Ferrocene-Based Polymeric Nanoparticles Carrying Doxorubicin for Oncotherapeutic Combination of Chemotherapy and Ferroptosis.

Mono-chemotherapy has significant side effects and unsatisfactory efficacy, limiting its clinical application. Therefore, a combination of multiple treatments is becoming more common in oncotherapy. Chemotherapy combined with the induction of ferroptosis is a potential new oncotherapy. Furthermore, polymeric nanoparticles (NPs) can improve the antitumor efficacy and decrease the toxicity of drugs. Herein, a polymeric NP, mPEG-b-PPLGFc@Dox, is synthesized to decrease the toxicity of doxorubicin (Dox) and enhance the efficacy of chemotherapy by combining it with the induction of ferroptosis. First, mPEG-b-PPLGFc@Dox is oxidized by endogenous H2 O2 and releases Dox, which leads to an increase of H2 O2 by breaking the redox balance. The Fe(II) group of ferrocene converts H2 O2 into ·OH, inducing subsequent ferroptosis. Furthermore, glutathione peroxidase 4, a biomarker of ferroptosis, is suppressed and the lipid peroxidation level is elevated in cells incubated with mPEG-b-PPLGFc@Dox compared to those treated with Dox alone, indicating ferroptosis induction by mPEG-b-PPLGFc@Dox. In vivo, the antitumor efficacy of mPEG-b-PPLGFc@Dox is higher than that of free Dox. Moreover, the loss of body weight in mice treated mPEG-b-PPLGFc@Dox is lower than in those treated with free Dox, indicating that mPEG-b-PPLGFc@Dox is less toxic than free Dox. In conclusion, mPEG-b-PPLGFc@Dox not only has higher antitumor efficacy but it reduces the damage to normal tissue.

Optical Microfiber with a Gold Nanorods-Black Phosphorous Nanointerface: An Ultrasensitive Biosensor and Nanotherapy Platform.

The detection and therapy of cancers in the early stage significantly alleviate the associated dangers. Optical devices offer new opportunities for these early measures. However, the clinical translation of the existing methods is severely hindered by their relatively low sensitivity or unclear physiological metabolism. Here, an optical microfiber sensor with a drug loading gold nanorod-black phosphorous nanointerface, as an ultrasensitive biosensor and nanotherapy platform, is developed to meet the early-stage requirement. With interface sensitization and functionalization of the hybrid nanointerface, the microfiber sensor presents an ultrahigh sensing performance, achieving the selective detection of the HER2 biomarker with limits of detection of 0.66 aM in buffer solution and 0.77 aM in 10% serum. It can also distinguish breast cancer cells from other cells in the early stage. Additionally, enabled by the interface, the optical microfiber is able to realize cellular nanotherapy, including photothermal/chemotherapy with pump laser coupling after diagnosis, and evaluate therapy results in real time. The immobilization of the interface on the optical microfiber surface prevents the damage to normal cells induced by nanomaterial enrichment, making the device more efficient and intelligent. This study opens up a new avenue for the development of smart optical platforms for sensitive biosensing and precision therapy.

CENPF/CDK1 signaling pathway enhances the progression of adrenocortical carcinoma by regulating the G2/M-phase cell cycle.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor and is prone to local invasion and metastasis. And, overexpressed Centromere Protein F (CENPF) is closely related to the oncogenesis of various neoplasms, including ACC. However, the prognosis and exact biological function of CENPF in ACC remains largely unclear. METHODS: In the present essay, the expression patterns and prognostic value of CENPF in ACC were investigated in clinical specimens and public cancer databases, including GEO and TCGA. The potential signaling mechanism of CENPF in ACC was studied based on gene-set enrichment analysis (GSEA). Furthermore, a small RNA interference experiment was conducted to probe the underlying biological function of CENPF in the human ACC cell line, SW13 cells. Lastly, two available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. RESULTS: The expression of CENPF in human ACC samples, GEO, and TCGA databases depicted that CENPF was overtly hyper-expressed in ACC patients and positively correlated with tumor stage. The aberrant expression of CENPF was significantly correlated with unfavorable overall survival (OS) in ACC patients. Then, the GSEA analysis declared that CENPF was mainly involved in the G2/M-phase mediated cell cycle and p53 signaling pathway. Further, the in vitro experiment demonstrated that the interaction between CENPF and CDK1 augmented the G2/M-phase transition of mitosis, cell proliferation and might induce p53 mediated anti-tumor effect in human ACC cell line, SW13 cells. Lastly, immune infiltration analysis highlighted that ACC patients with high CENPF expression harbored significantly different immune cell populations, and high TMB/MSI score. The gene-drug interaction network stated that CENPF inhibitors, such as Cisplatin, Sunitinib, and Etoposide, might serve as potential drugs for the therapy of ACC. CONCLUSION: The result points out that CENPF is significantly overexpressed in ACC patients. The overexpressed CENPF predicts a poor prognosis of ACC and might augment the progress of ACC. Thus, CENPF and related genes might serve as a novel prognostic biomarker or latent therapeutic target for ACC patients.

Suppression of Mll1-Complex by Stat3/Cebpß-Induced miR-21a/21b/181b Maintains the Accumulation, Homeostasis, and Immunosuppressive Function of Polymorphonuclear Myeloid-Derived Suppressor Cells.

Mixed-lineage leukemia 1 (MLL1), which exerts its H3K4 methyltransferase activity by interacting with WDR5, ASH2L, and RBBP5, plays a pivotal role in regulating hematopoietic stem cell homeostasis. Disrupting the integrity of MLL1-complex has been reported to be associated with acute leukemia. However, the exact role of MLL1-complex in myeloid cells is unknown. In this study, microarray analysis revealed that the core components of the Mll1-complex, Wdr5, Ash2l, and Mll1, were concurrently downregulated by tumor-secreted factors as well as GM-CSF + IL-6 during the accumulation and activation of murine myeloid-derived suppressor cells (MDSCs). These changes were further validated by quantitative RT-PCR and Western blotting both in vitro and in vivo. The expression levels of WDR5 and ASH2L were also significantly decreased in bone marrow MDSCs of lung cancer patients compared with that of healthy controls. Functionally, ectopic expression of Wdr5, Ash2l, and Mll1 (C terminus) reversed the accumulation and function of GM-CSF + IL-6-induced as well as tumor-cocultured polymorphonuclear MDSCs (PMN-MDSCs) by promoting them to differentiate into mature neutrophil-like cells. Mechanistically, GM-CSF + IL-6-activated Stat3 and Cebpß synergistically induced the expression of miR-21a, miR-21b, and miR-181b, and thus inhibited the expression of Wdr5, Ash2l, and Mll1 by targeting to their 3' untranslated regions, respectively. Furthermore, knockdown of these microRNAs also suppressed the expansion and function of GM-CSF + IL-6-induced PMN-MDSCs. Taken together, our findings indicate that the Stat3/Cebpß-miR-21a/b/181b-Mll1-complex axis may play a critical role in PMN-MDSC expansion, activation, and differentiation, and this axis may provide an effectively immunological therapeutic approach for patients with cancer or other immunological diseases.

Structure and Oxidation Effects on Conformation and Thermoresponsiveness of the OEGylated Poly(glutamic acid)-Bearing Side-Chain Thioether Linkers.

A series of side-chain thioether-linked OEGylated poly(glutamic acid) (PGAs) have been synthesized by "thiol-ene" synthetic methodology, where both the oligo-ethylene glycol (OEG) length and the hydrophobic linkers at the side chains are varied to learn how these structural features affect the secondary structure and thermoresponsive behaviors in water. Before side-chain oxidation, the structural factors affecting the α-helicity include the backbone length, the OEG length, and the hydrophobic linkers' length at the side chains; however, the OEG length plays the most crucial role among these factors because longer OEG around the peripheral side chains can stop water penetration into the backbone to disturb the intramolecular H bonds, which finally allows stabilizing the α-helix; after the oxidation, the polypeptides show increased α-helicity because of the enhanced hydrophilicity. More interestingly, a rare oxidation-induced conformation transition from the ordered ß-sheet to the ordered α-helix can be achieved. In addition, only the OEGylated poly(glutamic acids) (PGAs) with shorter hydrophobic linkers and longer OEG can display the thermoresponsive properties before the oxidation but the subsequent oxidation can cause the polypeptides bearing longer hydrophobic linkers to exhibit the thermosensitivity since sulfone formation at the side chain can lead to final hydrophilicity-hydrophobicity balance. This work is meaningful to understand the secondary structure-associated solution behaviors of the synthetic polypeptides.

Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis.

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

Analysis and Compensation of Modulation Angular Rate Error Based on Missile-Borne Rotation Semi-Strapdown Inertial Navigation System.

The Semi-Strapdown Inertial Navigation System (SSINS) provides a new solution to attitude measurement of a high-speed rotating missile. However, micro-electro-mechanical-systems (MEMS) inertial measurement unit (MIMU) outputs are corrupted by significant sensor errors. In order to improve the navigation precision, a rotation modulation technology method called Rotation Semi-Strapdown Inertial Navigation System (RSSINS) is introduced into SINS. In fact, the stability of the modulation angular rate is difficult to achieve in a high-speed rotation environment. The changing rotary angular rate has an impact on the inertial sensor error self-compensation. In this paper, the influence of modulation angular rate error, including acceleration-deceleration process, and instability of the angular rate on the navigation accuracy of RSSINS is deduced and the error characteristics of the reciprocating rotation scheme are analyzed. A new compensation method is proposed to remove or reduce sensor errors so as to make it possible to maintain high precision autonomous navigation performance by MIMU when there is no external aid. Experiments have been carried out to validate the performance of the method. In addition, the proposed method is applicable for modulation angular rate error compensation under various dynamic conditions.

Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer cells.

BACKGROUND: Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Nanoscale carriers that can target tumors to accumulate and release drugs intracellularly have the greatest potential for overcoming MDR. Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). However, whether this dual functional vector can overcome MDR in lung cancer is unknown. RESULTS: In this experiment, AG-PEG-SS-PLA was synthetized successfully, and paclitaxel (PTX)-loaded AG-PEG-SS-PLA (AG-PEG-SS-PLA/PTX) nanomicelles exhibited excellent physical properties. These nanomicelles show enhanced tumor targeting as well as drug accumulation and retention in MDR cancer cells. Caveolin-dependent endocytosis is mainly responsible for nanomicelle internalization. After internalization, the disulfide bond of AG-PEG-SS-PLA is cleaved in the presence of high intracellular glutathione levels, causing the hydrophobic core to become a polar aqueous solution, which subsequently results in nanomicelle disassembly and the rapid release of encapsulated PTX. Reduced drug resistance was observed in cancer cells in vitro. The caspase-9 and caspase-3 cascade was activated by the AG-PEG-SS-PLA/PTX nanomicelles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the anti-apoptotic protein Bcl-2, thereby increasing apoptosis. Furthermore, significantly enhanced tumor growth inhibition was observed in nude mice bearing A549/ADR xenograft tumors after the administration of AG-PEG-SS-PLA/PTX nanomicelles via tail injection. CONCLUSIONS: These promising results indicate that AG-PEG-SS-PLA/PTX nanomicelles could provide the foundation for a paradigm shift in MDR cancer therapy.

Marriage of a Dual-Plasmonic Interface and Optical Microfiber for NIR-II Cancer Theranostics.

The use of light as a powerful tool for disease treatment has introduced a new era in tumor treatment and provided abundant opportunities for light-based tumor theranostics. This work reports a photothermal theranostic fiber integrating cancer detection and therapeutic functions. Its self-heating effect can be tuned at ultralow powers and used for self-heating detection and tumor ablation. The fiber, consisting of a dual-plasmonic nanointerface and an optical microfiber, can be used to distinguish cancer cells from normal cells, quantify cancer cells, perform hyperthermal ablation of cancer cells, and evaluate the ablation efficacy. Its cancer cell ablation rate reaches 89% in a single treatment. In vitro and in vivo studies reveal quick, deep-tissue photonic hyperthermia in the NIR-II window, which can markedly ablate tumors. The marriage of a dual-plasmonic nanointerface and an optical microfiber presents a novel paradigm in photothermal therapy, offering the potential to surmount the challenges posed by limited light penetration depth, nonspecific accumulation in normal tissues, and inadvertent damage in current methods. This work thus provides insight for the exploration of an integrated theranostic platform with simultaneous functions in cancer diagnostics, therapeutics, and postoperative monitoring for future practical applications.

Synthesis and characterization of 3-in-1 multifunctional lipiodol-doped Fe3O4@Poly (diallyl isophthalate) microspheres for arterial embolization, chemotherapy, and imaging.

Transcatheter arterial embolization plays a pivotal role in treating various diseases. However, the efficacy of embolization therapy in cancer treatment can be limited by several factors, such as inevitable incomplete or non-target embolization, and the tumor recurrence and metastasis caused by the hypoxic microenvironment. Moreover, it is essential to explore simpler, more economical, and efficient methods for microsphere synthesis. Herein, we achieved one-step photocatalytic synthesis of lipiodol-doped Fe3O4@Poly (diallyliso-phthalate) multifunctional microspheres (IFeD MS) for arterial embolization, chemotherapy, and imaging. The prepared microspheres are in the shape of dried plums, with a particle size of 100-300 µm. Lipiodol demonstrates a certain degree of chemotherapeutic activity, and the incorporation of Fe3O4enables the microspheres to exhibit magnetothermal response and magnetic resonance imaging capabilities. Furthermore, the radiopaque characteristics of both agents provide the microspheres with promising potential for computed tomography and digital radiography imaging. The renal embolization experiment in rabbits demonstrated that IFeD MS achieved significant embolization and chemotherapeutic effects. Biocompatibility experiments revealed that this embolic agent did not induce tissue damage or inflammation beyond the treatment area. Additionally, IFeD MS exhibited promising imaging potential. The results of this study imply that the developed multifunctional embolic agent IFeD MS may have significant potential in transforming tumors previously only suitable for palliative cares into resectable radical treatments.

Preparation, evaluation and application of MRI detectable sunitinib-loaded calcium alginate/poly(acrylic acid) hydrogel microspheres.

Transcatheter arterial chemoembolization (TACE) is an effective method for the treatment of unresectable hepatocellular carcinoma. Although many embolic agents have been developed in TACE, there are few ideal embolic agents that combine drug loading, imaging properties and vessel embolization. Here, we developed novel magnetic embolic microspheres that could simultaneously load sunitinib malate (SU), be detected by magnetic resonance imaging (MRI) and block blood vessels. Calcium alginate/poly (acrylic acid) hydrogel microspheres (CA/PAA-MDMs) with superparamagnetic iron oxide nanoparticles (SPIONs) modified by citric acid were prepared by a drip and photopolymerization method. The embolization and imaging properties of CA/PAA-MDMs were evaluated through a series of experiments such as morphology, X-ray diffraction and X-ray photoelectron spectroscopy, magnetic responsiveness analysis, elasticity, cytotoxicity, hemolysis test, in vitro MRI evaluation, rabbit ear embolization and histopathology. In addition, the ability of drug loading and drug release of CA/PAA-MDMs were investigated by using sunitinib (SU) as the model drug. In conclusion, CA/PAA-MDMs showed outstanding drug loading capability, excellent imaging property and embolization effect, which would be expected to be used as a potential biodegradable embolic agent in the clinical interventional therapy.

Rheological behaviors of polypropylene/calcium carbonate nanocomposites under axial vibration force field.

Structures and data processing method of the self-developed multi-function and all-electric rheometer (MAR) for polymer composites were introduced. Polypropylene (PP)/Calcium Carbonate (CaCO3) nanocomposites were prepared. And the homogeneity of the composite was characterized by its rheological behavior. With MAR, the effects of vibration parameters on apparent shear viscosity of PP/CaCO3 nanocomposites were investigated. The results show that, the viscosity of the nanocomposites is much lower in dynamic test with proper vibration, comparing with it in corresponding steady-state test at same shear rate. This may be caused by the change of microstructure of the composites under vibration. The shear viscosity sharply decreases with the increase of vibration amplitude. However, the influence of vibration frequency on the shear viscosity of PP/CaCO3 nanocomposites is insignificant. Therefore, it is a good way to increase the superimposed vibration amplitude rather than the frequency to decrease the flow resistance. It is useful for discovering the energy saving mechanic of the polymer processing introduced the vibration energy into.

CXCL9 correlates with antitumor immunity and is predictive of a favorable prognosis in uterine corpus endometrial carcinoma.

Background: The C-X-C motif chemokine ligand-9 (CXCL9) is related to the progression of multiple neoplasms. Yet, its biological functions in uterine corpus endometrioid carcinoma (UCEC) remain shrouded in confusion. Here, we assessed the prognostic significance and potential mechanism of CXCL9 in UCEC. Methods: Firstly, bioinformatics analysis of the public cancer database, including the Cancer Genome Atlas / the Genotype-Tissue Expression project (TCGA+ GTEx, n=552) and Gene Expression Omnibus (GEO): GSE63678 (n=7), were utilized for the CXCL9 expression-related analysis in UCEC. Then, the survival analysis of TCGA-UCEC was performed. Futher, the gene set enrichment analysis (GSEA) was carried out to reveal the potential molecular signaling pathway in UCEC associated with CXCL9 expression. Moreover, the immunohistochemistry (IHC) assay of our validation cohort (n=124) from human specimens were used to demonstrate the latent significance of CXCL9 in UCEC. Results: The bioinformatics analysis suggested that CXCL9 expression was significantly upregulated in UCEC patients; and hyper-expression of CXCL9 was related to prolonged survival. the GSEA enrichment analysis showed various immune response-related pathways, including T/NK cell, lymphocyte activation, cytokine-cytokine receptor interaction network, and chemokine signaling pathway, mediated by CXCL9. In addition, the cytotoxic molecules (IFNG, SLAMF7, JCHAIN, NKG7, GBP5, LYZ, GZMA, GZMB, and TNF3F9) and the immunosuppressive genes (including PD-L1) were positively related to the expression of CXCL9. Further, the IHC assay indicated that the CXCL9 protein expression was mainly located in intertumoral and significantly upregulated in the UCEC patients; UCEC with high intertumoral CXCL9 cell abundance harbored an improved prognosis; a higher ratio of anti-tumor immune cells (CD4+, CD8+, and CD56+ cell) and PD-L1 was found in UCEC with CXCL9 high expression. Conclusion: Overexpressed CXCL9 correlates with antitumor immunity and is predictive of a favorable prognosis in UCEC. It hinted that CXCL9 may serve as an independent prognostic biomarker or therapeutic target in UCEC patients, which augmented anti-tumor immune effects to furnish survival benefits.

Targeting ESM1/ VEGFα signaling axis: a promising therapeutic avenue for angiogenesis in cervical squamous cell carcinoma.

Background: Endothelial-specific molecule 1 (ESM1) dysregulation is widespread in various malignancies. However, the exact significance of ESM1 in cervical squamous cell carcinoma (CSCC) is not yet well understood. Methods: The expression of ESM1 in CSCC was probed by immunohistochemistry (IHC) assay using human specimens and validated and explored ESM1 in CSCC based on TNMplot and TCGA (The Cancer Genome Atlas Program) data repository. Further, the GSEA analysis and in vitro experiments of human CSCC cell lines, including SiHa and ME-180, were performed to investigate the masked molecular mechanisms of ESM1 in CSCC. Results: ESM1 was overexpressed in clinical CSCC tissues compared with paracancer controls, was an independent prognostic factor and was associated with poor prognosis in CSCC patients. These findings were further confirmed in the TNMplot and TCGA datasets. Furthermore, GSEA analysis revealed that the ESM1 high expression group was significantly enriched in carcinoma angiogenesis and the VEGFα signaling pathway. In addition, in vitro assays with human CSCC cell lines, including SiHa and ME-180, demonstrated that knockdown of ESM1 expression inhibited tumor cell proliferation, migration and invasion, resulting in attenuated VEGFα expression and blocked phosphorylation of VEGFR2 and ERK-1/2. Conclusion: In CSCC patients, ESM1 was considerably overexpressed. Upregulation of ESM1 is predictive of poor clinical outcomes in CSCC. Furthermore, ESM1 overexpression promoted carcinoma angiogenesis and CSCC progression through the VEGF/ERK signaling pathway. Hence, ESM1 and associated genes might be useful prognostic biomarkers or therapeutic targets for CSCC individuals.

One-step photocatalytic synthesis of Fe3O4@polydiallyl isophthalate magnetic microspheres for magnetocaloric tumor ablation and its potential for tracing on MRI and CT.

Allyl monomers that were previously considered to be difficult to polymerize are applied, and Fe3O4@polydiallyl isophthalate (Fe3O4@PDAIP) magnetic were synthesized by one-step photopolymerization. The skeleton of the microspheres is made of diallyl isophthalate (DAIP). We obtained the microspheres using the photo-click technique in a soft template with Nano-Fe3O4 evenly disseminated in hydrophobic DAIP by cation-π and polar interaction. The obtained Fe3O4@PDAIP magnetic microspheres can achieve tumor cell necrosis temperatures (41-52 °C) in an alternating magnetic field due to their inherent magnetic response. The results of in vitro CT and MR imaging indicate that the microspheres might be monitored accurately in vivo. Then the structural characteristics of the microspheres were confirmed by morphological analysis and physicochemical property analysis. Experiments in vitro and in vivo revealed that the microspheres had an anti-tumor effect and their biocompatibility satisfies the standards. The stability experiment proves that the microspheres have the potential for long-term effectiveness in vivo. It demonstrates the promise of Fe3O4@PDAIP magnetic microspheres in clinical applications.

Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation.

Background: POLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved. Methods: The TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type. Results: The bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type. Conclusion: The infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.

The insulin long-acting chitosan - Polyethyleneimine nanoparticles to treat the type 2 diabetes mellitus and prevent the associated complications.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, which is ultimately treated by the insulin (INS). However, the subcutaneous (s. c.) injection of insulin solution faces the problems of pain and unsatisfactory patient compliance. In this study, the long-acting formulations of insulin are propsed to treat the T2DM and prevent the associated complications. The chitosan (CS) and/or branched polyethyleneimine (bPEI) nanoparticles (bPEI-INS NPs, CS-bPEI-INS NPs) were constructed to load insulin. The long -acting nanoparticles successfully achieved the sustained release of the INS in vitro and in vivo. After s. c. administration, the CS-bPEI-INS NPs greatly improved the INS bioavailability. As a result, the CS-bPEI-INS NPs produced sustained glucose-lowering effects, promising short-term and long-term hypoglycemic efficacy in the T2DM model. Furthermore, the treatment of the CS-bPEI-INS NPs greatly protected the islet in the pancreas and prevented the associated complications of the T2DM, such as cardiac fibrosis in the myocardial interstitium and the perivascular area. In a word, the CS-bPEI-INS NPs was an encouraging long-acting formulation of insulin and had great potential in the treatment of T2DM.

Coassembling functionalized glycopolypeptides to prepare pH-responsive self-indicating nanocomplexes to manipulate self-assembly/drug delivery and visualize intracellular drug release.

The pH-responsive polymeric micelles (PMs) have been widely used as smart nano drug delivery systems to treat tumors. However, synchronously manipulating these PMs' self-assembly properties, drug release dynamics and tracing their pH-dependent intracellular fate remain challenges. Herein, we have first synthesized hyaluronic acid (HA) based glycopolypeptides modified by tetraphenylethylene (TPE) and a pH-sensitive doxorubicin (DOX) prodrug through Diels-Alder reaction, respectively. Then, the pH-responsive nanocomplexes (NCs) were prepared by coassembling the two obtained glycopolypeptides with different formulations. Controllable size within the range of 60-125 nm and morphologies like spherical, vesicular and oblate micelles can be easily accomplished by using this method; High drug encapsulating and loading efficiency can be easily realized and adjusted within a range of 86-97% and 7-25%, respectively; Acid sensitive drug release dynamics of these NCs are also tunable by using this way. Additionally, the programmed drug release induced by subtle pH variations can be extracellularly self-indicated by detecting the blue AIE changes of the TPE units through fluorescence resonance energy transfer (FRET) effect between DOX and TPE. More importantly, the dynamic pH-triggered DOX release can be easily traced inside the tumor cells by visualizing blue emission changes of the TPE through the FRET effect. In addition, both the size and the shape can affect the endocytic routes of the NCs; The HA coated NCs targeting the tumor cells can effectively inhibit the proliferation of the HeLa cells. This work can provide a new route to acquire the stimuli-responsive self-indicating PMs with the ability to adjust their self-assembly properties and their pH-triggered drug release dynamics, and even to simultaneously visualize the PMs' intracellular fate in a real-time.

Identification and characterization of B220+/B220- subpopulations in murine Gr1+CD11b+ cells during tumorigenesis.

Although all murine MDSCs are defined as Gr1+CD11b+, their true immunophenotype remains elusive. In this study, we found murine Gr1+CD11b+ cells can be divided into two subsets: Gr1+CD11b+B220- and Gr1+CD11b+B220+, especially in the spleen tissues. Unlike the dominant B220- subset, the B220+ subpopulation was not induced by tumor in vivo. Moreover, Gr1+CD11b+B220+ cells from tumor-bearing mice spleens were unable to induce arginase 1 and inducible nitric oxide synthase expression, inhibit T cell proliferation, or promote tumor growth in primary tumor site. Nevertheless, these cells suppressed tumor metastasis in vivo and reduced cancer cell motility in vitro, while Gr1+CD11b+B220- cells from tumor-bearing mice spleens promoted tumor metastasis and enhanced cancer cell motility. Furthermore, both the polymorphonuclear (PMN-MDSCs) and monocytic MDSCs (Mo-MDSCs) could be further divided into B220- and B220+ subsets; interestingly, tumor only induced the expansion of B220- PMN-MDSCs and B220- Mo-MDSCs, but not the B220+ counterparts. Compared with B220- PMN-MDSCs and B220- Mo-MDSCs, the Ly6G+Ly6C-CD11b+B220+ and Ly6G-Ly6C+CD11b+B220+ cells from tumor-bearing mice spleens exhibited a more mature phenotype without immunosuppressive activity. Additionally, IL-6 deficiency attenuated the tumor-induced accumulation of MDSCs, B220- MDSCs and B220- PMN-MDSCs but increased the percentages of Gr1+CD11b+B220+, Ly6G+Ly6C-CD11b+B220+, and Ly6G-Ly6C+CD11b+B220+ cells, indicating the opposing roles of the IL-6 signaling pathway in the expansion of B220- MDSCs and their B220+ counterparts. Taken together, our findings indicate that the B220+ subset is a distinct subset of Gr1+CD11b+ cells functionally different from the B220- subpopulation during tumorigenesis and induction of MDSCs to B220+ cells may be helpful for cancer therapy.