Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma.

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.

Comparison of postoperative pain between patients who underwent primary and repeated cesarean section: a prospective cohort study.

BACKGROUND: The differences in post-operative pain are unclear between the primiparas who underwent a primary cesarean section and multiparas who underwent their first repeat cesarean section. The study aimed to explore the possible differences in postoperative pain between primiparas and multiparas. METHODS: A prospective cohort study was performed only including women who underwent cesarean deliveries under spinal anesthesia. Postoperative patient-controlled intravenous analgesia (PCIA) was administered to all subjects with 0.2 mg/kg hydromorphone and 4 mg/kg flurbiprofen; the pump was programmed as 2.0 mL/h background infusion with a loading dose of 1 mL and a lockout period of 15 min. Postoperative incision and visceral pain intensity were evaluated using the visual analogue scale, and inadequate analgesia was defined as a visual analogue scale score ≥ 40 during 48 h post-operation. Additionally, the patients' pain statuses in postoperative week 1 and week 4 were also assessed during follow-up via telephone. RESULTS: From January to May 2017, a total of 168 patients (67 primiparas and 101 multiparas) were included. The relative risk for multiparas to experience inadequate analgesia on incision pain was 0.42 (95% CI: 0.25 to 0.74) compared to primiparas. In patients aged < 30 years, inadequate analgesia on visceral pain was higher in multiparas than in primiparas (RR, 3.56 [1.05 to 12.04], P = 0.025). There was no significant difference in the combined incidence of inadequate analgesia in both types of pain between the multiparas and primiparas (33.7% vs. 40.2%, P = 0.381). No difference was found in PCIA use between the two groups (111.1 ± 36.0 mL vs. 110.9 ± 37.3 mL, P = 0.979). In addition, a significantly higher incidence of pain was noted 4 weeks post-surgery in primiparas than that in multiparas (62.2% vs. 37.7%, P = 0.011). CONCLUSION: Multiparas who underwent their first repeat cesarean section have a lower for inadequate analgesia on incision pain during the first 48 h after surgery than primiparas. Multiparas aged under 30 years may be more prone to experiencing postoperative inadequate analgesia on visceral pain. TRAIL REGISTRATION: ClinicalTrial.gov: NCT03009955 , Date registered: December 30, 2016.

Preoperative evaluation of cochlear implantation through the round window membrane in the facial recess using high-resolution computed tomography.

PURPOSE: We evaluated the risk of cochlear implantation through the round window membrane in the facial recess through a preoperative analysis of the angle between the facial nerve-round window and the cranial midline using high-resolution temporal bone CT. METHODS: Temporal bone CT films of 176 patients with profound sensorineural hearing loss at our hospital from 2013 to 2015 were reviewed. The preoperative temporal bone CT scans of the patients were retrospectively analysed. The vertical distance (d value) from the leading edge of the facial nerve to the posterior wall of the external auditory canal and the angle (α value) between the line from the leading edge of the facial nerve to the midpoint of the round window membrane and the median sagittal line on the round window membrane plane were measured. Based on intraoperative observation, the round window membrane was divided into complete round window membrane exposure (group A), partial exposure (group B), and unexposed (group C) groups, and statistical analysis was performed. RESULTS: The α value could be effectively measured for all 176 patients (62.60 ± 7.12), and the d value could be effectively measured for 95 cases (5.53 ± 1.00). An analysis of the correlation between the α and d values of these 95 cases found a negative correlation. Of the 176 cases, one-way analysis of variance (ANOVA) showed that the differences among the groups were significant [P = 0.000 (< 0.05)]. CONCLUSION: The angle (α value) between the line connecting the leading edge of the facial nerve to the midpoint of the round window and the median sagittal line measured in preoperative CT scans was associated with the difficulty of intraoperatively exposing the round window membrane. When the α value was larger than a certain degree, the difficulty of exposing the round window membrane was increased. In such cases, the surgeon should fully expose the round window membrane during surgery, which could result decrease the likelihood of complications.

Protein-protein interactions prediction based on iterative clique extension with gene ontology filtering.

Cliques (maximal complete subnets) in protein-protein interaction (PPI) network are an important resource used to analyze protein complexes and functional modules. Clique-based methods of predicting PPI complement the data defection from biological experiments. However, clique-based predicting methods only depend on the topology of network. The false-positive and false-negative interactions in a network usually interfere with prediction. Therefore, we propose a method combining clique-based method of prediction and gene ontology (GO) annotations to overcome the shortcoming and improve the accuracy of predictions. According to different GO correcting rules, we generate two predicted interaction sets which guarantee the quality and quantity of predicted protein interactions. The proposed method is applied to the PPI network from the Database of Interacting Proteins (DIP) and most of the predicted interactions are verified by another biological database, BioGRID. The predicted protein interactions are appended to the original protein network, which leads to clique extension and shows the significance of biological meaning.

Expression of concern: A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Expression of concern for 'A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma' by Yandong Xie, et al., Biomater. Sci., 2022, 10, 6791-6803, https://doi.org/10.1039/D2BM01145J.

An effective non-rigid registration approach for ultrasound image based on "demons" algorithm.

Medical image registration is an important component of computer-aided diagnosis system in diagnostics, therapy planning, and guidance of surgery. Because of its low signal/noise ratio (SNR), ultrasound (US) image registration is a difficult task. In this paper, a fully automatic non-rigid image registration algorithm based on demons algorithm is proposed for registration of ultrasound images. In the proposed method, an "inertia force" derived from the local motion trend of pixels in a Moore neighborhood system is produced and integrated into optical flow equation to estimate the demons force, which is helpful to handle the speckle noise and preserve the geometric continuity of US images. In the experiment, a series of US images and several similarity measure metrics are utilized for evaluating the performance. The experimental results demonstrate that the proposed method can register ultrasound images efficiently, robust to noise, quickly and automatically.

Influencing factors of community residents' pro-environmental behavior in East Dongting Lake National Nature Reserve under the policy intervention.

In the study of protected areas, the "Fences & fines" approach is increasingly becoming acknowledged as obsolete and ineffectual, and there is mounting evidence suggesting that the "Community-based conservation" approach is acquiring consideration. It is significant to identify which protection model or factors perform a definitive part in China. Taking the East Dongting Lake National Nature Reserve in China as a survey site, this paper utilizes semi-structured interviews and random questionnaires surveyed 431 households to investigate the relationship between "community-based conservation" approaches such aslegal system, ecological compensation, environmental education, community participation, concessions, livelihoods, job provision, intrinsic motivation and pro-environmental behavior. The regression results declare that intrinsic motivation (ß = 0.390) and legal system (ß = 0.212) are the most effective factors impacting on pro-environmental behavior; concessions has a negative conflict on preservation;but other "community-based conservation" approaches had insignificant positive impacts on pro-environmental behavior. Further mediating effects analysis indicated that intrinsic motivation (B = 0.3899, t = 11.9694, p < 0.01) mediates between legal system and pro-environmental behavior of community residents, legal system promotes pro-environmental behavior by promoting intrinsic motivation, which is more effective than legal system promoting pro-environmental behavior directly. This demonstrates that "Fence and fine approach" still is an effective management tool which can shape community residents' positive attitude towards conservation and pro-environmental behavior especially protected areas with large communities. And appropriate "community-based conservation" approaches can mitigate conflicts between special groups with the combination of these two approaches, the management of protected areas can be successful. This supplies a valuable real-world case for the current debate on conservation and improved human livelihoods.

Effect of Energy Utilization and Economic Growth on the Ecological Environment in the Yellow River Basin.

In the 21st century, problems relating to energy, economy, and the environment have become increasingly severe across the world, and critical issues around environmental pollution, ecological imbalance, and an energy crisis have emerged. The Yellow River basin is an important ecological barrier, economic region, and energy base in Northern China. Environmental pollution in the Yellow River basin has become increasingly problematic, especially since the reform and opening up of China, along with the rapid development of the industrial economy and mining for energy resources. In this study, 64 of the 73 prefecture-level cities in the Yellow River basin were selected as the research object, including 18 cities in the downstream region, 26 cities in the midstream region, and 20 cities in the upstream region. The data used in this study were from 2004 to 2019. On the basis of temporal variation and spatial differentiation of the three factors of economy, energy, and environment, the impulse response function and the generalized method of moments (GMM) were adopted to evaluate the effects of energy utilization and economic growth on the ecological environment. Their roles in affecting the ecological environment were analyzed along with the underlying mechanisms. Overall, energy utilization, economic growth, and ecological environment are in good condition, showing a steady upward trend. Regional differences still exist, but the gap is gradually narrowing. There are some differences in the impulse response of the ecological environment to the economic growth and energy utilization in the upstream, midstream, and downstream regions of the Yellow River basin. The effect is leveled out or weakened in the middle and later phases of the impact. Compared with the downstream and upstream regions, economic growth and energy utilization in the midstream regions have less impact on the ecological environment. The two factors of energy utilization potential and economic potential have significant positive impacts on the ecological environment. The current situation of energy utilization has to some extent a positive impact on the ecological environment. Economic scale has a certain negative impact on the ecological environment.

Variation of the stapes and its surrounding anatomical structures based on micro-computed tomography.

BACKGROUND: Stapedotomy is the most efficient treatment for otosclerosis. The anatomical structure of the operation area is complex, but it has a great impact on the postoperative effect. We measure the anatomical parameters of the stapes and its surrounding structures to provide an anatomical reference for stapes surgery in otosclerosis. MATERIALS AND METHODS: Fifteen adult cadaver heads (30 samples) were scanned using micro-CT. The stapes, facial nerve and external auditory canal were reconstructed by image processing. The stapes parameters and relationships between the stapes and surrounding structures were measured using a three-dimensional reconstruction model. RESULTS: The length, width and thickness of the stapes footplate were 2.93 ± 0.17 mm, 1.46 ± 0.08 mm and 0.30 ± 0.11 mm, respectively. The distance between the stapes footplate and long process of the incus was 3.79±0.39 mm. The angle of the incudostapedial joint was 88.29 ± 11.58°. The distance from the center of the stapes footplate to the facial canal was 1.60 ± 0.34 mm. In simulated stapes surgery, the minimum depth of the external auditory canal to be removed was 2.17 ± 0.91 mm, and no significant difference was found between the left and right sides and between men and women (P > 0.05). CONCLUSIONS: A three-dimensional model of the stapes bone and its surrounding anatomical structures was established based on Micro-CT imaging. Anatomical parameters of the stapes bone and its surrounding structures were measured using the model. In stapedotomy, the implanted piston diameter should be around 0.6mm, with a length of approximately 4.6mm. Care should be taken to protect the facial nerve canal during the surgery. These data provide reference for otologists.

Recent progress of hydrogel-based local drug delivery systems for postoperative radiotherapy.

Surgical resection and postoperative radiotherapy remained the most common therapeutic modalities for malignant tumors. However, tumor recurrence after receiving such combination is difficult to be avoided because of high invasiveness and radiation resistance of cancer cells during long-term therapy. Hydrogels, as novel local drug delivery systems, presented excellent biocompatibility, high drug loading capacity and sustained drug release property. Compared with conventional drug formulations, hydrogels are able to be administered intraoperatively and directly release the entrapped therapeutic agents to the unresectable tumor sites. Therefore, hydrogel-based local drug delivery systems have their unique advantages especially in sensitizing postoperative radiotherapy. In this context, classification and biological properties of hydrogels were firstly introduced. Then, recent progress and application of hydrogels for postoperative radiotherapy were summarized. Finally, the prospects and challenges of hydrogels in postoperative radiotherapy were discussed.

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma.

Radiotherapy-resistant glioblastoma (rrGBM) remains a significant clinical challenge because of high infiltrative growth characterized by activation of antiapoptotic signal transduction. Herein, we describe an efficiently biodegradable selenium-engineered mesoporous silica nanocapsule, initiated by high-energy X-ray irradiation and employed for at-site RNA interference (RNAi) to inhibit rrGBM invasion and achieve maximum therapeutic benefit. Our radiation-triggered RNAi nanocapsule showed high physiological stability, good blood-brain barrier transcytosis, and potent rrGBM accumulation. An intratumoral RNAi nanocapsule permitted low-dose X-ray radiation-triggered dissociation for cofilin-1 knockdown, inhibiting rrGBM infiltration. More importantly, tumor suppression was further amplified by electron-affinity aminoimidazole products converted from metronidazole polymers under X-ray radiation-exacerbated hypoxia, which sensitized cell apoptosis to ionizing radiation by fixing reactive oxygen species-induced DNA lesions. In vivo experiments confirmed that our RNAi nanocapsule reduced tumor growth and invasion, prolonging survival in an orthotopic rrGBM model. Generally, we present a promising radiosensitizer that would effectively improve rrGBM-patient outcomes with low-dose X-ray irradiation.

Contact Lens Sensor with Anti-jamming Capability and High Sensitivity for Intraocular Pressure Monitoring.

Contact lens sensors provide a noninvasive approach for intraocular pressure (IOP) monitoring in patients with glaucoma. Accurate measurement of this imperceptible pressure variation requires highly sensitive sensors in the absence of simultaneously amplifying IOP signal and blinking-induced noise. However, current noise-reduction methods rely on external filter circuits, which thicken contact lenses and reduce signal quality. Here, we introduce a contact lens strain sensor with an anti-jamming ability by utilizing a self-lubricating layer to reduce the coefficient of friction (COF) to remove the interference from the tangential force. The sensor achieves exceptionally high sensitivity due to the strain concentration layout and the confined occurrence of sympatric microcracks. The animal tests prove our lens can accurately detect IOP safely and reliably.

An effective approach of lesion segmentation within the breast ultrasound image based on the cellular automata principle.

In this paper, a novel lesion segmentation within breast ultrasound (BUS) image based on the cellular automata principle is proposed. Its energy transition function is formulated based on global image information difference and local image information difference using different energy transfer strategies. First, an energy decrease strategy is used for modeling the spatial relation information of pixels. For modeling global image information difference, a seed information comparison function is developed using an energy preserve strategy. Then, a texture information comparison function is proposed for considering local image difference in different regions, which is helpful for handling blurry boundaries. Moreover, two neighborhood systems (von Neumann and Moore neighborhood systems) are integrated as the evolution environment, and a similarity-based criterion is used for suppressing noise and reducing computation complexity. The proposed method was applied to 205 clinical BUS images for studying its characteristic and functionality, and several overlapping area error metrics and statistical evaluation methods are utilized for evaluating its performance. The experimental results demonstrate that the proposed method can handle BUS images with blurry boundaries and low contrast well and can segment breast lesions accurately and effectively.

Effects of Industrial Structure Adjustment on Pollutants Discharged to the Aquatic Environment in Northwest China.

Northwest China is located along China's Belt and Road Initiative routes and represents the frontier and core region for China's construction and development of the Silk Road Economic Belt. In recent years, the conflict between economic development and environmental pollution has become increasingly intense in this region, with the latter mainly caused by disorderly industrialization brought about by rapid urbanization processes. Inappropriate industrial structure is the primary reason for environmental degradation in Northwest China, which has limited precipitation and available water. Due to its fragile aquatic environment and unsustainable use of water resources, the pollution and degradation of the aquatic environment has become a bottleneck that severely restricts the sustainable development of China's northwest region. In the present study, five provinces or autonomous regions in Northwest China were selected as the study objects. Based on the vector autoregressive (VAR) model, quantitative research methods, such as impulse response function and variance decomposition analysis, were applied to quantify the dynamics between industrial structure adjustment and changes in industrial pollutant discharges to the aquatic environment, so that the impact of industrial structure adjustment on pollutants discharged to the aquatic environment could be quantified and characterized. Therefore, the present study has both theoretical and practical significance. The conclusions are as follows: (1) In general, industrial structure in most provinces in Northwest China imposes a positive effect over the discharge of pollutants to the aquatic environment. Adjusting industrial structure and reducing the proportion of secondary industry present can to some extent promote reductions in the discharge of pollutants to the aquatic environment. However, such beneficial effects may vary among different provinces. (2) Specifically, for Gansu, province industrial structure adjustment could help reduce the discharge of pollutants to the aquatic environment effectively during the early stages, but this positive effect gradually weakens and disappears during the later stages. In Qinghai province, industrial structure adjustment could not help reduce the discharge of pollutants to the aquatic environment effectively during the early stages, but a positive effect gradually increases and continues to function later. The performance in Shaanxi and Xinjiang provinces was quite similar, with industrial structure adjustment helping to effectively reduce the discharge of pollutants to the aquatic environment over a long period of time. This positive effect can play a more sustained and stable role. For Ningxia province, industrial structure adjustment can not only help significantly reduce the discharge of pollutants to the aquatic environment but also displays a significant positive effect. (3) Given the specific conditions and characteristics of the region under study, relevant policies for industrial structure adjustment should be formulated and implemented.

Spatially varying associations between the built environment and older adults' propensity to walk.

Population aging has become a severe issue facing most nations and areas worldwide-with Hong Kong being no exception. For older adults, walking is among the most well-liked travel modes, boosting their overall health and wellbeing. Some studies have confirmed that the built environment has a significant (spatially fixed) influence on older adults' walking behavior. However, little consideration has been given to the potential spatial heterogeneity in such influences. Hence, this study extracted data on older adults' (outdoor) walking behavior from the 2011 Hong Kong Travel Characteristics Survey and measured a series of built environment attributes based on geo-data (e.g., Google Street View imagery). Logistic regression and geographically weighted logistic regression models were developed to unveil the complicated (including spatially fixed and heterogeneous) association between the built environment and older adults' propensity to walk. We show that population density, land-use mix, street greenery, and access to bus stops are positively connected with the propensity to walk of older adults. Intersection density seems to impact walking propensity insignificantly. All built environment attributes have spatially heterogeneous effects on older adults' walking behavior. The percentage of deviance explained is heterogeneously distributed across space.

Crowdsourced Data for Physical Activity-Built Environment Research: Applying Strava Data in Chengdu, China.

The lack of physical activity has become a rigorous challenge for many countries, and the relationship between physical activity and the built environment has become a hot research topic in recent decades. This study uses the Strava Heatmap (novel crowdsourced data) to extract the distribution of cycling and running tracks in central Chengdu in December 2021 (during the COVID-19 pandemic) and develops spatial regression models for numerous 500 × 500 m grids (N = 2,788) to assess the impacts of the built environment on the cycling and running intensity indices. The findings are summarized as follows. First, land-use mix has insignificant effects on the physical activity of residents, which largely contrasts with the evidence gathered from previous studies. Second, road density, water area, green space area, number of stadiums, and number of enterprises significantly facilitate cycling and running. Third, river line length and the light index have positive associations with running but not with cycling. Fourth, housing price is positively correlated with cycling and running. Fifth, schools seem to discourage these two types of physical activities during the COVID-19 pandemic. This study provides practical implications (e.g., green space planning and public space management) for urban planners, practitioners, and policymakers.

Comprehensive exploration of long-wave emission carbon dots for brain tumor visualization.

Carbon dot (CD)-based tumor imaging has been proven to be a reliable nanodiagnostic technique. Although abundant types of CDs have been developed, it is still a major challenge to synthesize long-wavelength CDs with high quality and superior repetition due to the complicated synthetic process. Here, stable long-wavelength red-light emission carbon dots (R-CDs) have been synthesized using appropriate carbon sources via a solvothermal method, which enables effective visualization of deep brain glioblastoma (GBM) by a liposome-formulated delivery system. The luminescence phenomenon and structural growth characteristics of R-CDs have been fully investigated and it has been found that R-CDs exhibit different optical behaviors in different pH and solvent environments. In vitro and in vivo models have proved their excellent cell targeting capacity, bioluminescence imaging potential, and biosafety for GBM visualization. Considering their stability and biocompatibility, the in-depth tissue imagining and other extensive applications of R-CDs are strongly recommended.

Potential Mechanisms of Shu Gan Jie Yu Capsule in the Treatment of Mild to Moderate Depression Based on Systemic Pharmacology and Current Evidence.

Background: Shu Gan Jie Yu (SGJY) capsule has a good effect on relieving depressive symptoms in China. However, the mechanism of action is still unclear. Therefore, systemic pharmacology and molecular docking approaches were used to clarify its corresponding antidepressant mechanisms. Methods: Traditional Chinese Medicine Database and Analysis Platform (TCMSP), the Encyclopedia of Traditional Chinese Medicine (ETCM), and Swiss Target Prediction servers were used to screen and predict the bioactive components of the SGJY capsule and their antidepressive targets. Mild to moderate depression (MMD) related genes were obtained from GeneCards and DisGeNET databases. A network of bioactive components-therapeutic targets of the SGJY capsule was established by STRING 11.5 and Cytoscape 3.9.0 software. Gene function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by utilizing Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Active components were taken to dock with the hypothetical proteins by iGEMDOCK and SwissDock, and the docking details were visually displayed by UCSF Chimera software. Then, the related research literature of the SGJY capsule was reviewed, summarized, sorted, and analyzed, including experimental evidence and clinical experience. Results: Seven active components and 45 intersection targets were included in the study. PPI network had genuinely uncovered the potential therapeutic targets, such as AKT1, HSP90AA1, ESR1, EGFR, and PTGS2. KEGG pathway analysis showed that the mechanism of the SGJY capsule on MMD was mainly involved in the PI3K-Akt signaling pathway. Conclusions: In this study, we have successfully predicted the biochemically active constituents, potential therapeutic targets, and comprehensively predicted the related drug-gene interaction of the SGJY capsule for treating MMD and provided a basis for subsequent experiments.

Construction of a novel radiosensitivity- and ferroptosis-associated gene signature for prognosis prediction in gliomas.

Background: Gliomas are the most refractory intracranial disease characterized by high incidence and mortality rates. Therefore, radiotherapy plays a crucial role in the treatment of gliomas. However, recent evidence reveals that ferroptosis is highly associated with radiosensitivity in tumor cells. Therefore, this study aimed to investigate radiosensitivity- and ferroptosis-associated biomarkers. Moreover, the study aimed to provide new strategies for the treatment and evaluation of prognosis in gliomas. Methods: The mRNA sequencing and relevant clinical data were obtained from The Cancer Genome Atlas (TCGA). Secondly, differential analysis was conducted to reveal the radiosensitivity- and ferroptosis-associated differentially expressed genes (DEGs). Further, a predictive model based on the seven genes was constructed, and LASSO regression analysis was carried out. After that, the Chinese Glioma Genome Atlas (CGGA) was used for validation of the results. Results: A total of 36 radiosensitivity- and 19 ferroptosis-associated DEGs with a prognostic value were identified. Moreover, seven intersecting genes (HSPB1, STAT3, CA9, MAP1LC3A, MAPK1, ZEB1, and TNFAIP3) were identified as the risk signature genes. The ROC curves and K-M analysis revealed that the signature genes showed a good survival prediction. Furthermore, the functional analysis revealed that the differentially expressed genes between the high-risk and the low-risk groups were enriched in glioma-related biological processes. In addition, differences were reported in immune function status between the two groups. Conclusion: This study revealed that the seven biomarkers could help predict the prognosis in glioma patients. In addition, this study provides a basis for understanding the molecular mechanisms of radiosensitivity and ferroptosis in the treatment of gliomas.

A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood-brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.