Supramolecular H-Aggregates of Squaraines with Enhanced Type I Photosensitization for Combined Photodynamic and Photothermal Therapy.

Combined photodynamic and photothermal therapy (PDT and PTT) can achieve more superior therapeutic effects than the sole mode by maximizing the photon utilization, but there remains a significant challenge in the development of related single-molecule photosensitizers (PSs), particularly those with type I photosensitization. In this study, self-assembly of squaraine dyes (SQs) is shown to be a promising strategy for designing PSs for combined type I PDT and PTT, and a supramolecular PS (TPE-SQ7) has been successfully developed through subtle molecular design of an indolenine SQ, which can self-assemble into highly ordered H-aggregates in aqueous solution as well as nanoparticles (NPs). In contrast to the typical quenching effect of H-aggregates on reactive oxygen species (ROS) generation, our results encouragingly manifest that H-aggregates can enhance type I ROS (•OH) generation by facilitating the intersystem crossing process while maintaining a high PTT performance. Consequently, TPE-SQ7 NPs with ordered H-aggregates not only exhibit superior combined therapeutic efficacy than the well-known PS (Ce6) under both normoxic and hypoxic conditions but also have excellent biosafety, making them have important application prospects in tumor phototherapy and antibacterial fields. This study not only proves that the supramolecular self-assembly of SQs is an effective strategy toward high-performance PSs for combined type I PDT and PTT but also provides a different understanding of the effect of H-aggregates on the PDT performance.

Polyphenol-sodium alginate supramolecular injectable hydrogel with antibacterial and anti-inflammatory capabilities for infected wound healing.

Injectable hydrogel has attracted appealing attention for skin wound treatment. Although multifunctional injectable hydrogels can be prepared by introducing bioactive ingredients with antibacterial and anti-inflammatory capabilities, their preparation remains complicated. Herein, a polyphenol-based supramolecular injectable hydrogel (PBSIH) based on polyphenol gallic acid and biological macromolecule sodium alginate is developed as a wound dressing to accelerate wound healing. We show that such PBSIH can be rapidly formed within 15 s by mixing the sodium alginate and gallic acid solutions based on the hydrogen bonding and hydrophobic interactions. The PBSIH shows excellent cytocompatibility, antibacterial, and antioxidant properties, which enhance infected wound healing by inhibiting bacterial infection and alleviating inflammation after treatment of 11 days. Moreover, we show that the preparative strategies of injectable supramolecular hydrogels can be extended to other polyphenols, including protocatechuic and tannic acids. This study provides a facile yet highly effective method to design injectable polyphenol- sodium alginate hydrogel for wound dressing based on naturally bioactive ingredients.

Utilization and short-term outcomes of percutaneous left atrial appendage occlusion in patients with cancer.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) has been rapidly evolving since FDA's approval in 2015 and has become more of a same-day-discharge procedure. Cancer patient with atrial fibrillation/flutter (AF) population can benefit from the procedure but the in-hospital outcomes and readmission data were rarely studied. OBJECTIVES: We investigated the utilization, in-hospital and readmission outcomes in cancer patients with AF who underwent LAAO. METHODS: Data were derived from the National Inpatient Sample and National Readmissions Database from 2016 to 2019. Patients with primary diagnosis of AF admitted for LAAO (ICD-10 code 02L73DK) were grouped by cancer as a secondary diagnosis. We assessed in-hospital mortality, length of stay, total hospital charges, and complications. Thirty-day readmission rates were compared. RESULTS: LAAO was performed in 60,380 patients with AF and 3% were cancer patients. There were no differences in in-hospital mortality and total hospital charges; however, cancer patients tended to have longer hospital stay (1.59 ± 0.11 vs. 1.32 ± 0.02, p = 0.013). Among complications, cancer patients had higher rates in open or percutaneous pericardial drainage (adjusted odds ratio [aOR] 2.38; 95% confidence interval [CI] 1.19-4.76) and major bleeding events (aOR 7.07; 95% CI 1.82-27.38). There was no statistical significance of 30-day readmission rates between patients with and without cancer (10.0% vs. 9.1%, p = 0.34). The most common readmission reason in cancer patients was gastrointestinal bleeding. CONCLUSIONS: LAAO is a promising procedure in cancer patients complicated by AF with contraindication to anticoagulation. Readmission rate is comparable between patients with and without cancer.

l-Arginine-Modified CoWO4 /FeWO4 S-Scheme Heterojunction Enhances Ferroptosis against Solid Tumor.

Ferroptosis has recently attracted much attention as an anti-tumor therapy. Evidence suggests that ferroptosis can induce oxidative stress and accumulation of lethal lipid peroxides in cancer cells, leading to cell damage. However, unsuitable pH, H2 O2 levels, and high glutathione (GSH) expression in the tumor microenvironment hinder the development of ferroptosis-mediated therapy. In this study, an l-arginine (l-arg)-modified CoWO4 /FeWO4 (CFW) S-scheme heterojunction is strategically designed and constructed for ultrasound (US)-triggered sonodynamic- and gas therapy-induced ferroptosis. CFW not only has excellent Fenton-catalytic activity, outstanding GSH consumption capacity, and excellent ability to overcome tumor hypoxia, but its S-scheme heterostructure can also avoid the rapid combination of electron (e) and hole (h+ ) pairs, thereby enhancing the sonodynamic effects. As a precursor of nitric oxide (NO), l-arg is modified on the surface of CFW (CFW@l-arg) to achieve controlled NO release under US irradiation, thereby enhancing ferroptosis. In addition, poly(allylamine hydrochloride) is further modified on the surface of CFW@l-arg to stabilize l-arg and achieve controllable NO release. Both in vitro and in vivo results demonstrate that such a multifunctional therapeutic nanoplatform can achieve high therapeutic efficacy through sonodynamic and gas therapy-enhanced ferroptosis. This designed oncotherapy nanoplatform provides new inspiration for ferroptosis-mediated therapy.

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors.

Although phototherapy has attracted extensive attention in antitumor field in recent years, its therapeutic effect is usually unsatisfactory because of the complexity and variability of the tumor microenvironment (TME). Herein, we report novel CoSn(OH)6@CoOOH hollow carriers with oxidase properties that can enhance phototherapy. Hollow CoSn(OH)6@CoOOH nanocubes (NCs) with a particle size of ∼160 nm were synthesized via a two-step process of coprecipitation and etching. These NCs can react with O2 to generate singlet oxygen without hydrogen peroxide and consume glutathione, and their hollow structure can be utilized to carry drug molecules. After loading indocyanine green (ICG) and 1,2-bis(2-(4,5-dihydro-1H-imidazol-2-yl)propan-2-yl) diazene dihydrochloride (AIPH), the resulting nanosystem (HCIA) exhibited enhanced phototherapy effects through the catalytic activity of oxidase, production of alkyl radicals, and consumption of glutathione. Cell and mouse experiments showed that HCIA combined with near-infrared laser irradiation significantly inhibited the growth of 4T1 tumors. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that PI3K-Akt and MAPK signaling pathways were highly relevant to this therapeutic system. Such hollow NCs with oxidase activity have considerable potential for the design of multifunctional drug delivery vehicles for tumor therapy.

Morphological Transformation and In Situ Polymerization of Caspase-3 Responsive Diacetylene-Containing Lipidated Peptide Amphiphile for Self-Amplified Cooperative Antitumor Therapy.

In order to artificially regulate cell behaviors, intracellular polymerization as an emerging chemical technique has attracted much attention. Yet, it is still a challenge to achieve effective intracellular polymerization to conquer tumors in the complex cellular environment. Herein, this work develops a tumor-targeting and caspase-3 responsive nanoparticle composed of a diacetylene-containing lipidated peptide amphiphile and mitochondria-targeting photosensitizer (C3), which undergoes nanoparticle-to-nanofiber transformation and efficient in situ polymerization triggered by photodynamic treatment and activation of caspase-3. The locational nanofibers on the mitochondria membranes lead to mitochondrial reactive oxygen species (mtROS) burst and self-amplified circulation, offering persistent high oxidative stress to induce cell apoptosis. This study provides a strategy for greatly enhanced antitumor therapeutic efficacy through mtROS burst and self-amplified circulation induced by intracellular transformation and in situ polymerization.

Electrostatically Controlled ex Situ and in Situ Polymerization of Diacetylene-Containing Peptide Amphiphiles in Living Cells.

Precise control of diacetylene-containing peptide amphiphile (DPA) based supramolecular architectures is important for their in cellulo polymerization behaviors and biomedical applications. Herein, we reported two DPAs (cationic PA-NH2 and zwitterionic PA-OH) with a similar molecular structure, which exhibited completely opposite polymerization behaviors in aqueous solution and living cells. Specifically, PA-NH2 was unpolymerizable in aqueous solution but underwent in cellulo polymerization to respond to the intracellular microenvironment. On the contrary, zwitterionic PA-OH was polymerized in solution, rather than inside living cells. Based on the results of cell viability and total internal reflection fluorescent microscopy measurement, PA-OH exhibited higher affinity with cell membranes and lower cytotoxicity than those of PA-NH2. Therefore, it is suggested that the in cellulo polymerization of PA-NH2 should be responsive for greater cytotoxicity, rather than the membrane affinity. This study provides an in-depth understanding of the role of charge properties in the polymerization behavior of DPAs and seeks their potential biomedical applications.

Androgen-induced miR-135a acts as a tumor suppressor through downregulating RBAK and MMP11, and mediates resistance to androgen deprivation therapy.

The main challenge in the treatment of prostate cancer (PCa) is that the majority of patients inevitably develop resistance to androgen deprivation. However, the mechanisms involved in hormone independent behavior of PCa remain unclear. In the present study, we identified androgen-induced miR-135a as a direct target of AR. Functional studies revealed that overexpression of miR-135a could significantly decrease cell proliferation and migration, and induce cell cycle arrest and apoptosis in PCa. We identified RBAK and MMP11 as direct targets of miR-135a in PCa by integrating bioinformatics analysis and experimental assays. Mechanistically, miR-135a repressed PCa migration through downregulating MMP11 and induced PCa cell cycle arrest and apoptosis by suppressing RBAK. Consistently, inverse correlations were also observed between the expression of miR-135a and RBAK or MMP11 in PCa samples. In addition, low miR-135a and high RBAK and MMP11 expression were positively correlated with PCa progression. Also, PI3K/AKT pathway was confirmed to be an upstream regulation signaling of miR-135a in androgen-independent cell lines. Accordingly, we reported a resistance mechanism to androgen deprivation therapy (ADT) mediated by miR-135a which might be downregulated by androgen depletion and/or PI3K/AKT hyperactivation, in castration-resistant prostate cancer (CRPC), thus promoting tumor progression. Taken together, miR-135a may represent a new diagnostic and therapeutic biomarker for castration-resistant PCa.