Albumin-Based Microneedles for Spatiotemporal Delivery of Temozolomide and Niclosamide to Resistant Glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.

Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. METHODS: The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. RESULTS: The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). CONCLUSIONS: The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

Effects of dietary multienzymes on the growth performance, digestive enzyme activity, nutrient digestibility, excreta noxious gas emission, and nutrient transporter gene expression in white feather broilers.

Adding multienzymes to poultry feed rations is recognized as a nutritional strategy aimed at improving poultry performance and health status. Nonetheless, some literatures present an ongoing debate about the extent of multienzymes beneficial impact on poultry growth performance. This study aimed to explore the impacts of dietary multienzyme supplementation on broilers, focusing specifically on growth performance, carcass characteristics, apparent nutrient digestibility, excreta noxious gas emission, and intestinal nutrient transporter gene expression. A total of 3,200 broilers were randomly assigned to five groups (eight replicates per treatment group) and treated with the following: normal control (CON), CON + 100 g/t multienzyme (ME100), CON + 150 g/t multienzyme (ME150), CON + 200 g/t multienzyme (ME200), and CON + 250 g/t multienzyme (ME250). Supplementing with multienzymes significantly influenced the feed conversion rate (linear, P = 0.007; quadratic, P = 0.024) and the European broiler index (linear, P = 0.004; quadratic, P = 0.016) in broilers. Dietary multienzymes significantly influenced apparent metabolizable energy (quadratic, P = 0.015) and neutral detergent fiber (quadratic, P < 0.001). Moreover, multienzyme supplementation in the diet also decreased the emission of ammonia (linear, P = 0.001; quadratic, P = 0.006) and hydrogen sulfide (quadratic, P = 0.006) in the excreta. In addition, dietary multi-enzyme notably elevated (P < 0.05) the mRNA expression of nutrient transporter genes, including peptide transporter 1 (PePT1), Na-dependent neutral amino acid transporter (B0AT), glucose transporter 2 (GLUT2), and fatty acid binding protein1 (FABP1). These findings suggest that dietary supplementation with multienzymes can improve the efficiency of feed utilization, and the digestion and absorption of nutrients and reduce excreta gas emission. Furthermore, this study provides a theoretical basis for advancing the use of multienzymes in broiler production.

Multienzyme additives are increasingly used in animal feed, primarily to enhance growth performance and nutrient digestibility. This study focused on the effects of multienzyme additives (xylanase, mannanase, cellulase, arabinofuranosidase, ferulic acid esterase, amylase, and protease) on various aspects of broilers, including growth performance, carcass characteristics, digestive enzyme activities, apparent nutrient digestibility, excreta noxious gas emission, and intestinal nutrient transporter gene expression. The inclusion of multienzymes in the diet was found to significantly increase the weight of breast muscle in broilers. Additionally, it led to a notable decrease in the viscosity of the fecal and jejunal digesta. Furthermore, the present study revealed an increase in the mRNA expression of key nutrient transporters­peptide transporter 1 (PePT1), Na-dependent neutral amino acid transporter (B0AT), and fatty acid binding protein 1 (FABP1), in the intestine of broilers. These findings indicate that dietary multienzymes enhance the efficiency of feed nutrient digestion and absorption in broilers.

Effect of a novel alkaline protease from Bacillus licheniformis on growth performance, carcass characteristics, meat quality, antioxidant capacity, and intestinal morphology of white feather broilers.

BACKGROUND: The present study was conducted to investigate the effects of dietary novel alkaline protease from Bacillus licheniformis on the growth performance, meat quality, antioxidant status and intestinal morphology of broilers. In total, 4000 broilers were randomly assigned into five groups and treated with normal control, normal control + 100 mg kg-1 protease, normal control + 200 mg kg-1 protease, normal control + 300 mg kg-1 protease and normal control + 400 mg kg-1 protease. RESULTS: Supplementing protease impacted final body weight (linear, P = 0.003; quadratic, P = 0.006) and decreased feed conversion rate (linear, P = 0.036) in broilers. Moreover, dietary protease significantly increased breast muscle rate (linear, P = 0.005; quadratic, P = 0.021) and decreased drip loss (linear, P < 0.001; quadratic, P < 0.001). In addition, dietary protease notably increased protein digestibility (linear, P = 0.001; quadratic, P = 0.006) and trypsin activity (linear, P = 0.002; quadratic, P = 0.009) in jejunum. Light microscopy revealed that the jejunum villi in the 300 mg kg-1 and 400 mg kg-1 groups exhibited greater height and a denser arrangement compared to those in the control group. The addition of protease decreased malondialdehyde content (linear, P < 0.001; quadratic, P < 0.001) and increased total antioxidant capacity (linear, P = 0.001; quadratic, P < 0.001) in pectoral muscles. CONCLUSION: The results of the present study suggest that dietary novel alkaline protease from B. licheniformis improved growth performance by affecting trypsin activity, protein digestibility, antioxidant capacity and intestinal health. © 2024 Society of Chemical Industry.

Microneedle Patch Delivery of PLCG1-siRNA Efficient Enhanced Temozolomide Therapy for Glioblastoma.

The blood-brain barrier (BBB) and drug resistance present challenges for chemotherapy of glioblastoma (GBM). A microneedle (MN) patch with excellent biocompatibility and biodegradability was designed to bypass the BBB and release temozolomide (TMZ) and PLCG1-siRNA directly into the tumor site for synergistic treatment of GBM. The codelivery of TMZ and PLCG1-siRNA enhanced DNA damage and apoptosis. The potential mechanism behind this enhancement is to knockdown of PLCG1 expression, which positively regulates the expression of signal transducer and activator of transcription 3 genes, thereby preventing DNA repair and enhancing the sensitivity of GBM to TMZ. The MN patch enables long-term sustainable drug release through in situ implantation and increases local drug concentrations in diseased areas, significantly extending mouse survival time compared to other drug treatment groups. MN drug delivery provides a platform for the combination treatment of GBM and other central nervous system diseases.

ParaCM-PNet: A CNN-tokenized MLP combined parallel dual pyramid network for prostate and prostate cancer segmentation in MRI.

The precise prostate gland and prostate cancer (PCa) segmentations enable the fusion of magnetic resonance imaging (MRI) and ultrasound imaging (US) to guide robotic prostate biopsy systems. This precise segmentation, applied to preoperative MRI images, is crucial for accurate image registration and automatic localization of the biopsy target. Nevertheless, describing local prostate lesions in MRI remains a challenging and time-consuming task, even for experienced physicians. Therefore, this research work develops a parallel dual-pyramid network that combines convolutional neural networks (CNN) and tokenized multi-layer perceptron (MLP) for automatic segmentation of the prostate gland and clinically significant PCa (csPCa) in MRI. The proposed network consists of two stages. The first stage focuses on prostate segmentation, while the second stage uses a prior partition from a previous stage to detect the cancerous regions. Both stages share a similar network architecture, combining CNN and tokenized MLP as the feature extraction backbone to creating a pyramid-structured network for feature encoding and decoding. By employing CNN layers of different scales, the network generates scale-aware local semantic features, which are integrated into feature maps and inputted into an MLP layer from a global perspective. This facilitates the complementarity between local and global information, capturing richer semantic features. Additionally, the network incorporates an interactive hybrid attention module to enhance the perception of the target area. Experimental results demonstrate the superiority of the proposed network over other state-of-the-art image segmentation methods for segmenting the prostate gland and csPCa tissue in MRI images.

Bisphenol B induces developmental toxicity in zebrafish via oxidative stress.

Bisphenol A (BPA) is a typical endocrine disruptor, and the use of bisphenol B (BPB) as a substitute is gradually increasing. Some studies have shown that BPB also has endocrine disrupting effects, but its effects on the early stages of fish growth and development have not been reported. In this paper, zebrafish embryos were exposed to different concentrations of BPB until the 6th day post fertilization (dpf), and the toxic effects of BPB on the early development of zebrafish and the possible molecular mechanisms were investigated. The results showed that BPB exposure at 10, 100, and 1000 µg/L induced developmental toxic effects such as early neurotoxicity and cardiovascular toxicity in zebrafish, and the toxic effects were positively correlated with the degree of oxidative damage. These adverse results were ameliorated by the classical antioxidant N-acetyl-L-cysteine (NAC), suggesting the involvement of oxidative stress in BPB-induced early developmental toxicity. The above data suggest that BPB exposure increases oxidative damage and suppresses the expression of genes critical for early neurological and cardiovascular development, ultimately leading to early developmental toxicity in juvenile zebrafish. This study contributes to broadening our understanding of the toxic effects of BPB and provides a basic theoretical basis for the next management support of bisphenol analogs.

Association of lifestyle behaviors with health-related quality of life among patients with hematologic diseases.

PURPOSE: Health-related quality of life (HRQoL) is a multi-dimensional construct used to assess the impact of health status on quality of life, and it is known to be affected by lifestyle behaviors. This study focused on multiple lifestyle behaviors among patients with hematologic diseases, including physical activity, dietary intake, sleep quality, occupational exposure, alcohol consumption and smoking. The main objective was to investigate the association of both individual and clustering of health behaviors with HRQoL among the population with hematologic diseases based on a comprehensive lifestyle survey. METHODS: A total of 539 patients with hematologic diseases aged over 18 years were enrolled in this cross-sectional study. Latent class analysis was used to identify homogeneous, mutually exclusive lifestyle classes, and multinomial logistic regression was then performed to explore the association of lifestyle classes membership with HRQoL. Meanwhile, multiple linear regression and quantile regression were used to identify the relationship between individual lifestyle behaviors and HRQoL. RESULTS: A three-class model was selected based on conceptual interpretation and model fit. We found no association between multiple lifestyle behaviors and HRQoL in the 3-class model, either in the whole patients or in subgroups stratified by hematological malignancies. Further research on each lifestyle found that physical activity, dietary intake, occupational exposure, alcohol consumption or smoking were independent of HRQoL. Sleep quality was positively associated with HRQoL. CONCLUSION: Our findings suggested that clustering of lifestyle behaviors may not be an indicator to reflect the health quality of patients with hematologic diseases. Sleep represents a viable intervention target that can confer health benefits on the hematologic patients.

Identification of serum glycobiomarkers for Hepatocellular Carcinoma using lectin microarrays.

Objective: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer and ranks third in mortality among all malignant tumors; as a result, HCC represents a major human health issue. Although aberrant glycosylation is clearly implicated in HCC, changes in serum immunoglobulin (Ig)G and IgM glycosylation have not been comprehensively characterized. In this study, we used lectin microarrays to evaluate differences in serum IgG and IgM glycosylation among patients with HCC, hepatitis B cirrhosis (HBC), or chronic hepatitis B (CHB), and healthy normal controls (NC) and aimed to establish a model to improve the diagnostic accuracy of HCC. Methods: In total, 207 serum samples collected in 2019-2020 were used for lectin microarray analyses, including 97 cases of HCC, 50 cases of HBC, 30 cases of CHB, and 30 cases of NC. Samples were randomly divided into training and validation groups at a 2:1 ratio. Training group data were used to investigate the diagnostic value of the relative signal intensity for the lectin probe combined with alpha-fetoprotein (AFP). The efficacy of models for HCC diagnosis were analyzed by receiver operating characteristic (ROC) curves. Results: In terms of IgG, a model combining three lectins and AFP had good diagnostic accuracy for HCC. The area under the ROC curve was 0.96 (P < 0.05), the sensitivity was 82.54%, and the specificity was 100%. In terms of IgM, a model including one lectin combined with AFP had an area under the curve of 0.90 (P < 0.05), sensitivity of 75.41%, and specificity of 100%. Conclusion: Estimation of serum IgG and IgM glycosylation could act as complementary techniques to improve diagnosis and shed light on the occurrence and development of the HCC.

Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma.

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival.

Effect of Alloying Elements and Low Temperature Plasma Nitriding on Corrosion Resistance of Stainless Steel.

Although nitriding treatment usually improves the hardness and wear resistance of stainless steel, it also reduces its corrosion resistance. The effects of different nitriding temperatures and time and main alloying elements in stainless steel on the properties of the martensitic precipitation hardening of stainless steel were studied by first-principles calculations and experiments in this study. The results showed that the corrosion resistance of the martensitic stainless steel 0Cr17Ni4Cu4Nb was much lower than that of 1Cr15Ni2Mo2Cu before and after nitriding. According to the density functional theory calculation results, the molybdenum-containing stainless steel had higher stability and corrosion resistance and a lower Fermi level, electron conduction concentration and electrochemical activity than the niobium-containing stainless steel before and after nitriding. In addition, at the same temperature, the surface hardness of the 1Cr15Ni2Mo2Cu steel increased linearly with the prolongation of nitriding time, but its corrosion resistance decreased. Under the same nitriding time (24 h), the nitriding temperature increased from 300 to 450 °C, and the surface hardness and nitriding layer depth of the nitriding steel increased gradually, while the corrosion resistance decreased gradually. These results were attributed to the Cr-poor phenomenon caused by the formation of CrN. The 1Cr15Ni2Mo2Cu martensitic stainless steel obtained a high surface hardness after nitriding at 300 °C for 24 h, and the corrosion resistance did not decrease.

Development of protective agents against ovarian injury caused by chemotherapeutic drugs.

BACKGROUND: Chemotherapy is one of the causes of ovarian injury and infertility. Although assisted reproductive technology helps young female patients with cancer become pregnant, preventing chemotherapy-induced ovarian injury will often possess even more significant benefits. OBJECTIVE: We aimed at demonstrating the hazardous effects and mechanisms of ovarian injury by chemotherapeutic agents, as well as demonstrating agents that protect the ovary from chemotherapy-induced injury. RESULTS: Chemotherapeutic agents cause death or accelerate activation of follicles and damage to the blood vessels in the ovary, resulting in inflammation. These often require drug development to protect the ovaries from injury. CONCLUSIONS: Our findings provide a basis for the development of drugs to protect the ovaries from injury. Although there are many preclinical studies on potential protective drugs, there is still an urgent need for a large number of clinical experiments to verify their potential use.

Bone marrow mesenchymal stem cell-derived extracellular vesicles facilitate endometrial injury repair by carrying the E3 ubiquitin ligase WWP1.

Bone marrow mesenchymal stem cells-derived extracellular vesicles (BMSC-EVs) relieve endometrial injury. This study aimed to elucidate the BMSC-EV mechanism in alleviating endometrial injury. Endometrial injury model in vivo was induced using 95% ethanol, and endometrial epithelial cells (EECs) treated with mifepristone were applied as an endometrial injury model in vitro. After BMSCs and BMSC-EVs were isolated and identified, the BMSC-EV function was evaluated by hematoxylin-eosin and Masson staining, immunohistochemistry, quantitative real-time PCR, Cell Counting Kit-8 assay, flow cytometry, enzyme-linked immunosorbent assay, and Transwell and tubule formation assays. The BMSC-EV mechanism was assessed using Western blot, ubiquitination, and cycloheximide-chase assays. After isolation and identification, BMSC-EVs were effective in endometrial injury repair in vivo and facilitated EEC proliferation and repressed cell apoptosis in vitro; the EEC supernatants accelerated human umbilical vein endothelial cell proliferation, migration, and invasion and facilitated angiogenesis after endometrial injury in vitro. For the BMSC-EV mechanism, E3 ubiquitin ligase WWP1 in BMSC-EVs mediated the ubiquitination of peroxisome proliferator-activated receptor gamma (PPARγ), thus relieving the PPARγ inhibition on vascular endothelial growth factor expression. Furthermore, the WWP1 in BMSC-EVs alleviated endometrial injury in vitro and in vivo. BMSC-EVs facilitated endometrial injury repair by carrying WWP1.

Single-port laparoscopic appendectomy using a needle-type grasping forceps compared with conventional three-port laparoscopic appendectomy for patients with acute uncomplicated appendicitis: a single-center retrospective study.

OBJECTIVE: To compare the clinical outcomes between single-port laparoscopic appendectomy using a needle-type grasping forceps (SLAN) and conventional three-port laparoscopic appendectomy (CLA) for patients with uncomplicated appendicitis. METHODS: We retrospectively collected clinical data of patients with uncomplicated appendicitis who underwent SLAN or CLA from May 2019 to May 2021 in our center. The patients' baseline characteristics, perioperative outcomes, and follow-up data were compared between the two groups. Additionally, baseline characteristics were compared with postoperative outcomes in the SLAN group. RESULTS: Ninety-six patients were enrolled (SLAN group, n = 32; CLA group, n = 64). The SLAN group had a shorter hospital stay, lower 24-hour postoperative visual analogue scale scores, shorter postoperative fasting time, lower frequency of antibiotic administration, and longer operative time than the CLA group. In the SLAN group, younger patients had a longer appendix and male patients had a thicker appendix; additionally, patients with an appendiceal diameter of 0.6 to 1.0 cm had a longer postoperative hospital stay and higher frequency of antibiotic administration. CONCLUSIONS: Compared with CLA, SLAN may be less invasive, provide faster postoperative recovery, and result in better cosmesis for patients with uncomplicated appendicitis. Further research should be performed to evaluate the long-term outcomes.

Brain Co-Delivery of Temozolomide and Cisplatin for Combinatorial Glioblastoma Chemotherapy.

Glioblastoma (GBM) is an intractable malignancy with high recurrence and mortality. Combinatorial therapy based on temozolomide (TMZ) and cisplatin (CDDP) shows promising potential for GBM therapy in clinical trials. However, significant challenges include limited blood-brain-barrier (BBB) penetration, poor targeting of GBM tissue/cells, and systemic side effects, which hinder its efficacy in GBM therapy. To surmount these challenges, new GBM-cell membrane camouflaged and pH-sensitive biomimetic nanoparticles (MNPs) inspired by the fact that cancer cells readily pass the BBB and localize with homologous cells, are developed. This study's results show that MNPs can efficiently co-load TMZ and CDDP, transport these across the BBB to specifically target GBM. Incorporation of pH-sensitive polymer then allows for controlled release of drug cargos at GBM sites for combination drug therapy. Mice bearing orthotopic U87MG or drug-resistant U251R GBM tumor and treated with MNPs@TMZ+CDDP show a potent anti-GBM effect, greatly extending the survival time relative to mice receiving single-drug loaded nanoparticles. No obvious side effects are apparent in histological analyses or blood routine studies. Considering these results, the study's new nanoparticle formulation overcomes multiple challenges currently limiting the efficacy of combined TMZ and CDDP GBM drug therapy and appears to be a promising strategy for future GBM combinatorial chemotherapy.

Study on the preparation and activity of intelligent response poly(lactic-co-glycolic acid)-ss-polyethylene glycol copolymer micelles.

Amphiphilic polymer micellar carriers are the most commonly used nanocarriers for oral delivery of hydrophobic drugs because their hydrophilic shell can avoid the recognition of the reticuloendothelial system (RES), has excellent drug-carrying capacity, and protect the drug from inactivation in the gastrointestinal fluid. The polymer micelle shell can enter cancer cells by endocytosis, and autophagy in cells, degradation by lysosomal pathway, so as to release drugs, prolong the circulation time of drugs in vivo, and then achieve the effect of drug sustained release. In this study, the glutathione-responsive PLGA-ss-PEG loaded paclitaxel (PTX) micelles (PLGA-ss-PEG-PTX) were developed for anticancer therapy. With its long-term circulation and EPR (enhanced permeability and retention) effect, and the micelle had disulfide bond, which could be used as the recognition group of tumor microenvironment, so that the PLGA-ss-PEG-PTX could specifically accumulate at the tumor site, so as to produce better anti-tumor effect. The PLGA-ss-PEG-PTX was formulated by the emulsification method in this study. The drug loading was about 21.54%, the entrapment efficiency was about 94.2%, and the particle size range was about 90 nm with narrow particle size distribution. Cytotoxicity and embryonic toxicity experiments were carried out using mouse lung cancer cells (LLC) and zebrafish fertilized eggs. It was proved that the low concentration of blank micelles had little cytotoxicity, but high concentration of blank micelles had adverse effects on zebrafish embryonic development, resulting in embryonic malformation. The uptake of drugs by cancer cells was studied by a high connotation cell imaging analysis system. The experiments showed that the drug molecules encapsulated in micelles could achieve higher uptake by cells compared with free drug molecules. In addition, in the in vivo evaluation experiment of drugs, the PLGA-ss-PEG-PTX could significantly enhance the therapeutic effect of the PTX, improve its water solubility, and improve its oral bioavailability.

Brain-Targeted Codelivery of Bcl-2/Bcl-xl and Mcl-1 Inhibitors by Biomimetic Nanoparticles for Orthotopic Glioblastoma Therapy.

Glioblastoma (GBM) is among the most treatment-resistant solid tumors and often recurrs after resection. One of the mechanisms through which GBM escapes various treatment modalities is the overexpression of anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xl, and Mcl-1) in tumor cells. Small-molecule inhibitors such as ABT-263 (ABT), which can promote mitochondrial-mediated cell apoptosis by selectively inhibiting the function of Bcl-2 and Bcl-xl, have been proven to be promising anticancer agents in clinical trials. However, the therapeutic prospects of ABT for GBM treatment are hampered by its limited blood-brain barrier (BBB) penetration, dose-dependent thrombocytopenia, and the drug resistance driven by Mcl-1, which is overexpressed in GBM cells and further upregulated upon treatment with ABT. Herein, we reported that the Mcl-1-specific inhibitor A-1210477 (A12) can act synergistically with ABT to induce potent cell apoptosis in U87 MG cells, drug-resistant U251 cells, and patient-derived GBM cancer stem cells. We further designed a biomimetic nanomedicine, based on the apolipoprotein E (ApoE) peptide-decorated red blood cell membrane and pH-sensitive dextran nanoparticles, for the brain-targeted delivery of ABT and A12. The synergistic anti-GBM effect was retained after encapsulation in the nanomedicine. Additionally, the obtained nanomedicine possessed good biocompatibility, exhibited efficient BBB penetration, and could effectively suppress tumor growth and prolong the survival time of mice bearing orthotopic GBM xenografts without inducing detectable adverse effects.

Heme Oxygenase-1 targeting exosomes for temozolomide resistant glioblastoma synergistic therapy.

Glioblastoma (GBM) is a highly fatal and recurrent brain cancer without a complete prevailing remedy. Although the synthetic nanotechnology-based approaches exhibit excellent therapeutic potential, the associated cytotoxic effects and organ clearance failure rest major obstacles from bench to clinics. Here, we explored allogeneic bone marrow mesenchymal stem cells isolated exosomes (BMSCExo) decorated with heme oxygenase-1 (HMOX1) specific short peptide (HSSP) as temozolomide (TMZ) and small interfering RNA (siRNA) nanocarrier for TMZ resistant glioblastoma therapy. The BMSCExo had excellent TMZ and siRNA loading ability and could traverse the blood-brain barrier (BBB) by leveraging its intrinsic brain accumulation property. Notably, with HSSP decoration, the TMZ or siRNA encapsulated BMSCExo exhibited excellent TMZ resistant GBM targeting ability both in vitro and in vivo due to the overexpression of HMOX1 in TMZ resistant GBM cells. Further, the HSSP decorated BMSCExo delivered the STAT3 targeted siRNA to the TMZ resistant glioma and restore the TMZ sensitivity, consequently achieved the synergistically drug resistant GBM treatment with TMZ. Our results showed this biomimetic nanoplatform can serve as a flexible, robust and inert system for GBM treatment, especially emphasizing the drug resistant challenge.