MXene-based polysaccharide aerogel with multifunctional enduring antimicrobial effects for infected wound healing.

Wound infection is a predominant etiological factor contributing to delayed wound healing in open wounds. Hence, it holds paramount clinical significance to devise wound dressings endowed with superior antibacterial properties. In this study, a Schiff base-crosslinked aerogel comprising sodium alginate oxide (OSA), carboxymethyl chitosan (CMCS), and Nb2C@Ag/PDA (NAP) was developed. The resultant OSA/CMCS-Nb2C@Ag/PDA (OC/NAP) composite aerogel exhibited commendable attributes including exceptional swelling characteristics, porosity, biocompatibility, and sustained antimicrobial efficacy. In vitro antimicrobial assays unequivocally demonstrated that the OC/NAP composite aerogel maintained nearly 100 % inhibition of Staphylococcus aureus and Escherichia coli under an 808 nm laser even after 25 h. Crucially, the outcomes of in vivo infected wound healing experiments demonstrated that the wound healing rate of the OC/NAP composite aerogel group reached approximately 100 % within a span of 14 days, which was significantly greater than that of the blank control group. In vitro and in vivo hemostatic experiments also revealed that the composite aerogel had excellent hemostatic properties. The results of this study demonstrate the remarkable potential of OC/NAP aerogel as a multifunctional clinical wound dressing, especially for infected wounds.

Lipid-Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy.

In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid-polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.

Engineering MMP-2 Activated Nanoparticles Carrying B7-H3 Bispecific Antibodies for Ferroptosis-Enhanced Glioblastoma Immunotherapy.

Administration of bispecific antibodies (biAbs) in tumor therapy is limited by their short half-life and off-target toxicity. Optimized strategies or targets are needed to overcome these barriers. B7-H3 (CD276), a member of the B7 superfamily, is associated with poor survival in glioblastoma (GBM) patients. Moreover, a dimer of EGCG (dEGCG) synthesized in this work enhanced the IFN-γ-induced ferroptosis of tumor cells in vitro and in vivo. Herein, we prepared recombinant anti-B7-H3×CD3 biAbs and constructed MMP-2-sensitive S-biAb/dEGCG@NPs to offer a combination treatment strategy for efficient and systemic GBM elimination. Given their GBM targeted delivery and tumor microenvironment responsiveness, S-biAb/dEGCG@NPs displayed enhanced intracranial accumulation, 4.1-, 9.5-, and 12.3-fold higher than that of biAb/dEGCG@NPs, biAb/dEGCG complexes, and free biAbs, respectively. Furthermore, 50% of GBM-bearing mice in the S-biAb/dEGCG@NP group survived longer than 56 days. Overall, S-biAb/dEGCG@NPs can induce GBM elimination by boosting the ferroptosis effect and enhancing immune checkpoint blockade (ICB) immunotherapy and may be successful antibody nanocarriers for enhanced cancer therapy.

Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy.

Insulin receptor substrate 1 and 2 (IRS1/2) have been found involved in many cancers development and their inhibitors exert significant tumor-suppressive effects. Here, we tried to explore the function of NT157, an IGF1R-IRS1/2 inhibitor, in ovarian cancer. We treated ovarian cancer cells with varying doses of NT157. The MTT assay was employed to evaluate cell proliferation and colony formation assay was used for detecting colony-forming ability. TUNEL assay was adopted to test cell apoptosis. Cell invasion was checked by the Transwell assay. The expression of apoptosis-related proteins, autophagy markers, IRS1/2, and PI3K/AKT/mTOR pathway was compared by Western blot, immunofluorescence, or qRT-PCR. As indicated by the data, NT157 abated the viability, proliferation, and induced autophagy of ovarian cancer cells. Overexpressing IRS1/2 attenuated the tumor-suppressive effect of NT157 and heightened the PI3K/AKT/mTOR pathway activation. Inhibition of the PI3K/AKT/mTOR pathway enhanced the tumor-suppressive effect of NT157 and facilitated NT157-mediated autophagy. However, the autophagy inhibitor 3-MA partly reversed NT-157-mediated antitumor effects. In conclusion, this study disclosed that NT157 suppressed the malignant phenotypes of ovarian cancer cells by inducing autophagy and hampering the expression of IRS1/2 and PI3K/AKT/mTOR pathway.

Polydopamine-coated i-motif DNA/Gold nanoplatforms for synergistic photothermal-chemotherapy.

The combination of photothermal therapy with chemotherapy has gradually developed into promising cancer therapy. Here, a synergistic photothermal-chemotherapy nanoplatform based on polydopamine (PDA)-coated gold nanoparticles (AuNPs) were facilely achieved via the in situ polymerization of dopamine (DA) on the surface of AuNPs. This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs. The i-motif DNA nanostructure was assembled on PDA-coated AuNPs, which could be transformed into a C-quadruplex structure under an acidic environment, showing a characteristic pH response. The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure. To enhance the specific cellular uptake, the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand. In addition, Dox-loaded NPs (DAu@PDA-AS141) showed the pH/photothermal-responsive release of Dox. The photothermal effect of DAu@PDA-AS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared (NIR) irradiation. Overall, these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermal-chemotherapy.

Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor.

Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor (DOC@TA-Fe3+) based on tannic acid (TA), iron ion (Fe3+), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the DOC@TA-Fe3+ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe3+/Fe2+ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe3+ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of DOC@TA-Fe3+ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.

Multifunctional gold nanorods in low-temperature photothermal interactions for combined tumor starvation and RNA interference therapy.

Collateral damage to healthy tissue, uneven heat distribution, inflammatory diseases, and tumor metastasis induction hinder the translation of high-temperature photothermal therapy (PTT) from bench to practical clinical applications. In this report, a multifunctional gold nanorod (GNR)-based nanosystem was designed by attaching siRNA against B7-H3 (B7-H3si), glucose oxidase (GOx), and hyaluronic acid (HA) for efficient low-temperature PTT. Herein, GOx can not only exhaust glucose to induce starvation therapy but also reduce the heat shock protein (HSP), realizing the ablation of tumors without damage to healthy tissues. Evidence shows that B7-H3, a type I transmembrane glycoprotein molecule, plays essential roles in growth, metastasis, and drug resistance. By initiating the downregulation of B7-H3 by siRNA, siRNA-GOx/GNR@HA NPs may promote the effectiveness of treatment. By targeting cluster of differentiation 44 (CD44) and depleting B7-H3 and HSPs sequentially, siRNA-GOx/GNR@HA NPs showed 12.9-fold higher lung distribution than siRNA-GOx/GNR NPs. Furthermore, 50% of A549-bearing mice in the siRNA-GOx/GNR NPs group survived over 50 days. Overall, this low-temperature phototherapeutic nanosystem provides an appropriate strategy for eliminating cancer with high treatment effectiveness and minimal systemic toxicity. STATEMENT OF SIGNIFICANCE: To realize efficient tumor ablation under mild low-temperature (42-45 â„ƒ) and RNA interference simultaneously, here we developed a multifunctional gold nanorod (GNR)-based nanosystem (siRNA-GOx/GNR@HA NPs). This nanoplatform can significantly inhibit tumor cell proliferation and induce cell apoptosis by downregulation of HSP90α, HSP70, B7-H3, p-AKT, and p-ERK and upregulation of cleaved caspase-9 at mild low-temperature due to its superior tumor homing ability and the combined effect of photothermal effect, glucose deprivation-initiated tumor starvation, and B7-H3 gene silence effect. It is believed that this multifunctional low-temperature photothermal nanosystem with efficient and specific anticancer properties, shows a potential application in clinical tumor treatment.

Development and evaluation of a novel biodegradable implants with excellent inflammatory response suppression effect by hot-melt extrusion.

PURPOSE: Dexamethasone (Dex) is a widely used drug for the treatment of inflammatory and autoimmune conditions, however, long-term systemic use of Dex is associated with serious adverse effects. The objective of the present study was to develop an implantable device to avoid side effects and realize a controlled release of Dex at the implant site. METHODS: Hydrophobic Dex was incorporated into biodegradable polyesters derived from PCL and Pluronic® L64 (PCL-Pluronic L64-PCL, PCLC) by hot-melt extrusion (HME) method to prepare Dex/PCLC implantable devices. Drug loading and encapsulation efficiency, a series of physicochemical properties, and in vivo features of the implants were studied. RESULTS: The maximum value of the drug loading and encapsulation efficiency for the Dex/PCLC implants were up to 47% and 94%, respectively. Incorporation of Dex resulted in accelerated crystallization of PCLC, decreased the wettability, increased contact angles and viscosity, and accelerated Dex release rate and degradation rate from the implants in vivo. Moreover, Dex/PCLC implants showed excellent biocompatibility. Furthermore, the inflammatory response to the Dex/PCLC implants was less severe than that to the positive control group. CONCLUSION: All these results suggested that Dex/PCLC implants might be a safe and controlled local drug delivery system with excellent inflammatory response suppression effect.

Chitosan coated pH-responsive metal-polyphenol delivery platform for melanoma chemotherapy.

The safe and effective drug delivery system is important for cancer therapy. Here in, we first constructed a delivery system Cabazitaxel(Cab)@MPN/CS between metal-polyphenol (MPN) and chitosan (CS) to deliver Cab for melanoma therapy. The preparation process is simple, green, and controllable. After introducing CS coating, the drug loading was improved from 7.56 % to 9.28 %. Cab@MPN/CS NPs released Cab continuously under acid tumor microenvironment. The zeta potential of Cab@MPN/CS NPs could be controlled by changing the ratio of Cab@MPN and CS solutions. The positively charged Cab@MPN/CS accelerate B16F10 cell internalization. After internalized, Cab@MPN/CS NPs could escape from lysosomes via the proton sponge effect. The permeability of CS promotes the penetration of Cab@MPN/CS to the deeper B16F10 tumor spheroids. In vivo results showed that Cab@MPN/CS NPs have a longer retention time in tumor tissues and significantly inhibit tumor growth by up-regulating TUNEL expression and down-regulating KI67 and CD31 expression. Thus, this delivery system provides a promising strategy for the tumor therapy in clinic.

Fabrication and Properties of a Biomimetic Dura Matter Substitute Based on Stereocomplex Poly(Lactic Acid) Nanofibers.

BACKGROUND: Duraplasty is one of the most critical issues in neurosurgical procedures because the defect of dura matter will cause many complications. Electrospinning can mimic the 3D structure of the natural extracellular matrix whose structure is similar to that of dura matter. Poly(L-lactic acid) (PLLA) has been used to fabricate dura matter substitutes and showed compatibility to dural tissue. However, the mechanical properties of the PLLA substitute cannot match the mechanical properties of the human dura mater. METHODS AND RESULTS: We prepared stereocomplex nanofiber membranes based on enantiomeric poly(lactic acid) and poly(D-lactic acid)-grafted tetracalcium phosphate via electrospinning. X-ray diffraction results showed the formation of stereocomplex crystallites (SC) in the composite nanofiber membranes. Scanning electron microscope observation images showed that composites nanofibers with higher SC formation can keep its original morphologies after heat treatment, suggesting the heat resistance of composite nanofiber membranes. Differential scanning calorimeter tests confirmed that the melting temperature of composite nanofiber membranes was approximately 222°C, higher than that of PLLA. Tensile testing indicated that the ultimate tensile strength and the elongation break of the stereocomplex nanofiber membranes were close to human dura matter. In vitro cytotoxicity studies proved that the stereocomplex nanofiber membranes were non-toxic. The neuron-like differentiation of marrow stem cells on the stereocomplex nanofiber membranes indicated its neuron compatibility. CONCLUSION: The stereocomplex nanofiber membranes have the potential to serve as a dura mater substitute.

Development of a hybrid nanocarrier-recognizing tumor vasculature and penetrating the BBB for glioblastoma multi-targeting therapy.

The success of glioma chemotherapy is hampered by poor drug penetration ability across the blood-brain barrier (BBB) and low intratumoral drug concentration. Novel tumor-targeted delivery systems are useful in specifically accumulating in the tumor foci and penetrating into the glioma core after entering into the brain. Here we show that a multi-targeting hybrid nanocarrier (Pep-MLHA HNPs) system based on hyaluronic acid (HA)-modified polymer and a functional peptide possesses multi-target capability and stronger penetration ability into the core of three-dimensional tumor spheroids, could migrate efficiently across the BBB in vitro. The intensity of the Pep-MLHA HNPs after transporting across the BBB was 5.2-fold and 5.6-fold higher than that of ML NPs in C6 and U87 cells, respectively. More interestingly, this multi-targeting hybrid system displayed high colloidal stability in PBS solution, and weak negative zeta potential (-1.99 ± 0.655 mV) minimizing nonspecific interactions with plasma proteins and promoting long-term circulation in vivo. Additionally, the multi-targeting hybrid system induced enhanced tumor localization in U87 in situ-bearing nude mice and xenograft-bearing nude mice after systemic administration. Furthermore, docetaxel (DTX)-loaded Pep-MLHA HNPs showed negligible systemic toxicity and enhanced therapeutic efficacy, with significantly improved survival rates in intracranial C6 glioma-bearing rats. The 50% survival rate of DTX/Pep-MLHA HNPs-treated rats (40 days) was significantly longer than that of rats treated with NS (22 days), Taxotere® (25 days), DTX/ML NPs (25 days), DTX/Pep NPs (32 days) and DTX/MLHA NPs (29 days). All the results suggested that the multi-targeting hybrid nanocarrier system is promising for glioma treatment.

Chitosan for gene delivery: Methods for improvement and applications.

Gene therapy is a promising strategy for treating challenging diseases. The successful delivery of genes is a critical step for gene therapy. However, concerns about immunogenicity and toxicity are the main obstacles against the widespread use of effective viral systems. Therefore, nonviral vectors are regarded as good alternatives to viral vectors. Chitosan is a natural cationic polysaccharide that could be used to create nonviral gene delivery vectors. Various methods have been developed to improve the properties of chitosan related to gene delivery. This review introduces the features of chitosan in gene delivery, summarizes current progress toward methods promoting the properties of chitosan related to gene delivery, and presents different applications of chitosan in gene delivery vectors. Finally, future prospects of gene vectors based on chitosan are discussed.

A prognostic 11 genes expression model for ovarian cancer.

The symptoms of ovarian cancer at early stages are usually absent which makes the diagnosis in its early stages exceedingly difficult. Previous research has proven that ovarian cancer is a genetic disease, which depends on the alteration of multi-cancer related genes and anti-cancer genes, multi-stages and multi-pathways, involving a variety of oncogene activation and anti-oncogene inactivation. For a better understanding of the prognostic classification of ovarian cancer, gene expression profiles were used to analyze the prognostic factors of ovarian cancer, and the prognostic model was used to classify the ovarian cancer samples. The ovarian cancer samples data were downloaded from TCGA dataset. Rebust likelihood-based survival model was built to find the key genes that could function as prognostic markers. The samples were classified by unsupervised hierarchical clustering. Furthermore, Kaplan-Meier survival analysis was used to analyze the differences in the prognosis of the samples. The prognostic model was used to classify the samples, and then the best classification model was selected as the prognostic model of ovarian cancer. Finally, GEO datasets were used for external data validation. A total of 886 genes with influence on prognosis was obtained. Then genomic combinations of 11 genes were screened out by random sampling. Then the active number of influential factors was counted based on the expression level of featured genes. When the number of influencing factors is ≥7, the prognosis difference among these genes is the largest (P-value = 0.000775); and this was chosen as the final Classification model. To summary, a prognostic 11genes expression model was preliminarily built to classify the ovarian cancer samples.

Hospital-Based Study of the Frequency and Risk Factors of Stroke Recurrence in Two Years in China.

BACKGROUND: Stroke causes death and disability throughout the world and recurrent stroke events are more likely to be disabling or fatal. We conducted a hospital-based study to investigate the frequency and influence factors of stroke recurrence in China. METHODS: Data from patients hospitalized with stroke between January 2007 and December 2010 of 109 tertiary hospitals in China were used. Stroke recurrence and associated factors were ascertained. The zero-inflated model was used to evaluate the factors of recurrence. RESULTS: Of 101,926 discharged patients, the cumulative 2-year stroke recurrence rate was 3.80% for subarachnoid hemorrhage (SAH), 5.31% for intracerebral hemorrhage (ICH), and 8.71% for ischemic stroke (IS), respectively. Among patients with stroke recurrence, 54.11% with SAH, 60.42% with ICH, and 92.92% with IS relapsed for the same type of the first-onset stroke. For discharged patients with SAH with middle cerebral artery aneurysm clipping or artery aneurysm embolization, it was less likely to stroke relapse, but the times of recurrence would increase if 1 recurrence appeared. Cerebral artery aneurysms and hypertension were risk factors for recurrence frequency. For ICH, protective factors for recurrence were trepanation and drainage of intracranial hematoma, cerebral angiography, puncture and drainage of intracranial hematoma, and length of stay (LOS). But rheumatic heart disease and atrial fibrillation would further the relapse frequency. For IS, age and LOS were protective factors, but recurrence frequency would increase if the first recurrence happened. Cervical spondylopathy, male gender, and diabetes were risk factors for frequency of relapse. CONCLUSIONS: Associated factors were different for recurrence frequency among different stroke types.

Evaluation of visual quality of spherical and aspherical intraocular lenses by Optical Quality Analysis System.

AIM: To evaluate the impact of spherical and aspherical intraocular lenses on the postoperative visual quality of age-related cataract patients using Optical Quality Analysis System (OQAS). METHODS: Seventy-four eyes with age-related cataracts were randomly divided into spherical and aspherical lens implantation groups. Best-corrected visual acuity (BCVA) was measured preoperatively, one day, one week, two weeks, one month and two months after surgery. A biometric systems analysis using the OQAS objective scattering index (OSI) was performed. RESULTS: There were no significant differences in visual acuity (P>0.05) before and after spherical and aspheric lens implantation. There was a negative linear correction between the OSI value and BCVA (r=-0.634, P=0.000), and positive corrections between the OSI value and the lens LOCUS III value of nucleus color (NC), nucleus opacity (NO), cortex (C) and posterior lens capsular (P) (r=0.704, P=0.000; r=0.514, P=0.000; r=0.276, P=0.020; r=0.417, P=0.000, respectively). OSI values of spherical vs aspherical lenses were 11.5±3.6 vs 11.8±3.4, 4.1±0.9 vs 3.3±0.8, 3.5±0.9 vs 2.7±0.7, 3.3±0.8 vs 2.6±0.7, 3.2±0.7 vs 2.5±0.8, and 3.2±0.8 vs 2.5±0.8 before and 1d, 1, 2wk, 1 and 2mo after surgery, respectively. All time points varied significantly (P<0.01) between the two groups. CONCLUSION: Aspherical IOLs does not significantly affect visual acuity compared with spherical IOLs. The OSI value, was significantly lower in the aspherical lens group compared with the spherical lens. This study shows that objective visual quality of aspheric IOLs is better than that of the spherical lens by means of OQAS biological measurement method.