Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Vaccination of TLR7/8 Agonist-Conjugated Antigen Nanoparticles for Cancer Immunotherapy.

Nanovaccine-based immunotherapy can initiate strong immune responses and establish a long-term immune memory to prevent tumor invasion and recurrence. Herein, the assembly of redox-responsive antigen nanoparticles (NPs) conjugated with imidazoquinoline-based TLR7/8 agonists for lymph node-targeted immune activation is reported, which can potentiate tumor therapy and prevention. Antigen NPs are assembled via the templating of zeolitic imidazolate framework-8 NPs to cross-link ovalbumin with disulfide bonds, which enables the NPs with redox-responsiveness for improved antigen cross-presentation and dendritic cell activation. The formulated nanovaccines promote the lymphatic co-delivery of antigens and agonists, which can trigger immune responses of cytotoxic T lymphocytes and strong immunological memory. Notably, nanovaccines demonstrate their superiority for tumor prevention owing to the elicited robust antitumor immunity. The reported strategy provides a rational design of nanovaccines for enhanced cancer immunotherapy.

Sticktight-inspired PEGylation for low-fouling coatings.

Polyethylene glycol (PEG) has been widely used for modifying surfaces to reduce non-specific interactions with biomolecules, microorganisms, and cells. Herein, we report a sticktight-inspired PEGylation strategy to fabricate low-fouling coatings. The influence of PEG molecular architectures on the PEG density and biological adhesion were studied. Notably, an increase in the number of arms resulted in improved surface PEGylation and an improved antifouling ability against the adhesion of proteins, mammalian cells and bacteria. The molecular architecture-dependent PEGylation strategy is an attractive approach for developing advanced low-fouling coatings.

High-Voltage FDS of Thermally Aged XLPE Cable and Its Correlation with Physicochemical Properties.

This paper aims to investigate the influence of thermal aging on a crosslinked polyethylene (XLPE) cable, and the relationships between the macroscopical high-voltage dielectric and the microscopical physicochemical properties are also elucidated. To better simulate thermal aging under working condition, the medium-voltage-level cable is subjected to accelerated inner thermal aging for different aging times. Then, high-voltage frequency domain spectroscopy (FDS) (cable sample) and analyses of microscopic physical and chemical properties (sampling from the cable), including Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and elongation at the break (EAB), are conducted at different cable aging stages. The dielectric test results show that after a certain aging time, the high-voltage FDS curves of the cable have layered characteristics, and this phenomenon is more obvious as the aging degree increases. Moreover, the slope and the integral of the high-voltage FDS curves rise with aging time. The mechanism is deduced by the physicochemical results that thermo-oxidative aging results in increasing polar groups and dislocation defects in the crystal region, which leads to the above phenomenon. On the one hand, the appearance of polar groups increases the density of the dipole. On the other hand, the destruction of the crystal region increases the probability and amplitude of dipole reversal. In addition, the breaking of molecular bonds and the increase in the amorphous phase also reduce the rigidity of the XLPE molecular main chain. The above factors lead to obvious delamination and larger dielectric parameters of the thermally aged cable. Finally, according to the experimental results, an on-site diagnosis method of cable insulation thermal aging based on high-voltage FDS is discussed.

Confined microemulsion sono-polymerization of poly(ethylene glycol) nanoparticles for targeted delivery.

Confined sono-polymerization is developed to prepare poly(ethylene glycol) nanoparticles within water-in-oil microemulsion, followed by post-functionalization with a bispecific antibody (anti HER2 and anti PEG) for targeted delivery of photosensitizers (i.e., indocyanine green). The nanoparticles could specifically target to breast cancer cells (i.e., SKBR3) that overexpress HER2 receptors for the inhibition of cancer cell growth under 808 nm laser irradiation. This study highlights a facile and controllable method to fabricate therapeutic nanoparticles capable of targeted delivery.

Facile Synthesis of Water-Soluble Rhodamine-Based Polymeric Chemosensors via Schiff Base Reaction for Fe3+ Detection and Living Cell Imaging.

Quantitative and accurate determination of iron ions play a vital role in maintaining environment and human health, but very few polymeric chemosensors were available for the detection of Fe3+ in aqueous solutions. Herein, a water-soluble rhodamine-poly (ethylene glycol) conjugate (DRF-PEG), as a dual responsive colorimetric and fluorescent polymeric sensor for Fe3+ detection with high biocompatibility, was first synthesized through Schiff base reaction between rhodamine 6G hydrazide and benzaldehyde-functionalized polyethylene glycol. As expected, the introduction of PEG segment in DRF-PEG significantly improved the water solubility of rhodamine derivatives and resulted in a good biosensing performance. The detection limit of DRF-PEG for Fe3+ in pure water is 1.00 µM as a fluorescent sensor and 3.16 µM as a colorimetric sensor at pH 6.5. The specific sensing mechanism of DRF-PEG toward Fe3+ is proposed based on the intramolecular charge transfer (ICT) mechanism, in which the O and N atoms in rhodamine moiety, together with the benzene groups from benzaldehyde-modified PEG segment, participate in coordination with Fe3+. Furthermore, DRF-PEG was applied for the ratiometric imaging of Fe3+ in HeLa cells and showed the potential for quantitative determination of Fe3+ in fetal bovine serum samples. This work provides insights for the design of water-soluble chemosensors, which can be implemented in iron-related biological sensing and clinical diagnosis.

Polymorphic transient glycolipid assemblies with tunable lifespan and cargo release.

HYPOTHESIS: In living systems, dynamic processes like dissipative assembly, polymorph formation, and destabilization of hydrophobic domains play an indispensable role in the biochemical processes. Adaptation of biological self-assembly processes to an amphiphilic molecule leads to the fabrication of intelligent biomaterials with life-like behavior. EXPERIMENTS: An amphiphilic glycolipid molecule was engineered into various dissipative assemblies (vesicles and supramolecular nanotube-composed hydrogels) by using two activation steps, including heating-cooling and shear force in method-1 or boric acid/glycolipid complexation and shear force in method-2. The influence of number of activation steps on vesicle to nanotube phase transitions and activation method on the properties of hydrogels were investigated, where the morphological transformations and destabilization of hydrophobic domains resulted from a bilayer to a higher-order crystal structure. FINDINGS: Hydrophobic and hydrophilic cargos encapsulated in the dissipative assemblies (vesicles and injectable hydrogels) can be released in a controlled manner via changing the activation method. The reported adaptive materials engineered by dual activation steps are promising self-assembled systems for programmed release of loaded cargos at a tunable rate.

Sono-Fenton Chemistry Converts Phenol and Phenyl Derivatives into Polyphenols for Engineering Surface Coatings.

We report a sono-Fenton strategy to mediate the supramolecular assembly of metal-phenolic networks (MPNs) as substrate-independent coatings using phenol and phenyl derivatives as building blocks. The assembly process is initiated from the generation of hydroxyl radicals (. OH) using high-frequency ultrasound (412 kHz), while the metal ions synergistically participate in the production of additional . OH for hydroxylation/phenolation of phenol and phenyl derivatives via the Fenton reaction and also coordinate with the phenolic compounds for film formation. The coating strategy is applicable to various phenol and phenyl derivatives and different metal ions including FeII , FeIII , CuII , and CoII . In addition, the sono-Fenton strategy allows real-time control over the assembly process by turning the high-frequency ultrasound on or off. The properties of the building blocks are maintained in the formed films. This work provides an environmentally friendly and controllable method to expand the application of phenolic coatings for surface engineering.

Association Between Renal Dysfunction and Low HDL Cholesterol Among the Elderly in China.

Objective: Chronic kidney disease (CKD) and cardiovascular disease (CVD) have a high morbidity and mortality among the elderly. Low levels of high-density lipoprotein cholesterol (HDL-C), a traditional risk marker for CVD, are common in CKD patients. Little is known about the association of low HDL-C with renal dysfunction in the community dwelling population. Methods: This was a population-based cross-sectional study included 4,753 participants enrolled in a prospective study, the Shanghai Elderly Cardiovascular Health (SHECH) study. Estimated glomerular filtration rate (eGFR), calculated by the Chinese Modification of Diet in Renal Disease (C-MDRD equation), was used to assess renal dysfunction. Associations between renal dysfunction and low HDL-C were evaluated using multiple logistic regression models and restricted cubic splines. Results: Of 4,649 individuals who met inclusion criteria, 620 (13.34%) had low HDL-C at <40 mg/dl. In the fully adjusted model, lower eGFR of <60 ml/min/1.73 m2 (OR, 2.03; 95% CI, 1.21-3.43) and marginal eGFR of 60 to 90 ml/min/1.73 m2 (OR, 1.26; 95% CI, 1.01-1.58) were significantly associated with low HDL-C, compared with normal eGFR of ≥90 ml/min/1.73 m2. Moreover, consistent findings were obtained in subsidiary analyses using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Fully adjusted cubic spline models indicated a significant dose-response relationship between eGFR and low HDL-C (P for non-linearity, 0.356). Conclusion: In this general elderly population, renal dysfunction was independently and significantly associated with low HDL-C, and the prevalence of low HDL-C increased with decreasing eGFR, such that even slight changes in renal function may be associated with altered lipid levels.

Ultrasound expands the versatility of polydopamine coatings.

Polydopamine (PDA) coating of surfaces is a versatile strategy to fabricate functional films on various substrates, which typically requires oxygen and alkaline pH. Overcoming such limitations may enhance the versatility of this technique. Herein, we develop a simple and green sonochemical process for PDA coatings, which overcomes the limitations of traditional coating technique and expands the versatility of PDA chemistry. The oxidizing radicals generated by high frequency ultrasound (412 kHz) are utilized to initiate and accelerate the polymerization of dopamine. The sonochemical rate of film deposition is found to be about twice faster than that of the traditional method in the presence of oxygen. Importantly, the PDA coatings can be obtained in neutral or acidic aqueous solutions and even in the absence of oxygen. The PDA coatings can be moderated by turning on or off high frequency ultrasound. This study provides an environmentally friendly and economic method for the engineering of PDA coatings independent of the solution pH and nature of dissolved gas.

Computational Drug Repositioning with Random Walk on a Heterogeneous Network.

Drug repositioning is an efficient and promising strategy to identify new indications for existing drugs, which can improve the productivity of traditional drug discovery and development. Rapid advances in high-throughput technologies have generated various types of biomedical data over the past decades, which lay the foundations for furthering the development of computational drug repositioning approaches. Although many researches have tried to improve the repositioning accuracy by integrating information from multiple sources and different levels, it is still appealing to further investigate how to efficiently exploit valuable data for drug repositioning. In this study, we propose an efficient approach, Random Walk on a Heterogeneous Network for Drug Repositioning (RWHNDR), to prioritize candidate drugs for diseases. First, an integrated heterogeneous network is constructed by combining multiple sources including drugs, drug targets, diseases and disease genes data. Then, a random walk model is developed to capture the global information of the heterogeneous network. RWHNDR takes advantage of drug targets and disease genes data more comprehensively for drug repositioning. The experiment results show that our approach can achieve better performance, compared with other state-of-the-art approaches which prioritized candidate drugs based on multi-source data.

LDAP: a web server for lncRNA-disease association prediction.

Motivation: Increasing evidences have demonstrated that long noncoding RNAs (lncRNAs) play important roles in many human diseases. Therefore, predicting novel lncRNA-disease associations would contribute to dissect the complex mechanisms of disease pathogenesis. Some computational methods have been developed to infer lncRNA-disease associations. However, most of these methods infer lncRNA-disease associations only based on single data resource. Results: In this paper, we propose a new computational method to predict lncRNA-disease associations by integrating multiple biological data resources. Then, we implement this method as a web server for lncRNA-disease association prediction (LDAP). The input of the LDAP server is the lncRNA sequence. The LDAP predicts potential lncRNA-disease associations by using a bagging SVM classifier based on lncRNA similarity and disease similarity. Availability and Implementation: The web server is available at http://bioinformatics.csu.edu.cn/ldap Contact: jxwang@mail.csu.edu.cn. Supplimentary Information: Supplementary data are available at Bioinformatics online.

Facile Preparation and Radiotherapy Application of an Amphiphilic Block Copolymer Radiosensitizer.

Radiosensitizer plays an important role in the cancer radiotherapy for efficient killing of hypoxic cancer cells at a low radiation dose. However, the commercially available small molecular radiosensitizers show low efficiency due to poor bioavailability in tumor tissues. In this report, we develop a novel amphiphilic block copolymer radiosensitizer, metronidazole-conjugated poly(ethylene glycol)-b-poly(γ-propargyl-l-glutamate) (PEG-b-P(PLG-g-MN)), which can be self-assembled into core-shell micelles (MN-Micelle) with an optimal size of ∼60 nm in aqueous solution. In vitro cytotoxicity evaluation indicated that MN-Micelle sensitized the hypoxic cancer cells more efficiently under radiation with the sensitization enhancement ratio (SER) of 1.62 as compared with that of commercially available sodium glycididazole (GS; SER = 1.17) at the metronidazole-equivalent concentration of 180 µg/mL. Upon intravenous injection of MN-Micelle into the tumor-bearing mice, high tumor deposition was achieved, which finally suppressed tumor growth completely after electron beam radiation at a low radiation dose of 4 Gy. MN-Micelle with outstanding performance as an in vivo radiosensitizer holds great potentials for translation into radiotherapy application.

Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin.

Construction of efficient doxorubicin (DOX) delivery systems addressing a cascade of physiological barriers remains a great challenge for better therapeutic efficacy of tumors. Herein, we design well-defined enzyme-responsive peptide-linked block copolymer, PEG-GPLGVRGDG-P(BLA-co-Asp) [PEG and P(BLA-co-Asp) are poly(ethylene glycol) and partially hydrolyzed poly(ß-benzyl l-aspartate) (PBLA), respectively] (P3), with modular functionality for efficient delivery of DOX. The block copolymers were successfully obtained via click reaction to introduce peptide (alkynyl-GPLGVRGDG) into the end of PEG for initiating ring-opening polymerization of ß-benzyl l-aspartate N-carboxyanhydride (BLA-NCA) by terminal amino groups followed by partial hydrolysis of PBLA segments. P3 micelle was demonstrated to encapsulate DOX efficiently through synergistic effect of benzyl group-based hydrophobic and carboxyl moiety-based electrostatic interactions. Effective matrix metalloproteinase-2 (MMP-2)-triggered cleavage of peptide for dePEGylation of P3 micelles was confirmed and residual RGD ligands were retained on the surfaces. Against HT1080 cells overexpressing MMP-2, DOX-loaded P3 micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration (IC50) value of DOX-loaded P3 micelles was determined to be 0.38 µg/mL compared with 0.66 µg/mL of free DOX due to MMP-triggered dePEGylation, RGD-mediated cellular uptake, and rapid drug release inside cells. Binding and penetration evaluation toward HT1080 multicellular tumor spheroids (MCTs) confirmed high affinity and deep penetration of P3 micelles in tumor tissues. This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing a cascade of delivery barriers.

Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization and Triggered Drug Release.

Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles is frequently subjected to low drug loading efficiency (DLE) and loading content (DLC), as well as lower micellar stability and uncontrollable drug release. In this report, we prepare the copolymer prodrugs (PPEMA-co-PCPTM) via reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(piperidin-1-yl)ethyl methacrylate (PEMA) and reduction-responsive CPT monomer (CPTM), which were quantitatively encapsulated into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles. The polymer prodrug-loaded nanoparticles showed high stability for a long time in aqueous solution or blood serum and even maintain similar size after a lyophilization-dissolution cycle. The tumoral pH (∼6.8)-responsive properties of PPEMA segments endow the micellar cores with triggered transition from neutral to positively charged and swellable properties. The PEG-b-PCL nanoparticles loading polymer prodrugs (PPEMA-b-PCPTM) eliminated burst drug release. Simultaneously, CPT drug release can be triggered by reductive agents and solution pH. At pH 6.8, efficient cellular internalization was achieved due to positively charged cores of the nanoparticles. As compared with nanoparticles loading PCPTM, higher cytotoxicity was observed by the nanoparticles loading PPEMA-b-PCPTM at pH 6.8. Further multicellular tumor spheroid (MCTs) penetration and growth suppression studies demonstrated that high-efficiency penetration capability and significant size shrinkage of MCTs were achieved after treatment by PPEMA-b-PCPTM-loaded nanoparticles at pH 6.8. Therefore, the responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the nanoparticles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability.