Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2 O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

VO2 Films Decorated with an MXene Interface for Decreased-Power-Triggered Terahertz Modulation.

VO2, which exhibits semiconductor-metal phase transition characteristics occurring on a picosecond time scale, holds great promise for ultrafast terahertz modulation in next-generation communication. However, as of now, there is no reported prototype for an ultrafast device. The temperature effect has been proposed as one of the major obstacles. Consequently, reducing the excitation threshold for the phase transition would be highly significant. The traditional strategy typically involves chemical doping, but this approach often leads to a decrease in phase transition amplitude and a slower transition speed. In this work, we proposed a design featuring a highly conductive MXene interfacial layer between the VO2 film and the substrate. We demonstrate a significant reduction in the phase transition threshold for both temperature and laser-induced phase transition by adjusting the conductivity of the MXene layers with varying thicknesses. Our observations show that the phase transition temperature can be decreased by 9 °C, while the pump fluence for laser excitation can be reduced by as high as 36%. The ultrafast phase transition process on a picosecond scale, as revealed by the optical-pump terahertz-probe method, suggests that the MXene layers have minimal impact on the phase transition speed. Moreover, the reduced phase transition threshold can remarkably alleviate the photothermal effect and inhibit temperature rise and diffusion in VO2 triggered by laser. This study offers a blueprint for designing VO2/MXene hybrid films with reduced phase transition thresholds. It holds significant potential for the development of low-power, intelligent optical and electrical devices including, but not limited to, terahertz modulators based on phase transition phenomena.

A ferroptosis-reinforced nanocatalyst enhances chemodynamic therapy through dual H2O2 production and oxidative stress amplification.

The existence of a delicate redox balance in tumors usually leads to cancer treatment failure. Breaking redox homeostasis by amplifying oxidative stress and reducing glutathione (GSH) can accelerate cancer cell death. Herein, we construct a ferroptosis-reinforced nanocatalyst (denoted as HBGL) to amplify intracellular oxidative stress via dual H2O2 production-assisted chemodynamic therapy (CDT). Specifically, a long-circulating liposome is employed to deliver hemin (a natural iron-containing substrate for Fenton reaction and ferroptosis), ß-lapachone (a DNA topoisomerase inhibitor with H2O2 generation capacity for chemotherapy), and glucose oxidase (which can consume glucose for starvation therapy and generate H2O2). HBGL can achieve rapid, continuous, and massive H2O2 and •OH production and GSH depletion in cancer cells, resulting in increased intracellular oxidative stress. Additionally, hemin can reinforce the ferroptosis-inducing ability of HBGL, which is reflected in the downregulation of glutathione peroxidase-4 and the accumulation of lipid peroxide. Notably, HBGL can disrupt endo/lysosomes and impair mitochondrial function in cancer cells. HBGL exhibits effective tumor-killing ability without eliciting obvious side effects, indicating its clinical translation potential for synergistic starvation therapy, chemotherapy, ferroptosis therapy, and CDT. Overall, this nanocatalytic liposome may be a promising candidate for achieving potentiated cancer treatment.

Sulfur-Doped Organosilica Nanodots as a Universal Sensor for Ultrafast Live/Dead Cell Discrimination.

Rapid and accurate differentiation between live and dead cells is highly desirable for the evaluation of cell viability. Here, we report the application of the orange-emitting sulfur-doped organosilica nanodots (S-OSiNDs) for ultrafast (30 s), ultrasensitive (1 µg/mL), and universal staining of the dead bacterial, fungal, and mammalian cells but not the live ones, which satisfies the requirements of a fluorescent probe that can specifically stain the dead cells. We further verify that the fluorescence distribution range of S-OSiNDs (which are distributed in cytoplasm and nucleus) is much larger than that of the commercial dead/fixed cell/tissue staining dye RedDot2 (which is distributed in the nucleus) in terms of dead mammalian cell staining, indicating that S-OSiNDs possess a better staining effect of dead cells than RedDot2. Overall, S-OSiNDs can be used as a robust fluorescent probe for ultrafast and accurate discrimination between dead and live cells at a single cell level, which may find a variety of applications in the biomedical field.

Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity.

Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.

Long-Chain Poly-d-Lysines Interact with the Plasma Membrane and Induce Protective Autophagy and Intense Cell Necrosis.

Polylysines have been frequently used in drug delivery and antimicrobial and cell adhesion studies. Because of steric hindrance, chirality plays a major role in the functional difference between poly-l-lysine (PLL) and poly-d-lysine (PDL), especially when they interact with the plasma membranes of mammalian cells. Therefore, it is speculated that the interaction between chiral polylysines and the plasma membrane may cause different cellular behaviors. Here, we carefully investigated the interaction pattern of PLL and PDL with plasma membranes. We found that PDL could be anchored onto the plasma membrane and interact with the membrane lipids, leading to the rapid morphological change and death of A549 cells (a human lung cancer cell line) and HPAEpiCs (a human pulmonary alveolar epithelial cell line). In contrast, PLL exhibited good cytocompatibility and was not anchored onto the plasma membranes of these cells. Unlike PLL, PDL could trigger protective autophagy to prevent cells in a certain degree, and the PDL-caused cell death occurred via intense necrosis (featured by increased intracellular Ca2+ content and plasma membrane disruption). In addition, it was found that the short-chain PDL with a repeat unit number of 9 (termed DL9) could locate in lysosomes and induce autophagy at high concentrations, but it could not elicit drastic cell death, which proved that the repeat unit number of polylysine could affect its cellular action. This research confirms that the interaction between chiral polylysines and the plasma membrane can induce autophagy and intense necrosis, which provides guidance for the future studies of chiral molecules/drugs.

Efficient Synthesis of Glycosaminoglycan Analogs.

Glycosaminoglycans (GAGs) are among the most complex, biologically active polysaccharides in nature. The complexity of GAGs greatly impedes their synthesis, thus complicating the structure-property studies that are so necessary for us to understand the roles of GAGs in natural processes, in pathogen invasion, and to understand how to develop effective interventions, for example, to prevent undesired GAG hijacking by pathogens. Total synthesis of GAG oligomers from monosaccharide building blocks is useful, but incredibly labor-intensive, expensive, and inefficient. In this study, we report a regiospecific synthetic route to two types of designed GAG analogs by chemical modification of commercially available, inexpensive cellulose acetate. Cellulose acetate was first brominated, followed by azide displacement to introduce azides as the GAG amine precursors. The resulting 6-N3 cellulose acetate was then saponified to liberate 6-OH groups. Subsequent oxidation of the liberated primary hydroxyl groups to carboxyl groups was smoothly effected by a TEMPO-catalyzed process. Finally, the azides were reduced to amines using an aqueous process, new to polysaccharide chemistry, employing reduction by dithiothreitol (DTT). Alternatively, another process new to polysaccharide chemistry could be employed to convert most of the azides to acetamido groups (mimicking those present, for example, in native hyaluronic acid) by reduction with thioacetic acid. All the intermediates and products were characterized by 1H NMR, 13C NMR, and FT-IR spectroscopy. This synthetic route provides access to GAG analogs that will be of great interest for exploring structure-property relationships in various biomedical applications.

Morin Exhibits Anti-Inflammatory Effects on IL-1ß-Stimulated Human Osteoarthritis Chondrocytes by Activating the Nrf2 Signaling Pathway.

BACKGROUND/AIMS: Osteoarthritis (OA) is a multifactorial disease that is associated with inflammation in joints. The purpose of the present study was to investigate the anti-inflammatory activity and mechanism of morin on human osteoarthritis chondrocytes stimulated by IL-1ß. METHODS: The levels of NO and PGE2 were measured by the Griess method and ELISA. The levels of MMP1, MMP3, and MMP13 were also measured by ELISA. RESULTS: The results revealed that IL-1ß significantly increased the production of NO, PGE2, MMP1, MMP3, and MMP13. Additionally, the increases were significantly attenuated by treatment with morin. Furthermore, IL-1ß-induced NF-κB activation was suppressed by morin. In addition, the expression of Nrf2 and HO-1 were increased by morin and knockdown of Nrf2 could prevent the anti-inflammatory effects of morin. CONCLUSION: In conclusion, this study suggested that morin attenuated IL-1ß-induced inflammation by activating the Nrf2 signaling pathway.

Regioselective chlorination of cellulose esters by methanesulfonyl chloride.

Regioselective chlorination of cellulose is challenging due to its low reactivity, the small reactivity differences between cellulosic hydroxyl groups, and the high and diverse reactivity of most common chlorinating agents. Halogenation of cellulose affords useful precursors for subsequent nucleophilic substitution reactions, permitting incorporation of new functionality. Herein we report a simple and efficient pathway for preparation of 6-chloro-6-deoxycellulose esters and their derivatives. Cellulose acetate (degree of substitution (DS) 1.75, CA320S) can be chlorinated by essentially quantitative reaction of the primary alcohol groups with methanesulfonyl chloride (MsCl), yielding 6-chloro-6-deoxy cellulose acetate. Characterization methods including 1H NMR, 13C NMR, FT-IR spectroscopy, and elemental analysis, demonstrated chemo- and regioselective C-6 chlorination. We also demonstrate that chlorinated cellulose acetate is a useful intermediate for displacement reactions with nucleophiles including sodium azide, amines, and thiols to prepare functional cellulose ester derivatives.

Selective synthesis of curdlan ω-carboxyamides by Staudinger ylide nucleophilic ring-opening.

Chemoselective modification of polysaccharides is a significant challenge, and regioselective modification is even more difficult, due to the low and similar reactivity of the various polysaccharide hydroxyl groups. Bromination of glycans that possess free 6-OH groups is exceptional in that regard, giving regiospecific, high-yield access to 6-bromo-6-deoxyglycans. Herein we report a simple and efficient pathway for synthesizing 6-ω-carboxyalkanamido-6-deoxy-containing polysaccharide derivatives in a sequence starting from 6-bromo-6-deoxycurdlan, via azide displacement, then conversion of the azide to the iminophosphorane ylide by triphenylphosphine (Ph3P). We take advantage of the nucleophilicity of the iminophosphorane nitrogen by subsequent regioselective ring-opening reactions of cyclic anhydrides. These reactions of the useful polysaccharide curdlan were essentially completely regio- and chemo-selective, proceeding under mild conditions in the presence of ester groups, yet preserving those groups. These interesting polysaccharide-based materials have pendant carboxyls attached through a hydrocarbon tether and hydrolytically stable amide linkage; as such they are promising for diverse application areas, including aqueous dispersions for coatings, adhesives, and other consumer products, and for amorphous solid dispersions in oral drug delivery.

Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin.

To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 < 3 nM) were identified, among which compounds 38 (IC50 = 0.9 nM) and 39 (IC50 = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 µmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.