The development of efficient organic sonosensitizers is crucial for sonodynamic therapy (SDT) in the field of cancer treatment. Herein, a new strategy for the development of efficient organic sonosensitizers based on triarylboron‐doped acenethiophene scaffolds is presented. The attachment of boron to the linear acenethiophenes lowers the lowest unoccupied molecular orbital (LUMO) energy, resulting in redshifted absorptions and emissions. After encapsulation with the amphiphilic polymer DSPE‐mPEG2000, it is found that the nanostructured BAnTh‐NPs and BTeTh‐NPs (nanoparticles of BAnTh and BTeTh) shows efficient hydroxyl radical (•OH) generation under ultrasound (US) irradiation in aqueous solution with almost no phototoxicity, which can overcome the shortcomings of O2‐dependent SDT and avoid the potential cutaneous phototoxicity issue. In vitro and in vivo therapeutic results validate that boron‐doped acenethiophenes as sonosensitizers enable high SDT efficiency with low phototoxicity and good biocompatibility, indicating that boron‐functionalization of acenes is a promising strategy toward organic sonosensitizers for SDT.

Triarylboron‐Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low Phototoxicity

Sonodynamic therapy (SDT) has emerged as a promising therapeutic modality for anticancer treatments and is becoming a cutting-edge interdisciplinary research field. This review starts with the latest developments of SDT and provides a brief comprehensive discussion on ultrasonic cavitation, sonodynamic effect, and sonosensitizers in order to popularize the basic principles and probable mechanisms of SDT. Then the recent progress of MOF-based sonosensitizers is overviewed, and the preparation methods and properties (e.g., morphology, structure, and size) of products are presented in a fundamental perspective. More importantly, many deep observations and understanding toward MOF-assisted SDT strategies were described in anticancer applications, aiming to highlight the advantages and improvements of MOF-augmented SDT and synergistic therapies. Last but not least, the review also pointed out the probable challenges and technological potential of MOF-assisted SDT for the future advance. In all, the discussions and summaries of MOF-based sonosensitizers and SDT strategies will promote the fast development of anticancer nanodrugs and biotechnologies.

Metal-Organic Frameworks (MOF)-Assisted Sonodynamic Therapy in Anticancer Applications.

State of the Art Advancements in Sonodynamic Therapy (SDT): Metal-Organic Frameworks for SDT

Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair. Bacterial-host competition for micronutrients and inefficient immune responses undermine antimicrobial immunotherapy. Su et al. design an immunostimulatory metalloantibiotic and explore potential sono-metalloimmunotherapy (SMIT) for the treatment of clinical orthopaedic infections, in a murine model.

biodegradable

The intelligent responsive drug delivery system has great application potential in cancer precision therapy. Although many antitumor methods have been developed based on drug delivery systems, most of them yet suffer from poor antitumor efficiency. In this project, a near-infrared and pH dual-response multimodal collaborative platform for diagnosis and treatment (PCN-DOX@PDA) was constructed. We used PCN-600 as a vehicle loaded with antineoplastic drugs and polydopamine (PDA). Under 633 nm laser irradiation, the ligand tetrakis(4-carboxyphenyl)porphyrin (TCPP) in PCN-600 can generate singlet oxygen (1O2) and kill tumor cells. PDA is used as photothermal agent of PTT. PCN-DOX@PDA achieves the intelligent release of antitumor drugs by responding to the weak acidity of the tumor microenvironment and thermal stimulation generated by NIR irradiation. In addition, since the central ion of PCN is Fe3+, PCN-DOX@PDA realizes the diagnosis and treatment of tumors through magnetic resonance imaging-mediated tumor chemotherapy and photothermal and photodynamic synergistic therapy. This triple synergistic strategy showed excellent biocompatibility and antitumor ability in in vivo experiments on a 4T1 tumor-bearing mouse model, indicating that PCN-DOX@PDA has a good development prospect in the field of precision cancer therapy and diversified biomedical applications.

Dual-Responsive Triple-Synergistic Fe-MOF for Tumor Theranostics.

Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.

Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/ejp.1534

Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model

Recent studies have demonstrated the vital role of P2X4 receptors (a family of ATP-gated non-selective cation channels) in the transmission of neuropathic and inflammatory pain. In this study, we investigated the role of spinal P2X4 receptors in chronic functional visceral hypersensitivity of neonatal maternal separation (NMS) rats. A rat model of irritable bowel syndrome was established by neonatal maternal separation. Visceral sensitivity was assessed by recording the response of the external oblique abdominal muscle to colorectal distension. P2X4 receptor antagonist and agonist were administrated intrathecally. The expression of P2X4 receptor was examined by Western Blot and immunofluorescence. The effect of P2X4 receptor antagonist on expression of brain-derived neurotrophic factor (BDNF) was assessed by Western Blot. We found neonatal maternal separation enhanced visceral hypersensitivity and increased the expression of P2X4 receptor in spinal thoracolumbar and lumbosacral segments of rats. Pharmacological results showed that visceral sensitivity was attenuated after intrathecal injection of P2X4 receptor antagonist, 5-BDBD, at doses of 10 nM or 100 nM, while visceral sensitivity was enhanced after intrathecal injection of P2X4 receptor agonist C5-TDS at doses of 10 μM or 15 μM. In addition, the spinal expression of BDNF significantly increased in NMS rats and intrathecal injection of 5-BDBD significantly decreased the expression of BDNF especially in NMS rats. C5-TDS failed to increase EMG amplitude in the presence of ANA-12 in control rats. Our results suggested the spinal P2X4 receptors played an important role in visceral hypersensitivity of NMS rats through BDNF. 

Spinal P2X4 Receptors Involved in Visceral Hypersensitivity of Neonatal Maternal Separation Rats

Background Irritable bowel syndrome (IBS) is one of the typical representatives of chronic functional visceral pain that lacks effective treatment. Recently, attention has been given to the role of microglia in IBS, particularly the activation of spinal microglia and the subsequent release of Cathepsin S (Cat S), a proteolytic enzyme. However, the specific role of spinal Cat S in IBS remains to be elucidated. The purpose of this study is to investigate the mechanisms underlying the regulation of visceral hypersensitivity in IBS-like rats by Cat S. Methods An IBS-like rat model was developed, and visceral sensitivity was tested via the electromyographic (EMG) response to colorectal distention (CRD) and pain threshold. Western blot and immunofluorescence were used to examine the expressions of proteins. The effects of inhibitors or neutralizing antibodies on visceral pain and the downstream molecular expressions were detected. The open-field test was performed to evaluate locomotor activity and anxiety-like behaviors in rats. Results We discovered that spinal Cat S was upregulated and colocalized with microglia in IBS-like rats. Treatment with LY3000328, a selective inhibitor of Cat S, dose-dependently down-regulated EMG amplitude and Fractalkine (FKN) expression, indicating that Cat S regulated visceral hypersensitivity via activating FKN in IBS-like rats. Furthermore, the expressions of FKN, CX3CR1, and p-p38 MAPK were elevated in IBS-like rats whereas inhibition of these molecules could alleviate visceral pain. Moreover, pharmacological inhibitor experiments suggested the activation of CX3CR1 by FKN facilitated p38 MAPK phosphorylation, which in turn promoted Cat S expression in IBS-like rats. Conclusions Neonatal adverse stimulation might enhance the expression of spinal microglial Cat S, thereby activating the FKN/CX3CR1/p38 MAPK pathway and lead to visceral hypersensitivity in IBS-like rats. As a selective inhibitor of Cat S, LY3000328 could become a potential therapeutic option for IBS.

https://journals.sagepub.com/doi/pdf/10.1177/17448069231179118

Spinal Cathepsin S promotes visceral hypersensitivity via FKN/CX3CR1/p38 MAPK signaling pathways

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Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.

Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model

Spinal P2X4 Receptors Involved in Visceral Hypersensitivity of Neonatal Maternal Separation Rats

Spinal Cathepsin S promotes visceral hypersensitivity via FKN/CX3CR1/p38 MAPK signaling pathways