Tumor Vascular Destruction and cGAS-STING Activation Induced by Single Drug-Loaded Nano-Micelles for Multiple Synergistic Therapies of Cancer.

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS-STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic-co-glycolic) acid co-polymer (PLGA-PEG), obtaining PLGA-PEG/DMXAA (PPD) nanoparticles to induce the tumor-specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD-mediated therapies could trigger potent systemic anti-tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS-STING pathway. Together with anti-PD-L1, PPD-mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug-loaded nano-micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.

Anti-Inflammatory and Gut Microbiota Modulation Potentials of Flavonoids Extracted from Passiflora foetida Fruits.

This study aimed to explore the anti-inflammatory and gut microbiota modulation potentials of flavonoid-rich fraction (PFF) extracted from Passiflora foetida fruits. The results showed that PFF markedly reduced the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW 264.7 cells. Meanwhile, PFF treatment also effectively decreased the phosphorylation levels of MAPK, PI3K/Akt, and NF-κB signaling-pathway-related proteins (ERK, JNK, p38, Akt, and p65). Moreover, PFF had an impact on microbial composition and metabolites in a four-stage dynamic simulator of human gut microbiota (BFBL gut model). Specifically, PFF exhibited the growth-promoting ability of several beneficial bacteria, including Bifidobacterium, Enterococcus, Lactobacillus, and Roseburia, and short-chain fatty acid (SCFA) generation ability in gut microbiota. In addition, spectroscopic data revealed that PFF mainly contained five flavonoid compounds, which may be bioactive compounds with anti-inflammatory and gut microbiota modulation potentials. Therefore, PFF could be utilized as a natural anti-inflammatory agent or supplement to health products.

Recent advances in biological membrane-based nanomaterials for cancer therapy.

Nanomaterials have shown significant advantages in cancer theranostics, owing to their enhanced permeability and retention effect in tumors and multi-function integration capability. Biological membranes, which are collected from various cells and their secreted membrane structures, can further be applied to establish membrane-based nanomaterials with perfect biocompatibility, tumor-targeting capacity, immune-stimulatory activity and adjustable versatility for cancer therapy. In this review, according to their source, membranes are divided into four groups: (1) cell membranes; (2) secretory membranes; (3) engineered membranes; and (4) hybrid membranes. First, cell membranes can be extracted from natural cells of the body, tumor tissue cells, and bacteria. Furthermore, secretory membranes mainly refer to exosome, apoptotic body and bacterial outer membrane vesicle, and membranes with specific protein/peptide expression or therapeutic inclusions are obtained from engineered cells. Finally, a hybrid membrane will be constituted by two or more of the abovementioned membranes. These membranes can form drug-carrying nanoparticles themselves or coat multi-functional nanoparticles, further realizing efficient cancer therapy. We summarize the application of various biological membrane-based nanomaterials in cancer therapy and point out their advantages as well as the places that need to be further improved, providing systematic knowledge of this field and a strategy for further optimization.

Immunological Activity and Gut Microbiota Modulation of Pectin from Kiwano (Cucumis metuliferus) Peels.

For developing the recycling of fruit by-products from kiwano, a polysaccharide was extracted from kiwano (Cucumis metuliferus) peels, namely Cucumis metuliferus peels polysaccharide (CMPP), with the aim of investigating the potential beneficial effects. The composition of polysaccharides was analyzed by chemical methods. RAW264.7 macrophages cells and the microbiota dynamics simulator (BFBL gut model) were used for in vitro study. The result showed that CMPP mainly consists of glucuronic acid, arabinose, galactose and rhamnose. By intervening with RAW264.7 cells, CMPP promoted cell proliferation and showed immune-enhancing activity, which significantly (p < 0.05) induced the release of nitric oxide (NO), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) at a concentration of 50 µg/mL. In addition, CMPP had an impact on the composition of the gut bacteria, increasing the growth of Akkermansia, Bacteroides, Bifidobacterium, Feacalibacterium, and Roseburia. During the intake period, acetic, butyric and propionic acids were all increased, especially (p < 0.05) in the descending colon. Moreover, a decrease in ammonia concentration (10.17 ± 0.50 mM in the ascending colon, 13.21 ± 1.54 mM in the transverse colon and 13.62 ± 0.45 mM in the descending colon, respectively) was observed. In summary, CMPP can be considered as a pectin, showed immunological activity and function of gut microbiota modulation. This study could be the scientific basis of developing kiwano peels as beneficial to human health.

Photo-Driven Delivery of 125I-Labeled Nanomicelles for Nucleus-Targeted Internal Conversion Electron-Based Cancer Therapy.

As a kind of high linear energy transfer (LET) radiation, internal conversion electrons are emitted from some radionuclides, such as 125I, triggering severe DNA damage to tumor cells when transported into the nucleus. Herein, we develop a curcumin-loaded nanomicelle composed of a photosensitizer chlorin e6 (Ce6) and amphiphilic poly(ethylene glycol) (poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) (C18-PMH-PEG)) to deliver 125I into the nucleus under 660 nm laser irradiation, leading to the optimized imaging-guided internal conversion electron therapy of cancer. Ce6-containing nanomicelles (Ce6-C18-PEG) self-assemble with nucleus-targeted curcumin (Cur), obtaining Ce6-C18-PEG/Cur nanoparticles. After labeling Cur with 125I, Ce6-C18-PEG/Cur enables single-photon emission computed tomography and fluorescence imaging of the tumor, serving as a guide for follow-up laser irradiation. Notably, the 660 nm laser-triggered photodynamic reaction of Ce6 optimizes the delivery of Ce6-C18-PEG/125I-Cur at various stages, including tumor accumulation, cellular uptake, and lysosome escape, causing plenty of 125I-Cur to enter the nucleus. By this strategy, Ce6-C18-PEG/125I-Cur showed optimal antitumor efficacy and high biosafety in mice treated with local 660 nm laser irradiation using efficient energy deposition of internally converted electrons over short distances. Therefore, our work provides a novel strategy to optimize 125I delivery for tumor treatment.

Structural characterization and immunological activity of pectin polysaccharide from kiwano (Cucumis metuliferus) peels.

Two novel polysaccharides, namely CMPP-1 and CMPP-2, from kiwano (Cucumis metuliferus) peels were isolated through hot-water extraction, followed by ethanol precipitation and column chromatography. The results showed that CMPP-1 and CMPP-2 were hetero-galacturonans with different molecular weights of 7.35 kDa and 6.90 kDa, respectively. Both of CMPP-1 and CMPP-2 were mainly composed of glucuronic acid (45.93 % and 51.75 %, respectively), and other monosaccharides including rhamnose, arabinose, galactose, glucose, xylose, fucose, mannose, galacturonic acid, and mannuronic acid. The results of structural characterization from FT-IR and NMR confirmed that CMPP-1 and CMPP-2 were pectin with highly branched structure. Furthermore, both CMPP-1 and CMPP-2 possessed immune-enhancing activity and could enhance the secretion of nitric oxide and cytokines (TNF-α, IL-6) in a dose-dependent manner. Especially, CMPP-1 had higher immune activity than CMPP-2 as the minimum effective concentration were 0.78 µg/mL and 6.25 µg/mL, respectively. These findings provide a scientific basis for further utilization of polysaccharide from kiwano peels.

Structural Features of Three Hetero-Galacturonans from Passiflora foetida Fruits and Their in Vitro Immunomodulatory Effects.

Passiflora foetida is a horticultural plant and vital traditional Chinese herbal medicine. In our previous study, the characterization and immuno-enhancing effect of fruits polysaccharide 1 (PFP1), a water-eluted hetero-mannan from wild Passiflora foetida fruits, were investigated. Herein, another three salt-eluted novel polysaccharides, namely PFP2, PFP3, and PFP4, were obtained and structurally characterized. The results showed that PFP2, PFP3, and PFP4 were three structurally similar hetero-galacturonans with different molecular weights of 6.11 × 104, 4.37 × 104, and 3.48 × 105 g/mol, respectively. All three of these hetero-galacturonans are mainly composed of galacturonic acid, galactose, arabinose (75.69%, 80.39%, and 74.30%, respectively), and other monosaccharides including mannose, fucose, glucose, ribose, xylose, and glucuronic acid (24.31%, 19.61, and 25.70%, respectively), although differences in their backbone structure exist. Additionally, immunomodulatory assay indicated that the three hetero-galacturonans possess the ability to promote the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in RAW264.7 macrophages in a concentration-dependent manner (p < 0.05). Especially, PFP3 displayed a stronger enhancing effect than PFP2 and PFP4 at the minimum effective concentration. Therefore, the results suggested that the obtained three salt-eluted hetero-galacturonans, especially PFP3, could be utilized as immunomodulatory effectivity ingredients in nutritional/pharmaceutical industries.

Structure characterization of a novel polysaccharide from Chinese wild fruits (Passiflora foetida) and its immune-enhancing activity.

A novel polysaccharide (PFP1) with an average molecular weight of 2.02 × 105 g/mol was isolated from Passiflora foetida fruits through hot water extraction, ethanol precipitation and column chromatography. The structure of PFP1 was determined by GPC-MALS-RI, IC, FT-IR, GC-MS and NMR. The structural analysis showed that PFP1 was a heteropolysaccharide and composed of mannose (48.83%), galactose (32.46%), glucose (6.21%), arabinose (5.88%), fructose (2.24%), galacturonic acid (2.20%), xylose (1.17%), fucose (0.17%), ribose (0.05%), and glucuronic acid (0.78%), with a backbone structure of →1)-α-D-Manp→1,2)-ß-D-Manp-linked 1,2,6)-ß-D-Manp residues and side chains consisted of →1)-ß-D-Galp, →1,4)-α-D-Manp, →1, 4)-ß-D-Glcp, →1,3)-α-D-Galp, →1,6)-ß-D-Manp, →1,6)-ß-D-Galp, →1,2,3)-ß-D-Manp and →1,3,6)-ß-D-Galp residues. The results of immune-enhancing assays revealed that PFP1 could obviously promote the production of NO and secretion of cytokines (TNF-α and IL-6) of macrophage RAW264.7. These findings demonstrate that P. foetida fruit polysaccharides can be utilized as a potential immune-enhancing functional food.