Photoactivation of Boronic Acid Prodrugs via a Phenyl Radical Mechanism: Iridium(III) Anticancer Complex as an Example.

Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH2 even in limited O2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.

Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein Response Regulator BiP.

Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.

Organogold(III) Complexes Display Conditional Photoactivities: Evolving From Photodynamic into Photoactivated Chemotherapy in Response to O2 Consumption for Robust Cancer Therapy.

Photodynamic therapy (PDT) is a spatiotemporally controllable, powerful approach in combating cancers but suffers from low activity under hypoxia, whereas photoactivated chemotherapy (PACT) operates in an O2 -independent manner but compromises the ability to harness O2 for potent photosensitization. Herein we report that cyclometalated gold(III)-alkyne complexes display a PDT-to-PACT evolving photoactivity for efficient cancer treatment. On the one hand, the gold(III) complexes can act as dual photosensitizers and substrates, leading to conditional PDT activity in oxygenated condition that progresses to highly efficient PACT (ϕ up to 0.63) when O2 is depleted in solution and under cellular environment. On the other hand, the conditional PDT-to-PACT reactivity can be triggered by external photosensitizers in a similar manner in vitro and in vivo, giving additional tumor-selectivity and/or deep tissue penetration by red-light irradiation that leads to robust anticancer efficacy.

Anion Exchange of Ni-Co Layered Double Hydroxide (LDH) Nanoarrays for a High-Capacitance Supercapacitor Electrode: A Comparison of Alkali Anion Exchange and Sulfuration.

A facile and new anion exchange process is presented, which involves the conversion of NiCo-CO3 layered double hydroxide (LDH) nanosheet arrays in an alkaline solution. The anion exchange between CO3 2- and OH- results in the construction of a reservoir for OH- anions, and the decoration of thin nanoflakes on the surface of nanosheets effectively enlarges the surface area of NiCo LDH nanoarrays. The capacitance of the as-soaked NiCo LDH nanoarrays electrode increases from 1.78 F cm-2 (684 F g-1 ) to 6.22 F cm-2 (2391 F g-1 ) at 2 mA cm-2 after soaking for 12 h. Moreover, the soaked NiCo-OH LDH electrode exhibits an enhanced rate capacity, high coulombic efficiency, and good cycling stability compared with the Ni-Co-S nanosheet electrode synthesized through a hydrothermal sulfuration process. The as-assembled all-solid-state NiCo LDH//active carbon asymmetric supercapacitor shows a maximum energy density of 83.4 W h kg-1 at a power density of 1066 W kg-1 .

REST-repressed lncRNA LINC01801 induces neuroendocrine differentiation in prostate cancer via transcriptional activation of autophagy.

The association between REST reduction and the development of neuroendocrine prostate cancer (NEPC), a novel drug-resistant and lethal variant of castration-resistant prostate cancer (CRPC), is well established. To better understand the mechanisms underlying this process, we aimed to identify REST-repressed long noncoding RNAs (lncRNAs) that promote neuroendocrine differentiation (NED), thus facilitating targeted therapy-induced resistance. In this study, we used data from REST knockdown RNA sequencing combined with siRNA screening to determine that LINC01801 was upregulated and played a crucial role in NED in prostate cancer (PCa). Using The Cancer Genome Atlas (TCGA) prostate adenocarcinoma database and CRPC samples collected in our laboratory, we demonstrated that LINC01801 expression is upregulated in NEPC. Functional experiments revealed that overexpression of LINC01801 had a slight stimulatory effect on the NED of LNCaP cells, while downregulation of LINC01801 significantly inhibited the induction of NED. Mechanistically, LINC01801 is transcriptionally repressed by REST, and transcriptomic analysis revealed that LINC01801 preferentially affects the autophagy pathway. LINC01801 was found to function as a competing endogenous RNA (ceRNA) to regulate the expression of autophagy-related genes by sponging hsa-miR-6889-3p in prostate cancer cells. In conclusion, our data expand the current knowledge of REST-induced NED and highlight the contribution of the REST-LINC01801-hsa-miR-6889-3p axis to autophagic induction, which may provide promising avenues for therapeutic opportunities.

Regenerative Efficacy of Supercritical Carbon Dioxide-Derived Bone Graft Putty in Rabbit Bone Defect Model.

Bone defects can arise from numerous reasons, such as aging, tumor, trauma, infection, surgery, and congenital diseases. Bone grafts are commonly used as a substitute to fill the void and regenerate the defect. Due to its clean and green technology, the supercritical carbon dioxide (SCCO2) extraction aided the production of bone grafts is a recent trend. The SCCO2-derived bone graft has osteoconductive and osteoinductive properties along with excellent biocompatible, nontoxic, bioabsorbable, osteoconductive, and good mechanical properties; however, clinical usage during surgery is time-consuming. Therefore, we produced a putty material combining bone graft powder and acellular dermal matrix (ADM) powder and tested its regenerative efficacy in the critical defect in the rabbit model. The putty was found to retain the tubular structure. In addition, the putty depicted excellent stickiness and cohesiveness in both saline and blood medium. The bone regeneration of bone graft and putty was similar; both had excellent bone healing and regeneration of critical defects as evaluated by the X-ray, microtomography, hematoxylin-eosin, Masson trichrome, and alizarin red staining. Putty contains a less washout rate, good mechanical strength, and biocompatibility. In conclusion, the SCCO2-derived moldable putty could be a promising easy-to-use alternative for bone grafts at present which might have real-world usage in orthopedics as a potential bone void filler and dental socket preservation.

HOTAIR is a REST-regulated lncRNA that promotes neuroendocrine differentiation in castration resistant prostate cancer.

Long non-coding RNAs (lncRNAs) are emerging as novel diagnostic markers of prostate cancer (PCa) and new determinants of castration-resistant PCa (CRPC), an aggressive and metastatic form of PCa. In addition to androgen receptor (AR) signaling, neuroendocrine differentiation (NED) is associated with CRPC. Recent reports demonstrate that the downregulation of repressor element-1 silencing transcription factor (REST) protein is a key step in NED of PCa cells. Here, we report HOTAIR as a novel REST-repressed lncRNA that is upregulated in NED PCa cells and in CRPC. HOTAIR overexpression is sufficient to induce, whereas knockdown of HOTAIR suppressed NED of PCa cells. Gene ontology (GO) analysis of differentially expressed genes under HOTAIR overexpression and in CRPC versus benign prostatic hyperplasia (BPH) suggests that HOTAIR may participate in PCa progression. Taken together, our results provide the first evidence of lncRNA HOTAIR as a driver for NED of PCa cells.