models upon two-photon irradiation in NIR demonstrate the outstanding therapeutic performance of 6DBF2 in two-photon excited photodynamic therapy. This work thus discusses a rare example of lipid droplets targeting two-photon excited photodynamic therapy for deep cancer tissue imaging and treatment under near-infrared light irradiation.

Self-Monitoring the Endo-Lysosomal Escape and Near-Infrared-Activated Mitophagy To Guide Synergistic Type-I Photodynamic and Photothermal Therapy.

Considering the multiple biological barriers before the entry of photosensitizers (PSs) into cytoplasm, it is of paramount importance to track PSs to elucidate their behaviors and distributions to guide the photodynamic therapy (PDT). Also, the developed PSs suffer from strong oxygen dependency. However, reports on such ideal theranostic platforms are rare. Herein, we developed a theranostic platform (CMTP-2) based on the coumarin-based D-π-A system, which, for the first time, can reveal the holistic intracellular delivery pathway and near-infrared (NIR)-activated mitophagy to guide synergistic type-I PDT and photothermal therapy. The dynamic endo-lysosomal escape of CMTP-2 was monitored, as well as its changeable distributions in endosomes, lysosomes, and mitochondria, demonstrating the preferential accumulation in mitochondria at the end. Upon NIR-I irradiation, CMTP-2 generated toxic radicals and heat, triggering the execution of mitophagy and apoptosis. In vivo experiments on mice indicated that CMTP-2 under 808 nm irradiation realized complete cancer ablation, showing great potential for advancements in synergistic phototherapy.

Defective transition metal hydroxide-based nanoagents with hypoxia relief for photothermal-enhanced photodynamic therapy.

Recently, phototherapy has attracted much attention due to its negligible invasiveness, insignificant toxicity and excellent applicability. The construction of a newly proposed nanosystem with synergistic photothermal and photodynamic tumor-eliminating properties requires a delicate structure design. In this work, a novel therapeutic nanoplatform (denoted as BCS-Ce6) based on defective cobalt hydroxide nanosheets was developed, which realized hypoxia-relieved photothermal-enhanced photodynamic therapy against cancer. Defective cobalt hydroxide exhibited high photothermal conversion efficacy at the near-infrared region (49.49% at 808 nm) as well as enhanced catalase-like activity to produce oxygen and greatly boost the singlet oxygen generation by a photosensitizer, Ce6, realizing efficacious dual-modal phototherapy. In vivo and in vitro experiments revealed that BCS-Ce6 can almost completely extinguish implanted tumors in a mouse model and present satisfactory biocompatibility during the treatment. This work sets a new angle of preparing photothermal agents and constructing comprehensive therapeutic nanosystems with the ability to modulate the hypoxic tumor microenvironment for efficient cancer therapy.

A novel flurophore-cyano-carboxylic-Ag microhybrid: Enhanced two photon absorption for two-photon photothermal therapy of HeLa cancer cells by targeting mitochondria.

In this study, a novel two-photon photothermal therapy (TP-PTT) agent based on an organic-metal microhybrid with surface Plasmon resonance (SPR) enhanced two-photon absorption (TPA) characteristic was designed and synthesized using a fluorescent cyano-carboxylic derivative 2-cyano-3-(9-ethyl-9H-carbazol-3-yl) -acrylic acid (abbreviated as CECZA) and silver nanoparticles through self-assembly process induced by the interfacial coordination interactions between the O/N atom of CECZA and Ag+ion at the surface of Ag nanoparticles. The coordination interactions caused electron transfer from the Ag nanoparticles to CECZA molecules at the excited state, resulting in a decreased fluorescence quantum yield. The interfacial coordination interactions also enhanced the nonlinear optical properties, including 13 times increase in the TPA cross-section (δ). The decreased fluorescence quantum yield and increased two photon absorption caused by the SPR effect led excellent two-photon photothermal conversion, which was beneficial for the TP-PTT effect on HeLa cancer cells.

Activated carbon N-acetylcysteine microcapsule protects against nonalcoholic fatty liver disease in young rats via activating telomerase and inhibiting apoptosis.

Non-alcoholic fatty liver disease (NAFLD) is becoming one of the world's most common chronic liver diseases in childhood, yet no therapy is available that has been approved by the food and drug administration (FDA). Previous studies have reported that telomere and telomerase are involved the development and progression of NAFLD. This study was designed to investigate the potential beneficial effects of activated carbon N-acetylcysteine (ACNAC) microcapsules on the development of NAFLD in young rats as well as the underlying mechanism(s) involved. Three-week old male Sprague Dawley rats were given high-fat diet (HFD) with/without ACNAC treatment for 7 consecutive weeks. Liver pathologies were determined by hematoxylin and eosin (H&E) and Oil Red O staining, as well as by changes in biochemical parameters of plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, respectively. Glucose homeostasis was evaluated by the glucose tolerance test and the liver telomere length and activity were measured by real time PCR and telomeric repeat amplification protocol (TRAP). Western blot analysis was performed to determine the expression level of Bcl-2, Bax and Caspase-3. Our results demonstrated that ACNAC supplementation improved liver pathologies of rats that received long-term HFD feeding. ACNAC supplementation prevented HFD-induced telomere shortening and improved telomerase activity. Moreover, in comparison to HFD-fed rats, ACNAC supplementation markedly increased the expression of Bcl-2, but significantly decreased the expression of Bax and Caspase-3 in juvenile rats. Together, these results indicate that ACNAC may be a promising choice for preventing and treating NAFLD among children.

[The protective effect of N-acetylcysteine magnesium against liver cirrhosis with portal hypertension in rat].

OBJECTIVE: To study the effects of acetylcysteine magnesium on the vasoactive substances and hepatic fibrosis indexes in liver cirrhosis and portal hypertension of rats. METHODS: The rat liver cirrhosis model was made with 12 microg/kg dimethylnitrosamines. Then acetylcysteine magnesium was injected respectively with 25, 50, and 100 mg x kg(-1) dose daily into abdominal cavity. After 8 weeks treatment, pathological section, TGF-beta1, NO, TNOS and iNOS of hepatic tissue were detected to assess the effect of acetylcysteine magnesium against cirrhosis portal hypertension. RESULTS: After the DMNA modeling was completed, the HE and Sweet reticulocyte staining of liver pathological section showed that cirrhosis of the liver was in the III-IV phase, the infiltration of lymphocytes and formation of pseudolobuli in liver were alleviated in three acetylcysteine magnesium treatment groups (low, medium, and high dose), and the degree of liver fiber sclerosis in three groups was significantly lower than control group. Compared with control group, TGF-beta1, NO, TNOS and iNOS were significantly reduced in all treatment groups (P < 0.05). CONCLUSION: Acetylcysteine magnesium is probably a distinctive antioxidant which can remove various free radical in body and modulate ligand-dependent signal transduction and the growth of cell. It also have protection in the liver cirrhosis and portal hypertension of rats induced by dimethylnitrosamine.