An AIEgen and Iodine Double-Ornamented Platinum(II) Complex for Bimodal Imaging-Guided Chemo-Photodynamic Combination Therapy.

Real-time biodistribution monitoring and enhancing the therapeutic efficacy of platinum(II)-based anticancer drugs are urgently required to elevate their clinical performance. Herein, a tetraphenylethene derivative (TP) with aggregation-induced emission (AIE) properties and an iodine atom are selected as ligands to endow platinum (II) complex TP-Pt-I with real-time in vivo self-tracking ability by fluorescence (FL) and computerized tomography (CT) imaging, and improved anticancer efficacy by the combination of chemotherapy and photodynamic therapy. Especially, benefiting from the formation of a donor-acceptor-donor structure between the AIE photosensitizer TP and Pt-I moiety, the heavy atom effects of Pt and I, and the presence of I, TP-Pt-I displayed red-shifted absorption and emission wavelengths, enhanced ROS generation efficiency, and improved CT imaging capacity compared with the pristine TP and the control agent TP-Pt-Cl. As a result, the enhanced intratumoral accumulation of TP-Pt-I loaded nanoparticles is readily revealed by dual-modal FL and CT imaging with high contrast. Meanwhile, the TP-Pt-I nanoparticles show significantly improved tumor growth-inhibiting effects on an MCF-7 xenograft murine model by combining the chemotherapeutic effects of platinum(II) and the photodynamic effects of TP. This self-tracking therapeutic complex thus provides a new strategy for improving the therapeutic outcomes of platinum(II)-based anticancer drugs.

Risk factors analyses associated with postoperative infection in choledochoscopy for intrahepatic bile duct stones (IHDs): a single-center retrospective study in real-world setting.

BACKGROUND: Choledochoscopy is a highly effective approach for managing intrahepatic bile duct stones (IHDs). However, postoperative infection is a common complication that significantly impacts treatment outcomes. Despite its clinical relevance, the risk factors associated with this procedure remain largely unexplored. METHODS: This study focused on a consecutive cohort of patients who underwent choledochoscopy for IHDs at our institution between January 2016 and December 2022. The primary objective was to analyze the relationship between various clinical factors and postoperative infection, and to compare the postoperative infection of different choledochoscopic procedures. RESULTS: The study cohort consisted of 126 patients, with 60 individuals (47.6%) experiencing postoperative infection. Notably, preoperative biliary obstruction (odds ratio [OR] 1.861; 95% confidence interval [CI] 1.314-8.699; p = 0.010) and operation time (OR 4.414; 95% CI 1.635-12.376; p = 0.004) were identified as risk factors for postoperative infection. Additionally, biliary tract infections (60.00%) were primarily responsible for postoperative infection, with Escherichia coli (47.22%) being the predominant bacterial strain identified in bile cultures. Furthermore, biliary tract obstruction (OR 4.563; 95% CI 1.554-13.401; p = 0.006) and body mass index (BMI) (OR 1.186; 95% CI 1.015-1.386; p = 0.031) were determined to be independent risk factors for postoperative biliary tract infection. CONCLUSIONS: The occurrence of postoperative infection in patients undergoing choledochoscopy was primarily associated with the duration of the operation and the presence of preoperative biliary obstruction.

Maskless lithography for large area patterning of three-dimensional microstructures with application on a light guiding plate.

This paper presents a maskless lithography system that can perform three-dimensional (3D) ultraviolet (UV) patterning on a photoresist (PR) layer. After PR developing processes, patterned 3D PR microstructures over a large area are obtained. This maskless lithography system utilizes an UV light source, a digital micromirror device (DMD), and an image projection lens to project a digital UV image on the PR layer. The projected UV image is then mechanically scanned over the PR layer. An UV patterning scheme based on the idea of obliquely scanning and step strobe lighting (OS3L) is developed to precisely control the spatial distribution of projected UV dose, such that desired 3D PR microstructures can be obtained after PR development. Two types of concave microstructures with truncated conical and nuzzle-shaped cross-sectional profiles are experimentally obtained over a patterning area of 160 ×115 mm2. These patterned microstructures are then used for replicating nickel molds and for mass-production of light-guiding plates used in back-lighting and display industry. Potential improvements and advancements of the proposed 3D maskless lithography technique for future applications will be addressed.

Retrospective Study on the Effect of Adipose-Derived Stem Cells on the Proliferation and Apoptosis of Keloid Fibroblasts Through the Suppression of ITGA2.

BACKGROUND: Keloid is characterized by excessive collagen accumulation and fibroblast growth, which are fibroproliferative disorders of injured skin, causing functional limitations. Studies have shown that adipose-derived stem cells (ADSCs) inhibit the bioactivity and fibrosis of keloid fibroblasts. However, the molecular mechanism of this effect of ADSCs on keloid formation has not been fully elucidated. METHODS: This in vitro study used fibroblasts obtained from keloids. A consensus gene co-expression network was constructed to focus on identifying consensus gene co-expression modules associated with keloid fibroblasts. Differentially expressed genes (DEGs) were identified between keloid fibroblasts and normal dermal fibroblasts. A functional enrichment analysis was also performed with the DAVID database. A weighted gene co-expression network analysis (WGCNA) was used to screen keloid-related modules using the "WGCNA" R package, followed by hub gene selection in modules from the Protein-protein interaction network through the STRING database. Keloid fibroblasts and ADSCs were extracted and cultured. Proliferation and apoptosis were examined using a 5-ethynyl-2-deoxyuridine (Edu) kit and flow cytometry. RESULTS: We identified 302 DEGs overlapping with a consensus analysis of clusters and a differential expression analysis between keloid fibroblasts and normal dermal fibroblasts. Most of these were involved in collagen binding, extracellular matrix organization, and the PI3K-Akt signaling pathway. WGCNA analysis selected a keloid-associated brown module. ITGA2 was identified as a novel marker in hub genes from the PPI network based on the degree and function of collagen modulation. Furthermore, the proliferation ability of keloid fibroblasts cultured in ADSC medium was inhibited while apoptosis was dramatically increased. Overexpression of ITGA2 reversed the decrease in ADSC-induced apoptosis and increased ADSC-reduced proliferation. CONCLUSION: Our study demonstrated that activation of ITGA2 plays a crucial role in ADSC-induced keloid fibroblast apoptosis and anti-proliferation effects. These results also improved our understanding of the molecular mechanism of the pathogenesis of keloid in response to ADSCs and may contribute to the further development of keloid therapy.

Reduction-Sensitive Fluorinated-Pt(IV) Universal Transfection Nanoplatform Facilitating CT45-Targeted CRISPR/dCas9 Activation for Synergistic and Individualized Treatment of Ovarian Cancer.

Compared to traditional clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, CRISPR/dead Cas9 (dCas9) system can precisely regulate endogenous gene expression without damaging the host gene, representing a greater potential for cancer therapy. Cancer/testis antigen 45 (CT45) is proved to enhance platinum-based chemosensitivity for individualized ovarian cancer therapy. However, the development of a single nanocarrier codelivering CRISPR/dCas9 system and chemotherapeutics for synergistic cancer therapy still faces challenges. Herein, a reduction-sensitive fluorinated-Pt(IV) universal transfection nanoplatform (PtUTP-F) is developed for the CT45-targeted CRISPR/dCas9 activation to achieve synergistic and individualized treatment of ovarian cancer. Overcoming multiple physiological barriers, PtUTP-F condensed gene can efficiently transfect into different cells including 293T cells, A2780, SKOV3, A549, and A2780/cisplatin (DDP) cancer cells, which is superior to Lipofectamine 6000. With the responsive release of gene and Pt(II) in the intracellular reducing microenvironment, PtUTP-F/dCas9-CT45 can generate CRISPR/dCas9 activation of CT45 expression for protein phosphatase 4C (PP4C) activity inhibition to hinder the DNA repair pathway and thus enhances the sensitivity to Pt(II) drugs for individualized A2780 tumor therapy. The PtUTP-F not only represents a powerful nanoplatform for CRISPR/dCas9 system delivery but also initiates a novel strategy for synergistic and individualized treatment of CRISPR/dCas9-based gene therapy with chemotherapy.

Self-compensation method for dual-beam roll angle measurement of linear stages.

In this paper, a self-compensation method for improving the accuracy of roll angle measurement of a linear stage caused by the non-parallelism of dual-beam due to time-dependent mechanical deformation of the support is proposed and integrated into a 5-DOF sensor to verify the feasibility. The non-parallelism between two laser beams is online real-time monitored by a pair of small autocollimator units. Through the ray-tracing analysis, the method to separate the roll angle of the moving stage and non-parallelism induced roll error is determined. A series of experiments under different supporting forces and ambient conditions have been carried out. The compensated P-V values of the roll angles are all within ±4 arc-sec, no matter how bad the originally measured value of the linear stage is. The average improvement of about 95% is significant. The effectiveness and robustness of the proposed measurement system in the changing environment are verified.

A self-healing, recyclable, and degradable fire-retardant gelatin-based biogel coating for green buildings.

Wood is one of the oldest building materials and commonly employed in construction. However, the inherent fire hazard of wood restricts its practical application. Application of fire retardant coatings has been proved to be a highly efficient method for improving the fire retardancy of structural materials during combustion. However, developing sustainable, renewable and environmentally-friendly coatings is challenging because of the dependence on traditional flame retardants. In this study, a self-healable, fully-recyclable and biodegradable biogel coating was proposed, derived entirely from natural and food-safe constituents, which has rarely been demonstrated for wood safety. A uniform and strongly-adhesive coating could be obtained on wood surfaces via a facile preparation process without compromising the inherent mechanical properties of wood. Meanwhile, the coating showed excellent self-healing properties after damage, full degradability and good recyclability when disposed. Remarkably, biogel-coated wood exhibited enhanced fire-retardant properties, reflected by a 24.0% decrease in peak heat release rate and 17.2% reduction in total heat release with a 350 µm thick coating, along with a sixfold enhancement in ignition delay time and self-extinguishing behavior. We merged all merits in one fire-retardant coating which can be easily reproduced, and is low cost and scalable, making the biogel-coated wood a promising candidate for widespread application in green buildings.

Green, tough and highly efficient flame-retardant rigid polyurethane foam enabled by double network hydrogel coatings.

Designing eco-friendly fireproof rigid polyurethane foam (RPUF) that can completely stop fire ignition or spread has significant technological implications, which has been proved to be extremely challenging. Herein, a novel green strategy based on double network hydrogel coating was developed to enhance the flame retardancy of RPUF via a facile casting and curing process. This strategy can create a homogeneous hydrogel fire-resistant layer with strong adhesion on the outermost surface of the substrate. Due to good water holding capacity and excellent thermal management properties, the hydrogel coating showed excellent fire retardancy. As a proof-of-concept, polyacrylic-polydopamine (PAAm-PDA) double network hydrogel coating was applied to an extremely flammable RPUF substrate. Compared with the neat foam, the PAAm-PDA coated RPUF exhibited an overall improvement in fire-safety performance, including a rapid self-quenching behavior, a six-fold enhancement in time to ignition (TTI), and 39.7% and 42.2% decreases in the mean heat release rate (HRR) and total smoke production (TSP), respectively. Furthermore, the tough hydrogel-coated RPUF possessed enough mechanical properties to meet the requirement of its practical applications. Benefiting from its low cost, easy-to-process and eco-friendly characteristics, this hydrogel fireproof coating strategy provides a new direction for developing green and safe structural materials with widespread use.

Photoactivatable Prodrug-Backboned Polymeric Nanoparticles for Efficient Light-Controlled Gene Delivery and Synergistic Treatment of Platinum-Resistant Ovarian Cancer.

Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos) generates oxygen-independent N3• with mild oxidation energy for efficient endo/lysosomal escape through N3•-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.

Dual Cross-linked HHA Hydrogel Supplies and Regulates MΦ2 for Synergistic Improvement of Immunocompromise and Impaired Angiogenesis to Enhance Diabetic Chronic Wound Healing.

Immunocompromise and impaired angiogenesis of diabetes lead to chronic inflammation when wounds occur, which is the primary reason for the long-term incurable nature of diabetic chronic wounds. Herein, a high-molecular-weight hyaluronic acid (HHA) hydrogel is developed to supply and regulate M2 phenotype macrophages (MΦ2) for synergistic improvement of immunocompromise and impaired angiogenesis. MΦ2 are seeded on the Cu-HHA/PVA hydrogels prepared by Cu2+ cross-linking of low degree and physical cross-linking (one freeze-thaw cycle and unique lyophilization) to form Cu-HHA/PVA@MΦ2 hydrogels. The Cu-HHA/PVA@MΦ2 hydrogel can directly supply the MΦ2 in the wound site, maintain the consistent phenotype of loaded MΦ2, and transform the M1 phenotype macrophages (MΦ1) in the wound bed to MΦ2 by HHA. Furthermore, Cu2+ could be released from the hydrogels to further stimulate angiogenesis, thus accelerating the wound-healing phase transition from inflammation to proliferation and remodeling. The average wound area after the 0.5Cu-HHA/PVA@MΦ2 (ionic cross-linking degree 0.5%) treatment was much smaller than that of other diabetic groups at day 12 and close to that of the wild nondiabetic control group. Therefore, this facile hydrogel strategy with multiple modulation mechanisms of immunocompromise and angiogenesis may act as a safe and effective treatment strategy for a diabetic chronic wound.

Human umbilical cord mesenchymal stem cell-derived exosomes suppress dermal fibroblasts-myofibroblats transition via inhibiting the TGF-ß1/Smad 2/3 signaling pathway.

OBJECTIVE: Exosomes originated from mesenchymal stem cells (MSCs) benefit wound healing. This study investigated effects of exosomes originated from human umbilical cord MSCs (hUC-MSCs) on dermal fibroblasts-myofibroblasts transition via the TGF-ß1/Smad2/3 signaling pathway. METHODS: Firstly, hUC-MSCs were collected and identified. Alizarin red, oil red O staining and toluidine blue staining were used to determine the osteogenic, adipogenic and chondrogenic differentiation abilities of hUC-MSCs. Then exosomes from hUC-MSCs were extracted and identified. To figure out the roles of exosomes and TGF-ß1 in dermal fibroblasts-myofibroblasts transition, dermal fibroblasts were treated with TGF-ß1 or/and exosomes at different concentrations. RT-qPCR, Western blot analyses were employed to examine levels of Collagen I, Collagen III, α-smooth muscle actin (α-SMA), and Smad2/3 phosphorylation, and immunofluorescence was employed to test α-SMA content and the localization and nucleation of Smad2/3 protein in cells. RESULTS: hUC-MSCs and exosomes were successfully cultured and extracted. Levels of Collagen I, Collagen III, α-SMA, and Smad2/3, and Smad2/3 phosphorylation in fibroblasts treated with exosomes decreased markedly. After treatment with exosomes and TGF-ß1 together, levels of Collagen I, Collagen III, α-SMA, and Smad2/3, and Smad2/3 phosphorylation in fibroblasts decreased significantly as compared to TGF-ß1-treated fibroblasts. Exosome treatment reduced the entry of Smad2/3 into fibroblasts. CONCLUSION: Our data suggested that hUC-MSCs-derived exosomes could inhibit dermal fibroblasts-myofibroblasts transition by inhibiting the TGF-ß1/Smad2/3 signaling pathway.

Amino-Modified Polymer Nanoparticles as Adjuvants to Activate the Complement System and to Improve Vaccine Efficacy in Vivo.

Subunit vaccines are safer but often poorly immunogenic in comparison to traditional vaccines, and thus, adjuvants and delivery vehicles are needed to enhance the immune response. The complement system is a part of the innate immune system, which plays an important role in innate and adaptive immunity. Therefore, the activation of the complement system could be utilized as a potential strategy for vaccine applications. Herein, cysteamine hydrochloride was grafted onto a methoxy poly(ethylene glycol)-block-poly (allyl glycidyl ether)-block-poly(ε-caprolactone) copolymer to synthesize a triblock polymer mPEG5k-PAGE15(NH2)-PCL5k(TPCAH) with amino groups on the side chain. The positive charge of the amino groups could bind with the negatively charged protein (like ovalbumin (OVA)) to form a stable complex by electrostatic interaction. The triblock copolymer TPCAH we designed can easily self-assemble into polymer nanomicelles, and the size of the nanoparticles is similar to that of the pathogens, which was beneficial to the uptake by lymphocytes. Furthermore, the amino groups modified on the side chain can not only integrate with proteins but also activate the complement system, thereby enhancing the immune response of subunit vaccines. The results showed that the complex TPCAH@OVA could efficiently promote powerful anti-OVA-specific antibody production, enhance CD4+ T- and CD8+ T-cell activation, improve the lymphocyte proliferation efficiency, and increase the secretion of different cytokines. In addition, the abundant amino groups on the surface of TPCAH@OVA could effectively activate the complement system to further enhance adaptive immunity. Overall, these results indicated that the triblock copolymer TPCAH as an adjuvant and carrier can effectively improve the ability of innate and adaptive immune responses to resist pathogens, making it a potential candidate for vaccine applications.

Different Signaling Pathways Define Different Interferon-Stimulated Gene Expression during Mycobacteria Infection in Macrophages.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) represents one of the greatest threats to human health., Interferons (IFNs) in combination with the first-line of anti-TB drugs have been used for treating TB for decades in the clinic, but how Mtb infection regulates interferon-stimulated genes (ISGs) in human macrophages (Mϕs) remains unknown. In this study, we investigated the expression-signature and associated innate signaling mechanisms of ISGs in Mtb-infected human monocyte-derived Mϕs (hMDMs) and THP-1-derived Mϕs (THP-1-Mϕs). Among 28 of the detected ISGs, 90% of them exerted a significant increase in Mtb-infected Mϕs. Additionally, we found that cytosolic cyclic (GMP-AMP) synthase (cGAS), toll-like receptor-2 (TLR-2) and TLR-4 signaling pathways participated in ISG induction. Their downstream elements of TANK-binding kinase 1 (TBK1), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) were selectively involved in Mtb-mediated ISG production. Finally, the numerous types of ISG expression in hMDMs of TB patients were more susceptible to restimulation of Mtb infection or/and IFN treatment than that of healthy people. Hence, different signaling pathways define different ISG expression during Mtb infection and this helps to illustrate how ISGs are elucidated and to better understand the host immune responses to Mtb infection in Mϕs.

Low cost, compact 4-DOF measurement system with active compensation of beam angular drift error.

In this paper, a compact four-degree-of-freedom (4-DOF) measurement system is presented. With a special optical configuration, the pitch error, yaw error, and two straightness errors of the moving target are able to be detected by only a single laser beam from a collimated laser diode. A 2D hybrid mirror angle steering mount is designed to perform the large angle turning for the axis alignment and very fine angle tuning by PZT actuators for real-time beam drift compensation. A series of calibration and comparison experiments have been carried out to verify the performance of the proposed system. The developed active compensation system could effectively suppress the beam's angular drift to within ± 0.01 arc-sec in both of yaw and pitch directions. The developed 4-DOF measuring system is compact, low cost, and suitable for long distance geometric error measurement of linear stages.

Development of Organic/Inorganic Compatible and Sustainably Bioactive Composites for Effective Bone Regeneration.

In this paper, we demonstrate a strategy of covalently bonding bioactive molecules onto inorganic hydroxyapatite (HAp) to improve the compatibility between organic and inorganic components and endow the bone composites with sustainable bioactivity. Bone morphogenetic protein-2 (BMP-2) peptide covalently immobilized nano-hydroxyapatite (nHAp-BMP-2) is developed to preserve the bioactivity and slow the release of the BMP-2 peptide. Then nHAp-BMP-2 was further incorporated into an ultraviolet-curable mixture of gelatin methacrylamide (GelMA) and four-armed PEG methacrylamide (four-armed PEGMA) to form a Gel/(nHAp-BMP-2) composite. The hydrogen bonding between gelatin and BMP-2 on nHAp-BMP-2 enhanced the compatibility between inorganic and organic components. The Gel/(nHAp-BMP-2) composite exhibited superior biocompatibility caused by gelatin and nHAp-BMP-2, except in a two-dimensional cell culture, the hydrogel was also capable of a three-dimensional cell culture. In addition, the introduction of nHAp-BMP-2 had a positive influence on bone marrow mesenchymal stem cell proliferation, differentiation, and the subsequent calcification on the composite. After treatment of a rat calvarial defect model for 12 weeks, the Gel/(nHAp-BMP-2) group showed the largest new bone volume and the highest ratio of new bone (50.54 ± 13.51 mm3 and 64.38 ± 17.22%, respectively) compared to those of the other groups. These results demonstrate that this way of controlling BMP-2 release is effective and the Gel/(nHAp-BMP-2) composite has great potential in bone regeneration therapy.

LncRNA-MALAT1 Promotes Angiogenesis of Thyroid Cancer by Modulating Tumor-Associated Macrophage FGF2 Protein Secretion.

Tumor-associated macrophages (TAMs) in the tumor microenvironment have been associated with enhanced tumor progression. In this study, we investigated the role and molecular mechanisms of MALAT1 in TAMs derived from thyroid cancer. The expression of MALAT1 and FGF2 in thyroid cancer tissues and cells were measured by quantitative real-time PCR and Western blot. TAMs were transfected with indicated constructs. Then the culture medium (CM) from TAMs was harvested for assay. Secreted FGF2 protein levels and TNF-α, IL-12, and IL-10 levels were detected by ELISA. The cell proliferation, migration, and invasion of FTC133 cells were determined with a CCK-8 assay and a Transwell assay, respectively. In addition, HUVEC vasculature formation was measured by matrigel angiogenesis assay. The higher levels of MALAT-1 and FGF2 were observed in thyroid cancer tissues and in thyroid cancer cells compared to that in the control. Besides, in the presence of si-MALAT1, the levels of TNF-α and IL-12 were significantly up-regulated whereas IL-10 was down-regulated in the CM from TAMs. Moreover, down-regulation of MALAT1 in TAMs reduced proliferation, migration, and invasion of FTC133 cells and inhibited angiogenesis. However, overexpression of FGF2 blocked the effects of MALAT1 siRNAs on cell migration, invasion, and angiogenesis. Our results suggest that MALAT1-mediated FGF2 protein secretion from TAMs inhibits inflammatory cytokines release, promotes proliferation, migration, and invasion of FTC133 cells and induces vasculature formation. J. Cell. Biochem. 118: 4821-4830, 2017. © 2017 Wiley Periodicals, Inc.

Amphiphilic Polycarbonates from Carborane-Installed Cyclic Carbonates as Potential Agents for Boron Neutron Capture Therapy.

Carboranes with rich boron content have showed significant applications in the field of boron neutron capture therapy. Biodegradable derivatives of carborane-conjugated polymers with well-defined structure and tunable loading of boron atoms are far less explored. Herein, a new family of amphiphilic carborane-conjugated polycarbonates was synthesized by ring-opening polymerization of a carborane-installed cyclic carbonate monomer. Catalyzed by TBD from a poly(ethylene glycol) macroinitiator, the polymerization proceeded to relatively high conversions (>65%), with low polydispersity in a certain range of molecular weight. The boron content was readily tuned by the feed ratio of the monomer and initiator. The resultant amphiphilic polycarbonates self-assembled in water into spherical nanoparticles of different sizes depending on the hydrophilic-to-hydrophobic ratio. It was demonstrated that larger nanoparticles (PN150) were more easily subjected to protein adsorption and captured by the liver, and smaller nanoparticles (PN50) were more likely to enter cancer cells and accumulate at the tumor site. PN50 with thermal neutron irradiation exhibited the highest therapeutic efficacy in vivo. The new synthetic method utilizing amphiphilic biodegradable boron-enriched polymers is useful for developing more-selective and -effective boron delivery systems for BNCT.

Dual-Sensitive Charge-Conversional Polymeric Prodrug for Efficient Codelivery of Demethylcantharidin and Doxorubicin.

A tumor is a complicated system, and tumor cells are typically heterogeneous in many aspects. Polymeric drug delivery nanocarriers sensitive to a single type of biosignals may not release cargos effectively in all tumor cells, leading to low therapeutic efficacy. To address the challenges, here, we demonstrated a pH/reduction dual-sensitive charge-conversional polymeric prodrug strategy for efficient codelivery. Reduction-sensitive disulfide group and acid-labile anticancer drug (demethylcantharidin, DMC)-conjugated ß-carboxylic amide group were repeatedly and regularly introduced into copolymer chain simultaneously via facile CuAAC click polymerization. The obtained multifunctional polymeric prodrug P(DMC), mPEG-b-poly(disulfide-alt-demethylcantharidin)-b-mPEG was further utilized for DOX encapsulation. Under tumor tissue/cell microenvironments (pH 6.5 and 10 mM GSH), the DOX-loaded polymeric prodrug nanoparticles (P(DMC)@DOX NPs) performed surface negative-to-positive charge conversion and accelerated/sufficient release of DMC and DOX. The remarkably enhanced cellular internalization and cytotoxicity in vitro, especially against DOX-resistant SMMC-7721 cells, were demonstrated. P(DMC)@DOX NPs in vivo also exhibited higher tumor accumulation and improved antitumor efficiency compared to P(SA)@DOX NPs with one drug and without charge-conversion ability. The desired multifunctional polymeric prodrug strategy brings a new opportunity for cancer chemotherapy.

Single-Stimulus Dual-Drug Sensitive Nanoplatform for Enhanced Photoactivated Therapy.

Photoactivated therapy has become a complementary and attractive modality for traditional cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nanoplatform, Cur-loaded Dex-Pt(N3) nanoparticles (Cur@DPNs) for enhanced photoactivated therapy. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant reactive oxygen species from Cur for fast photodynamic therapy and release lasting Pt(II) from Pt(N3) for long-acting photochemotherapy. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photoactivated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future.

Structure of pneumococcal peptidoglycan hydrolase LytB reveals insights into the bacterial cell wall remodeling and pathogenesis.

Streptococcus pneumoniae causes a series of devastating infections in humans. Previous studies have shown that the endo-ß-N-acetylglucosaminidase LytB is critical for pneumococcal cell division and nasal colonization, but the biochemical mechanism of LytB action remains unknown. Here we report the 1.65 Å crystal structure of the catalytic domain (residues Lys-375-Asp-658) of LytB (termed LytBCAT), excluding the choline binding domain. LytBCAT consists of three structurally independent modules: SH3b, WW, and GH73. These modules form a "T-shaped" pocket that accommodates a putative tetrasaccharide-pentapeptide substrate of peptidoglycan. Structural comparison and simulation revealed that the GH73 module of LytB harbors the active site, including the catalytic residue Glu-564. In vitro assays of hydrolytic activity indicated that LytB prefers the peptidoglycan from the lytB-deficient pneumococci, suggesting the existence of a specific substrate of LytB in the immature peptidoglycan. Combined with in vitro cell-dispersing and in vivo cell separation assays, we demonstrated that all three modules are necessary for the optimal activity of LytB. Further functional analysis showed that the full catalytic activity of LytB is required for pneumococcal adhesion to and invasion into human lung epithelial cells. Structure-based alignment indicated that the unique modular organization of LytB is highly conserved in its orthologs from Streptococcus mitis group and Gemella species. These findings provided structural insights into the pneumococcal cell wall remodeling and novel hints for the rational design of therapeutic agents against pneumococcal growth and thereby the related diseases.