A BRD4-Targeting Photothermal Agent for Controlled Protein Degradation.

BRD4 protein plays a pivotal role in cell cycle regulation and differentiation. Disrupting the activity of BRD4 has emerged as a promising strategy for inhibiting the growth and proliferation of cancer cells. Herein, we introduced a BRD4-targeting photothermal agent for controlled protein degradation, aiming to enhance low-temperature photothermal therapy (PTT) for cancer treatment. By incorporating a BRD4 protein inhibitor into a cyanine dye scaffold, the photothermal agent specifically bond to the bromodomain of BRD4. Upon low power density laser irradiation, the agent induced protein degradation, directly destroying the BRD4 structure and inhibiting its transcriptional regulatory function. This strategy not only prolonged the retention time of the photothermal agent in cancer cells but also confined the targeted protein degradation process solely to the tumor tissue, minimizing side effects on normal tissues through the aid of exogenous signals. This work established a simple and feasible platform for future PTT agent design in clinical cancer treatment.

GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy.

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.

A Protein-Binding Molecular Photothermal Agent for Tumor Ablation.

Photothermal therapy usually requires a high power density to activate photothermal agent for effective treatment, which inevitably leads to damage to normal tissues and inflammation in tumor tissues. Herein, we rationally design a protein-binding strategy to build a molecular photothermal agent for photothermal ablation of tumor. The synthesized photothermal agent can covalently bind to the thiol groups on the intracellular proteins. The heat generated by the photothermal agent directly destroyed the bioactive proteins in the cells, effectively reducing the heat loss and the molecular leakage. Under a low power density of 0.2 W cm-2 , the temperature produced by the photothermal agent was sufficient to induce apoptosis. In vitro and in vivo experiments showed that the therapeutic effect of photothermal therapy can be efficiently improved with the protein-binding strategy.

Asymmetric kinetic resolution of sulfides for the construction of unsymmetric sulfides and chiral 3,3-disubstituted oxindoles.

A range of 3,3-disubstituted oxindoles accessed using para-quinone methides derived from isatins with thiols were used for the formation of unsymmetrical disulfides, and 3,3-disubstituted oxindoles with a chiral quaternary carbon center and unsymmetric disulfides could also be directly obtained with high selectivities catalyzed by chiral phosphines in one step.

Interleukin-6 deficiency facilitates myocardial dysfunction during high fat diet-induced obesity by promoting lipotoxicity and inflammation.

OBJECTIVE: Obesity is associated with metabolic disorder and chronic inflammation that plays a crucial role in cardiovascular diseases. IL-6 is involved in regulating obesity-related lipid metabolism and inflammation. In this study, we sought to determine the role of IL-6 in high-fat diet (HFD)-induced cardiomyopathy and explore the signaling pathway. METHODS: Female, 5-week-old IL-6 knockout (KO) and littermate mice were fed a normal diet (ND, 10% fat) or HFD (45% fat) for 14 weeks. At the end of treatment, cardiac function was assessed by echocardiography. Adipose tissues and plasma were collected for further measurement. Immunohistology of CD68 was performed to detect inflammation in the heart. Masson's trichrome staining and Oil Red O staining was applied to evaluated cardiac fibrosis and lipid accumulation. Real-time PCR and Western immunoblotting analyses on heart tissue were used to explore the underlying mechanism. RESULTS: IL-6 KO mice displayed increased insulin resistance compared to WT mice at baseline. When fed HFD, IL-6 KO mice showed decreased gains in body weight and fat mass, increased insulin resistance relative to IL-6 KO mice feed ND. Furthermore, IL-6 KO mice developed cardiac dysfunction during HFD-induced obesity. Histological analysis suggested increased lipid accumulation, fibrosis and inflammation without affecting cardiac morphology during HFD treatment in the heart of IL-6 KO mice. Finally, IL-6 deficiency increased the phosphorylation of AMPK and ACC in the heart during HFD-induced obesity. CONCLUSION: Our results suggest that IL-6 contributes to limit lipid metabolic disorder, cardiac hypertrophy, fibrosis, inflammation and myocardium lipotoxicity during HFD-induced obesity.

A Golgi Apparatus-Targeted Photothermal Agent with Protein Anchoring for Enhanced Cancer Photothermal Therapy.

The Golgi apparatus (GA) is central in shuttling proteins from the endoplasmic reticulum to different cellular areas. Therefore, targeting the GA to precisely destroy its proteins through local heat could induce apoptosis, offering a potential avenue for effective cancer therapy. Herein, a GA-targeted photothermal agent based on protein anchoring is introduced for enhanced photothermal therapy of tumor through the modification of near-infrared molecular dye with maleimide derivative and benzene sulfonamide. The photothermal agent can actively target the GA and covalently anchor to its sulfhydryl proteins, thereby increasing its retention within the GA. Under laser irradiation, the heat generated by the photothermal agent efficiently disrupts sulfhydryl proteins in situ, leading to GA dysfunction and ultimately inducing cell apoptosis. In vivo experiments demonstrate that the photothermal agent can precisely treat tumors and significantly reduce side effects.

Activated tissue-resident macrophages contribute to hair cell insults in noise-induced hearing loss in mice.

Macrophages serve as the primary immune cell population and assume a pivotal role in the immune response within the damaged cochleae. Yet, the origin and role of macrophages in response to noise exposure remain controversial. Here, we take advantage of Ccr2RFP/+ Cx3cr1GFP/+ dual-reporter mice to identify the infiltrated and tissue-resident macrophages. After noise exposure, we reveal that activated resident macrophages change in morphology, increase in abundance, and migrate to the region of hair cells, leading to the loss of outer hair cells and the damage of ribbon synapses. Meanwhile, peripheral monocytes are not implicated in the noise-induced hair cell insults. These noise-induced activities of macrophages are abolished by inhibiting TLR4 signaling, resulting in alleviated insults of hair cells and partial recovery of hearing. Our findings indicate cochlear resident macrophages are pro-inflammatory and detrimental players in acoustic trauma and introduce a potential therapeutic target in noise-induced hearing loss.

A small-molecule Fenton reagent for self-augmented chemodynamic therapy by intelligently regulating intracellular acidosis.

A small-molecule Fenton reagent, integrating ferrocene with a carbonic anhydrase inhibitor, was designed to intelligently regulate intracellular acidosis for self-augmented chemodynamic therapy. Acidosis coupled with up-regulated ROS levels demonstrated potent cytotoxicity and effective tumor suppression.

Electrical stimulation of cochlear implant promotes activation of macrophages and fibroblasts under inflammation.

Objectives: The implanted electrodes deliver electric signals to spiral ganglion neurons, conferring restored hearing of cochlear implantation (CI) recipients. Postimplantation intracochlear fibrosis, which is observed in most CI recipients, disturbs the electrical signals and impairs the long-term outcome of CI. The macrophages and fibroblasts activation is critical for the development of intracochlear fibrosis. However, the effect of electric stimulation of cochlear implant (ESCI) on the activity of macrophages and fibroblasts was unclear. In the present study, a human cochlear implant was modified to stimulate cultured macrophages and fibroblasts. Methods: By measuring cellular marker and the expression level of cytokine production, the polarization and activity of macrophages and fibroblasts were examined with or without ESCI. Results: Our data showed that ESCI had little effects on the morphology, density, and distribution of culturing macrophages and fibroblasts. Furthermore, ESCI alone did not affect the polarization of macrophages or the function of fibroblasts without the treatment of inflammatory factors. However, in the presence of LPS or IL-4, ESCI further promoted the polarization of macrophages, and increased the expression of pro-inflammatory or anti-inflammatory factors, respectively. For fibroblasts, ESCI further increased the collagen I synthesis induced by TGF-ß1 treatment. Nifedipine inhibited ESCI induced calcium influx, and hereby abolished the promoted polarization and activation of macrophages and fibroblasts. Conclusion: Our results suggest that acute inflammation should be well inhibited before the activation of cochlear implants to control the postoperative intracochlear fibrosis. The voltage-gated calcium channels could be considered as the targets for reducing postimplantation inflammation and fibrosis. Level of Evidence: NA.

Fabrication of betamethasone micro- and nanoparticles using supercritical antisolvent technology: In vitro drug release study and Caco-2 cell cytotoxicity evaluation.

Poor solubility limits the pharmacological activities of betamethasone (BM), including its anti-inflammatory and anti-allergic effects. To improve the aqueous solubility and dissolution rate of BM, supercritical antisolvent (SAS) technology was used to prepare BM microparticles and BM-polyvinylpyrrolidone (PVP) solid dispersion nanoparticles. The effects of temperature, pressure, solution feeding rate, and drug concentration on particle formation were investigated using both single-factor and orthogonal experimental methods, and the optimal preparation process was screened. The physicochemical properties of the BM particles were characterized by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction. After the SAS process, the particle size was reduced significantly and the crystalline shape was altered, which considerably increased the solubility and dissolution rate of BM. Furthermore, the toxicity of BM to live cells was reduced because of the BM-PVP solid dispersions.

A hypoxia-activated photothermal agent inhibits multiple heat shock proteins for low-temperature photothermal therapy.

A near-infrared (NIR) organic photothermal agent (PTA) to inhibit three types of heat shock proteins (HSPs) was synthesized, which could be activated under hypoxic conditions for low-temperature photothermal therapy (PTT) of cancer.

An active tumor-targeting organic photochemotherapy agent with naproxen for enhanced cancer therapy.

An active tumor-targeting organic photochemotherapy agent via the combination of a an organic photothermal material and a naproxen prodrug was developed to precisely kill cancer cells and suppress the inflammatory response induced by cell necrosis; in vitro, and in vivo experiments illustrated its low cytotoxicity and excellent tumor inhibitory effect.

Imaging strategies for monitoring the immune response.

Real-time monitoring of the immune response can be used to evaluate the immune status of the body and to distinguish immune responders and non-responders, so as to better guide immunotherapy. Through direct labelling of immune cells and imaging specific biomarkers of different cells, the activation status of immune cells and immunosuppressive status of tumor cells can be visualized. The immunotherapeutic regimen can then be adjusted accordingly in a timely manner to improve the efficacy of immunotherapy. In this review, various imaging methods, immune-related imaging probes, current challenges and opportunities are summarized and discussed.

A heat shock protein-inhibiting molecular photothermal agent for mild-temperature photothermal therapy.

A heat shock protein-inhibiting photothermal agent (PTA) with endoplasmic reticulum targeting was synthesized to reduce the thermal resistance and enhance the effect of mild-temperature photothermal therapy (PTT).

A protein-conjugated photosensitizer with mitochondrial targeting for enhanced photodynamic therapy.

A protein-conjugated photosensitizer with mitochondrial targeting ability was synthesized to enhance the therapeutic effects of PDT. The ROS produced by the photosensitizer under laser irradiation could effectively destroy key intracellular proteins and disrupt mitochondrial redox homeostasis, thereby causing mitochondrial dysfunction and irreversible cell death.

Avoiding False Positive Signals: A Powerful and Reliable Au-Se Dual-Color Probe.

Nucleic acids as the important tumor markers play a crucial role in the identification of cancer. Various kinds of probes such as gold nanoparticles and graphene oxide have been explored to detect different nucleic acid markers. However, the existing probes are mostly used to detect a single tumor marker and susceptible to harsh conditions in the complex and dynamic physiological environment, which may lead to false positive results and greatly limit the sensing performance of the probe. Herein, a powerful and reliable Au-Se probe was developed for high-fidelity imaging of two cancer markers simultaneously in living cells. Compared with the traditional nucleic acid probe based on the Au-S bond, this probe was more stable against biological thiols and could effectively distinguish normal cells and cancer cells to avoid false positive results, which is more suitable for imaging in a complex physiological environment. This strategy will provide more valuable insights into designing and exploring novel biosensors in the future.

ATP-triggered mitochondrial cascade reactions for cancer therapy with nanoscale zeolitic imidazole framework-90.

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.

Stimuli-activated molecular photothermal agents for cancer therapy.

Taking advantage of activatable and imaging-guided properties, stimuli-activated molecular photothermal agents (MPTAs) have drawn great attention in photothermal therapy (PTT) over the past decades. In this review, the recent progress in the study of stimuli-activated MPTAs is summarized from different stimuli, including pH, bioactive small molecules, and enzymes. The features and challenges of stimuli-activated MPTAs are also discussed. This review aims to motivate readers to design and synthesise more efficient MPTAs.

Dual-targeted photothermal agents for enhanced cancer therapy.

Photothermal therapy, in which light is converted into heat and triggers local hyperthermia to ablate tumors, presents an inherently specific and noninvasive treatment for tumor tissues. In this area, the development of efficient photothermal agents (PTAs) has always been a central topic. Although many efforts have been made on the investigation of novel molecular architectures and photothermal materials over the past decades, PTAs can cause severe damage to normal tissues because of the poor tumor aggregate ability and high irradiation density. Recently, dual-targeted photothermal agents (DTPTAs) provide an attractive strategy to overcome these problems and enhance cancer therapy. DTPTAs are functionalized with two classes of targeting units, including tumor environment targeting sites, tumor targeting sites and organelle targeting sites. In this perspective, typical targeted ligands and representative examples of photothermal therapeutic agents with dual-targeted properties are systematically summarized and recent advances using DTPTAs in tumor therapy are highlighted.

A portable point-of-care testing system to diagnose lung cancer through the detection of exosomal miRNA in urine and saliva.

A lung cancer diagnostic kit (LCDK) with the advantages of low cost, easy operation and high sensitivity for the rapid diagnosis of lung cancer was developed. The proposed LCDK is able to noninvasively discriminate lung cancer using clinical salivary and urine samples in a short period of time.