Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.

Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.

Dried tangerine peel polysaccharide accelerates wound healing by recruiting anti-inflammatory macrophages.

Macrophage polarization is a key process involved in wound healing. The continuous release of proinflammatory cytokines by macrophages inhibits the healing process of chronic wounds, such as diabetic wounds. To promote wound healing, it is important to change the phenotype of resident macrophages to prevent inflammation. We previously reported that dried tangerine peel polysaccharide (DTPP) binds to and inhibits the TLR4/MD-2 complex, which is crucial for the inflammatory activation of macrophages, suggesting the potential of DTPP in wound healing applications. Both zebrafish and mouse models were used to evaluate the therapeutic efficacy of DTPP. Moreover, we found that DTPP recruited macrophages to the wound area and promoted their M2 repolarization. Using hyperglycaemic zebrafish and db/db mouse models, we discovered that DTPP accelerated wound healing in vivo in metabolic disorders. Our results suggest that DTPP promotes the recruitment of macrophages, shifts macrophages towards the anti-inflammatory M2 phenotype, and ultimately accelerates the wound healing process.

Dried tangerine peel polysaccharide (DTPP) alleviates hepatic steatosis by suppressing TLR4/MD-2-mediated inflammation and endoplasmic reticulum stress.

Non-alcoholic fatty liver disease (NAFLD) is a complex pathogenic metabolic syndrome characterized by increased inflammation and endoplasmic reticulum stress. In recent years, natural polysaccharides derived from traditional Chinese medicine have shown significant anti-inflammatory effects, making them an attractive therapeutic option. However, little research has been conducted on the therapeutic potential of dried tangerine peel polysaccharide (DTPP) - one of the most important medicinal resources in China. The results of the present study showed that DTPP substantially reduced macrophage infiltration in vivo and suppressed the expression of pro-inflammatory factors and endoplasmic reticulum stress-related genes. Additionally, surface plasmon resonance analysis revealed that DTPP had a specific affinity to myeloid differentiation factor 2, which consequently suppressed lipopolysaccharide-induced inflammation via interaction with the toll-like receptor 4 signaling pathway. This study provides a potential molecular mechanism underlying the anti-inflammatory effects of DTPP on NAFLD and suggests DTPP as a promising therapeutic strategy for NAFLD treatment.

Dendritic polymer-functionalized nanomedicine potentiates immunotherapy via lethal energy crisis-induced PD-L1 degradation.

The advent of immune checkpoint inhibitors ushers in a new era of anti-tumor immunity. However, current clinical anti-PD-L1 antibodies only interdict PD-L1 on the membrane, which cannot diminish the complex cancer-promoting effects of intracellular PD-L1. Therefore, directly reducing the PD-L1 abundance of cancer cells might be a potential PD-L1 inhibitory strategy to circumvent the issues of current anti-PD-L1 antibodies. Herein, we develop a dendritic polymer-functionalized nanomedicine with a potent cellular energy depletion effect on colon cancer cells. Treatment with the nanomedicine significantly promotes phosphorylation of AMPK, which in turn leads to PD-L1 degradation and eventual T cell activation. Meanwhile, the nanomedicine can potently induce immunogenic cell death (ICD) to enhance the anti-cancer immunity. Moreover, the combination of the nanomedicine with PD-1 blockade further enhances the activity of cytotoxic T lymphocytes, and dramatically inhibits tumor growth in vivo without distinct side effects. Overall, this study provides a promising nanoplatform to induce lethal energy crisis and ICD, and suppress PD-L1 expression, thus potentiating cancer immunotherapy.

Enzyme-triggered deep tumor penetration of a dual-drug nanomedicine enables an enhanced cancer combination therapy.

Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species (ROS) via emerging nanomedicines. However, tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site, and ROS at a low level promote tumor cell growth, thus diminishing the therapeutic effect of these nanomedicines. Herein, we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine (Lap@pOEGMA-b-p(GFLG-Dendron-Ppa), GFLG-DP/Lap NPs) that incorporates a photosensitizer, Pyropheophorbide a (Ppa), for ROS therapy and Lapatinib (Lap) for molecular targeted therapy. Lap, an epidermal growth factor receptor (EGFR) inhibitor that plays a role in inhibiting cell growth and proliferation, is hypothesized to synergize with ROS therapy for effectively killing cancer cells. Our results suggest that the enzyme-sensitive polymeric conjugate, pOEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), releases in response to cathepsin B (CTSB) after entering the tumor tissue. Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes, which promotes efficient penetration and long-term retention. Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity. Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis. Meanwhile, Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions, thus generating a significant synergistic anti-tumor therapeutic effect. This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.

Impairing Tumor Metabolic Plasticity via a Stable Metal-Phenolic-Based Polymeric Nanomedicine to Suppress Colorectal Cancer.

Targeting metabolic vulnerability of tumor cells is a promising anticancer strategy. However, the therapeutic efficacy of existing metabolism-regulating agents is often compromised due to tolerance resulting from tumor metabolic plasticity, as well as their poor bioavailability and tumor-targetability. Inspired by the inhibitive effect of N-ethylmaleimide on the mitochondrial function, a dendronized-polymer-functionalized metal-phenolic nanomedicine (pOEG-b-D-SH@NP) encapsulating maleimide-modified doxorubicin (Mal-DOX) is developed to enable improvement in the overall delivery efficiency and inhibition of the tumor metabolism via multiple pathways. It is observed that Mal-DOX and its derived nanomedicine induces energy depletion of CT26 colorectal cancer cells more efficiently than doxorubicin, and shifts the balance of programmed cell death from apoptosis toward necroptosis. Notably, pOEG-b-D-SH@NP simultaneously inhibits cellular oxidative phosphorylation and glycolysis, thus potently suppressing cancer growth and peritoneal intestinal metastasis in mouse models. Overall, the study provides a promising dendronized-polymer-derived nanoplatform for the treatment of cancers through impairing metabolic plasticity.

Polymeric dual-modal imaging nanoprobe with two-photon aggregation-induced emission for fluorescence imaging and gadolinium-chelation for magnetic resonance imaging.

Nanoprobes that offer both fluorescence imaging (FI) and magnetic resonance imaging (MRI) can provide supplementary information and hold synergistic advantages. However, synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups, high stability, great biocompatibility and desired dual-modality imaging results remains challenging. In this study, we used an amphiphilic block polymer from (ethylene glycol) methyl ether methacrylate (OEGMA) and N-(2-hydroxypropyl) methacrylamide (HPMA) derivatives as a carrier to conjugate a MR contrast agent, Gd-DOTA, and a two-photon fluorophore with an aggregation-induced emission (AIE) effect, TPBP, to construct a MR/two-photon fluorescence dual-modality contrast agent, Gd-DOTA-TPBP. Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r 1 value for Gd-DOTA-TPBP, revealing a great MR imaging resolution. The contrast agent specifically accumulated in the tumor region, allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging. Meanwhile, coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity, but also significantly enhanced its imaging performance in an aqueous phase. Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI. Since high-resolution, complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP, it has great potential in the early phase of disease diagnosis.

Attenuating Metabolic Competition of Tumor Cells for Favoring the Nutritional Demand of Immune Cells by a Branched Polymeric Drug Delivery System.

Tumor cells are dominant in the nutritional competition in the tumor microenvironment, and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the antitumor therapeutic effect. Herein, a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells are reported. Compared with the control nanoparticles prepared from its linear counterpart, the branched-conjugate-based nanoparticles can more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieves an enhanced antitumor effect. The work presents a promising approach for targeting metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers.

Anticancer nanomedicines harnessing tumor microenvironmental components.

INTRODUCTION: Small-molecular drugs are extensively used in cancer therapy, while they have issues of nonspecific distribution and consequent side effects. Nanomedicines that incorporate chemotherapeutic drugs have been developed to enhance the therapeutic efficacy of these drugs and reduce their side effects. One of the promising strategies is to prepare nanomedicines by harnessing the unique tumor microenvironment (TME). AREAS COVERED: The TME contains numerous cell types that specifically express specific antibodies on the surface. The physicochemical environment is characterized with a low pH, hypoxia, and a high redox potential resulting from tumor-specific metabolism. Therefore, intelligent nanomedicines designed based on the characteristics of the tumor microenvironment can be divided into two groups: the first group which is rapidly responsive to extracellular chemical/biological factors in the TME and the second one which actively and/or specifically targets cellular components in the TME. EXPERT OPINION: In this paper, we review recent progress of nanomedicines by harnessing the TME and illustrate the principles and advantages of different strategies for designing nanomedicines, which are of great significance for exploring novel nanomedicines or translating current nanomedicines into clinical practice. We will discuss the challenges and prospects of preparing nanomedicines to utilize or alter the TME for achieving effective, safe anticancer treatment.

Direct [4 + 2] Cycloaddition to Isoquinoline-Fused Porphyrins for Near-Infrared Photodynamic Anticancer Agents.

The synthesis of efficient porphyrin-based photosensitizers with intense near-infrared (NIR) absorption is in high demand for photodynamic therapy (PDT) but remains a challenging task. Herein we show the construction of a type of isoquinoline-fused porphyrins 3 and 4 with an impressive NIR-absorbing capacity. In light of the extraordinary singlet oxygen generation capabilities of 3 upon NIR irradiation, the representative nanoparticles (3a-NPs) assembled show excellent tumoricidal behavior with good biocompatibility in the phototherapeutic window (650-850 nm).

Plate-type elastic metamaterials for low-frequency broadband elastic wave attenuation.

In this paper, we numerically and experimentally demonstrate the low-frequency broadband elastic wave attenuation and vibration suppression by using plate-type elastic metamaterial, which is constituted of periodic double-sides stepped resonators deposited on a two-dimensional phononic plate with steel matrix. The dispersion relations, the power transmission spectra, and the displacement fields of the eigenmodes are calculated by using the finite element method. In contrast to the typical phononic plates consisting of periodic stepped resonators deposited on a homogeneous steel plate, the proposed elastic metamaterial can yield large band gap in the low-frequency range, resulting in the low-frequency broadband elastic wave attenuation. The formation mechanisms of the band gap as well as the effects of material and geometrical parameters on the band gap are further explored numerically. Numerical results show that, the formation mechanism of opening the low-frequency band gap is attributed to the coupling between the local resonant Lamb modes of two-dimensional phononic plate and the resonant modes of the stepped resonators. The band gap can be significantly modulated by the material and geometrical parameters. The properties of broadband gaps of the proposed subwavelength scale elastic metamaterials can potentially be applied to vibration and noise reduction in the audio regime as well as broadband elastic wave confinement and modulation in ultrasonic region.

[Effects of stumping on Calligonum mongolicum shelterbelt growth and soil moisture and salt distribution along Tarim Desert Highway, Xinjiang of Northwest China].

In order to ensure the stability and sustainability of the Calligonum mongolicum shelterbelt along Tarim Desert Highway, the aged C. mongolicum was stumped to investigate its growth and soil moisture and salt distribution. After stumping twice, C. mongolicum grew rapidly in its height, crown width, maximum basal diameter, and sprout number. Three years after stumping, the average height of the sprouts exceeded the control (no stumping), and the crown width and maximum basal diameter was 92.0% and 73.0% of the control, respectively. The fresh mass of the branches and assimilating branches, their dry mass, and the total fresh mass and dry mass of the aboveground parts reached 80.0%, 115.0%, 80.0%, 116.0%, 93.5%, and 88.0% of the control, respectively. Four years after stumping, the aboveground biomass surpassed the control. Comparing with the control, stumping increased the soil moisture content significantly and decreased the soil salt concentration. It was suggested that, to stump the aged C. mongolicum repeatedly could increase the soil moisture content and decrease the soil salt concentration in root zone, and effectively promote the rejuvenation and renewing of C. mongolicum.

[Effects of thinning on Calligonum arborescens growth and soil water-salt distribution in Tarim Desert Highway shelterbelt, Xinjiang of Northwest China].

In order to understand the effects of thinning on the growth of Calligonum arborescens and the soil water-salt distribution in Tarim Desert Highway shelterbelt, a thinning experiment was conducted on an aged and declined C. arborescens woodland in a demonstration section of the shelterbelt, with the growth of C. arborescens and the soil water-salt distribution monitored. Thinning had no effects on the phenophase of C. arborescens, but after thinning, the growth of the current year plant height, crown width, ground diameter, and new branch length of reserved trees was larger than that of the control, and the increment was in the order of planting space 2 mx 1 m > 1 m x 1 m > the control, with significant differences among the treatments. The assimilation branch surface area in treatments 2 mx 1 m and 1 m x 1 m were 5.97 m2 and 5.22 m2 per plant, respectively, being significantly larger than the control (3.1 m2 per plant). The soil moisture content in 0-160 cm layer was significantly higher in treatments 2 m x 1 m and 1 mx 1 m than in the control, and increased obviously with thinning intensity. The soil salt content was in the order of control > planting space 1 m x 1 m > 2 m x 1 m, and the differences among the treatments were significant. It was suggested that the best reserved plant density after thinning was planting space 2 m x 1 m.

Visualizing large-scale uncertainty in astrophysical data.

Visualization of uncertainty or error in astrophysical data is seldom available in simulations of astronomical phenomena, and yet almost all rendered attributes possess some degree of uncertainty due to observational error. Uncertainties associated with spatial location typically vary signicantly with scale and thus introduce further complexity in the interpretation of a given visualization. This paper introduces effective techniques for visualizing uncertainty in large-scale virtual astrophysical environments. Building upon our previous transparently scalable visualization architecture, we develop tools that enhance the perception and comprehension of uncertainty across wide scale ranges. Our methods include a unified color-coding scheme for representing log-scale distances and percentage errors, an ellipsoid model to represent positional uncertainty, an ellipsoid envelope model to expose trajectory uncertainty, and a magic-glass design supporting the selection of ranges of log-scale distance and uncertainty parameters, as well as an overview mode and a scalable WIM tool for exposing the magnitudes of spatial context and uncertainty.

Scalable WIM: effective exploration in large-scale astrophysical environments.

Navigating through large-scale virtual environments such as simulations of the astrophysical Universe is difficult. The huge spatial range of astronomical models and the dominance of empty space make it hard for users to travel across cosmological scales effectively, and the problem of wayfinding further impedes the user's ability to acquire reliable spatial knowledge of astronomical contexts. We introduce a new technique called the scalable world-in-miniature (WIM) map as a unifying interface to facilitate travel and wayfinding in a virtual environment spanning gigantic spatial scales: Power-law spatial scaling enables rapid and accurate transitions among widely separated regions; logarithmically mapped miniature spaces offer a global overview mode when the full context is too large; 3D landmarks represented in the WIM are enhanced by scale, positional, and directional cues to augment spatial context awareness; a series of navigation models are incorporated into the scalable WIM to improve the performance of travel tasks posed by the unique characteristics of virtual cosmic exploration. The scalable WIM user interface supports an improved physical navigation experience and assists pragmatic cognitive understanding of a visualization context that incorporates the features of large-scale astronomy.

[The short-term outcomes of patients with acute leukemia treated by thalidomide].

OBJECTIVE: To study the efficacy of thalidomide for treating acute leukemia (AL). METHODS: 38 cases of AL were studied. 27 of the 38 cases receiving initial treatment were randomly divided into two groups, one treated with routine chemotherapy plus thalidomide (A) and the other with routine chemotherapy alone (B). 11 of the 38 were relapsing cases and all treated with routine chemotherapy plus thalidomide (C). Marrow microvascular density (MVD) and vascular endothelial growth factor (VEGF) were examined with factor-VIII related antigen/CD(34) immunohistological stain and ELISA respectively before and after the treatment. The initial dose of thalidomide was 200 mg/d and increased to 400 - 500 mg/d by increasing 50 mg/d weekly for 4 to 6 months. RESULTS: The complete remission (CR) rate and efficacy rate were 57.1%, 53.8% and 78.6%, 76.9% in the two groups respectively with no statistical difference. The CR rate and efficacy rate in the relapsing group were 27.3%, 54.5%. The relapsing rate 6 months after the treatment was low in the thalidomide group. MVD and VEGF were significantly different before and after the treatment (P < 0.001). There was a negative correlation between the MVD, VEGF and efficacy. The relapsing rate was low in cases with low MVD, VEGF. No particular side effects were observed in thalidomide group. CONCLUSION: Anti-angiogenesis may decrease relapse and maintain recovery state of AL patients. There are no severe side effects in the thalidomide group.

[Therapeutic effectiveness of thalidomide to multiple myeloma and its mechanism].

OBJECTIVE: To observe the effective mechanism and side effects of thalidomide to multiple myeloma (MM). METHODS: Ten cases of MM were studied, of which 3 were previously untreated and 7 refractory or relapsed. Bone marrow microvascular density (MVD) was detected by factor-VIII related antigen and CD(34) immunohistological staining and serum concentration of vascular endothelial growth factor (VEGF) before and after treatment was determined by ELISA. The initial dosage of thalidomide was 100 approximately 200 mg/d with a weekly escalation of 50 mg/d to 450 approximately 650 mg/d. The therapeutic effectiveness is classified into partial remission, improvement and uneffective according to the decrease of serum M protein and bone marrow myeloma cells. Anemia, renal function and blood electrolytes were also observed. RESULTS: Before treatment, MVD was 73.32 +/- 28.80 and 32.30 +/- 12.50 in MM and control group, respectively, (P < 0.01). MVD in MM group decreased to 56.12 +/- 19.34 after treatment, and was of significant difference (P < 0.05) as compared to the pretreatment value. However, there was still a significant difference as compared to control (56.12 +/- 19.34 vs 32.30 +/- 12.50, P < 0.01). The concentration of VEGF significantly decreased after treatment [from (178.23 +/- 26.56) ng/L to (78.48 +/- 19.98) ng/L, P < 0.01)]. The total effective rate was 70%. There were no serious side effects. CONCLUSION: MVD and VEGF concentration were decreased obviously by thalidomide treatment. The dosage of 450 approximately 650 mg/d might be effective in refractory or initial MM.