LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.

BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.

Palladium-Catalyzed Hydrogenation of Black Barium Titanate for Multienzyme-Piezoelectric Synergetic Tumor Therapy.

Piezocatalytic tumor therapy is an emerging reactive oxygen species (ROS)-generating therapeutic approach that relies on piezoelectric polarization under ultrasound (US) irradiation. Optimizing ROS production is a primary objective for enhancing treatment efficiency. In this study, oxygen-vacancy-rich Pd-integrated black barium titanate (BTO) nanoparticles are rationally engineered to boost the ROS generation efficiency via the introduction of Pd. Pd-catalyzed hydrogenation at low temperatures narrows the bandgap of BTO and reduces the recombination rate of electron-hole pairs. Furthermore, Pd has dual-enzyme-mimicking characteristics, including peroxidase- and catalase-mimicking activities, which further heighten the therapeutic efficacy by enhancing ROS production and reversing the hypoxic tumor microenvironment. Importantly, the dual enzymatic activity of Pd can be amplified by multiple redox processes sparked by the piezoelectric potential under US stimulation, resulting in bilaterally enhanced multienzyme-piezoelectric synergetic therapy. In vitro and in vivo results confirm high tumor inhibition in murine breast cancer cells. This work stresses the critical effects of defect engineering-optimized piezodynamic tumor therapy.

Phase-transition nanodroplets with immunomodulatory capabilities for potentiating mild magnetic hyperthermia to inhibit tumour proliferation and metastasis.

BACKGROUND: Magnetic hyperthermia (MHT)-mediated thermal ablation therapy has promising clinical applications in destroying primary tumours. However, traditional MHT still presents the challenges of damage to normal tissues adjacent to the treatment site and the destruction of tumour-associated antigens due to its high onset temperature (> 50 °C). In addition, local thermal ablation of tumours often exhibits limited therapeutic inhibition of tumour metastasis. RESULTS: To address the above defects, a hybrid nanosystem (SPIOs + RPPs) was constructed in which phase transition nanodroplets with immunomodulatory capabilities were used to potentiate supermagnetic iron oxide nanoparticle (SPIO)-mediated mild MHT (< 44 °C) and further inhibit tumour proliferation and metastasis. Magnetic-thermal sensitive phase-transition nanodroplets (RPPs) were fabricated from the immune adjuvant resiquimod (R848) and the phase transition agent perfluoropentane (PFP) encapsulated in a PLGA shell. Because of the cavitation effect of microbubbles produced by RPPs, the temperature threshold of MHT could be lowered from 50℃ to approximately 44℃ with a comparable effect, enhancing the release and exposure of damage-associated molecular patterns (DAMPs). The exposure of calreticulin (CRT) on the cell membrane increased by 72.39%, and the released high-mobility group B1 (HMGB1) increased by 45.84% in vivo. Moreover, the maturation rate of dendritic cells (DCs) increased from 4.17 to 61.33%, and the infiltration of cytotoxic T lymphocytes (CTLs) increased from 10.44 to 35.68%. Under the dual action of mild MHT and immune stimulation, contralateral and lung metastasis could be significantly inhibited after treatment with the hybrid nanosystem. CONCLUSION: Our work provides a novel strategy for enhanced mild magnetic hyperthermia immunotherapy and ultrasound imaging with great clinical translation potential.

[Immune-related Adverse Events Induced by ICIs in Advanced NSCLC:
A Meta-analysis and Systematic Review].

BACKGROUND: In recent years, immune checkpoint inhibitors (ICIs) have become a hot spot in cancer because of their remarkable survival benefits on non-small cell lung cancer (NSCLC) patients. However, the immune-related adverse events (ir-AEs) induced by ICIs have been frequently reported due to its specificity and severity. This article is to summarize and evaluate ir-AEs induced by ICIs. Hopefully it can provide guidance for advanced NSCLC patients treatment options, early recognition and management of ir-AEs. METHODS: Randomized controlled trials (RCT) which involved ICIs in the treatment of advanced NSCLC were retrieved in the Cochrane Libraby, PubMed, EMBASE and other databases. The primary outcome includes the incidence, grade and organ specificity of ir-AEs. Relative risk (RR) was used as the effect size, which was expressed as 95% confidence interval (CI). The Stata 15.0 and RevMan 5.3 software are used to conduct the meta analysis. RESULTS: A total of 17 RCTs were included. The ir-AEs were generally more than those in the traditional chemotherapy group. The risk and severity of ir-AEs induced by ICIs combined group were generally higher than that of ICI monotherapy, while the incidence of severe ir-AEs induced by ICIs combination therapy was similar to that of anti-cytotoxic T-lymphocyte-asscociated antigen 4 (CTLA-4) group. CONCLUSIONS: ICIs have different toxicity profile compared with chemotherapy, and their immune-related toxicity is stronger than that of traditional chemotherapy. ICIs induced ir-AEs is organ-specific, and different ICI has specific immune-related toxicity profiles. As ICIs represent a new and distinct class of treatment for NSCLC, this article has systematically illustrated the efficacy and ir-AEs induced by ICIs, hopefully it can be useful for clinicians and patients to get a further understanding of ICIs, and facilitate early prediction, comprehensive diagnosis, and prompt management of ir-AEs by providing status reference and management suggestions, so that ICI can bring more benefit for advanced NSCLC patients.

GMDS knockdown impairs cell proliferation and survival in human lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer and one of the most lethal and prevalent cancers. Aberrant glycosylation was common and essential in tumorigenesis, with fucosylation as one of the most common types disrupted in cancers. However, it is still unknown whether genes involved in fucosylation are important for lung adenocarcinoma development and process. METHODS: GMDS is involved in cellular fucosylation. Here we examined GMDS expression level at both mRNA and protein level in lung adenocarcinoma. The impact of GMDS knockdown on lung adenocarcinoma in vitro and in vivo was investigated. Transcriptome changes with GMDS knockdown in lung adenocarcinoma cells were also examined to provide insights into related molecular mechanisms. RESULTS: GMDS expression is significantly upregulated in lung adenocarcinoma at both mRNA and protein levels. Lentivirus-mediated shRNA strategy inhibited GMDS expression efficiently in human lung adenocarcinoma cells A549 and H1299, and GMDS knockdown impaired cell proliferation, colony formation ability, induced cell cycle arrest, and apoptosis in both cell lines. Furthermore, GMDS knockdown inhibited tumorigenesis in a xenograft mice model of lung adenocarcinoma. Microarray analysis explored the GMDS-mediated molecular network and revealed that the CASP8-CDKN1A axis might be critical for lung adenocarcinoma development. CONCLUSIONS: These findings suggest that GMDS upregulation is critical for cell proliferation and survival in human lung adenocarcinoma and might serve as a potential biomarker for lung adenocarcinoma diagnosis and treatment.