Innovation and entrepreneurship of Chinese returning migrant workers in their home region.

This study aims to investigate the influence of pre-entrepreneurial career mobility frequency and job changes among returning migrant workers (RMWs) on the innovation level of enterprises, with a particular focus on the mediating role of urban social capital accumulated by RMWs. Using data from the "current entrepreneurial status of RMWs", we applied an ordered probit model to validate our hypotheses. To address endogeneity, a recursive bivariate probit model was used, and stepwise regression combined with bootstrap methods was employed to ascertain the mediating influence of urban social capital. Our results demonstrate a significant positive correlation (P < 0.01) between pre-entrepreneurial career mobility frequency and the innovation level of enterprises among RMWs. However, there's a notable negative correlation (P < 0.01) between experiences as elementary workers and enterprise innovation level, while technical and marketing roles correlate positively (P < 0.01) with enterprise innovation level. Urban social capital mediates the relationship between career mobility and enterprise innovation level, suggesting that career mobility enhance urban social capital accumulation, influencing RMWs' enterprise innovation levels. This empirical evidence holds even after robustness tests. We further observed that RMWs with fewer than three career moves lean towards low level of enterprise innovation, while those with three or more gravitate towards high level of enterprise innovation. This study advances the theory of career mobility and enriches the understanding of enterprise innovation levels. Additionally, it provides critical theoretical insights for prospective RMWs entrepreneurs in strategizing their career mobility and job changes. Policy implications suggest that, in addition to providing entrepreneurial support, the government should facilitate pre-entrepreneurial career mobility channels for migrant workers and consider the transition from rural to urban employment as a socialized ritual for RMWs engaging in entrepreneurship.

Genomic Characterization of a Carbapenem-Resistant Raoultella planticola Strain Co-Harboring blaIMP-4 and blaSHV-12 Genes.

Raoultella planticola is an emerging bacterial pathogen responsible for causing infections in both humans and animals. Unfortunately, sporadic reports of carbapenem-resistant R. planticola (CRRP) have been documented worldwide. Here we first reported the complete genome sequence of a CRRP isolate RP_3045 co-carrying blaIMP-4 and blaSHV-12, recovered from a patient in China, and its genetic relatedness to 82 R. planticola strains deposited in the NCBI GenBank database, sourced from humans, animals, and the environment. Whole-genome sequencing was performed using the Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms. Phylogenetic analysis was also performed and visualized using a single nucleotide polymorphism (SNP)-based strategy. The complete genome of R. planticola strain RP_3045 was determined to be 6,312,961 bp in length, comprising five contigs that included one chromosome and four plasmids. RP_3045 was found to be multidrug-resistant and harbored several antimicrobial resistance genes, including both blaIMP-4 and blaSHV-12 genes located on a single plasmid. The most closely related strain was hkcpe63, recovered from humans in Hong Kong, China, in 2014, with 506 SNP differences. R. planticola strains were distributed globally and exhibited strong associations among isolates obtained from different sectors. This study provides evidence for the potential of R. planticola to disseminate carbapenem resistance across different sectors, highlighting the critical need for active and continuous surveillance of CRRP.

Application of targeted liposomes-based salvianolic acid A for the treatment of ischemic stroke.

Novel therapeutics for the treatment of ischemic stroke remains to be the unmet clinical needs. Previous studies have indicated that salvianolic acid A (SAA) is a promising candidate for the treatment of the brain diseases. However, SAA has poor absolute bioavailability and does not efficiently cross the intact blood-brain barrier (BBB), which limit its efficacy. To this end we developed a brain-targeted liposomes for transporting SAA via the BBB by incorporating the liposomes to a transport receptor, insulin-like growth factor-1 receptor (IGF1R). The liposomes were prepared by ammonium sulfate gradients loading method. The prepared SAA-loaded liposomes (Lipo/SAA) were modified with IGF1R monoclonal antibody to generate IGF1R antibody-conjugated Lipo/SAA (IGF1R-targeted Lipo/SAA). The penetration of IGF1R-targeted Lipo/SAA into the brain was confirmed by labeling with Texas Red, and their efficacy were evaluate using middle cerebral artery occlusion (MCAO) model. The results showed that IGF1R-targeted Lipo/SAA are capable of transporting SAA across the BBB into the brain, accumulation in brain tissue, and sustained releasing SAA for several hours. Administration o IGF1R-targeted Lipo/SAA notably reduced infarct size and neuronal damage, improved neurological function and inhibited cerebral inflammation, which had much higher efficiency than no-targeted SAA.

Identifying hypothermia death in a mouse model by ATR-FTIR.

The identification of hypothermia death (HD) is difficult for cadavers, especially the distinction from death due to alternative causes. A large number of studies have shown that brown adipose tissue (BAT) plays critical roles in thermoregulation of mammals. In this study, BAT of mice was used for the discrimination of HD using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). A modified mouse HD model conducted by Feeney DM was used in this study to obtain infrared spectra of BAT. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to establish discrimination models. The PLS-DA and OPLS-DA models exhibit prominent discriminative efficiency, and the accuracy of HD identification using fingerprint regions and ratios of absorption intensity is near 100% in both the calibration and validation sets. Our preliminary study suggests that BAT may be an extremely effective target tissue for identification of cadavers of HD, and ATR-FTIR spectra combined with chemometrics have also shown potential for cadaver identification in forensic practice in a fast and accurate manner.

Recurrent hemichorea in an adolescent with systemic lupus erythematosus and previous ipsilateral cerebral infarction.

Systemic lupus erythematosus (SLE) can present with movement disorders, among which chorea is closely associated with antiphospholipid (aPL) antibodies. Brain imaging results obtained in patients with chorea are generally inconsistent with the clinical manifestation of chorea; moreover, medical tests for hemichorea, which are expected to reveal distinct localization, may show negative findings. Herein, we present a case of a 15-year-old girl with SLE who had a history of left cerebral infarction; tests revealed elevated aPL levels, and she developed recurrent left hemichorea 2 years later. Brain magnetic resonance imaging (MRI) results revealed no acute lesions during each episode of involuntary movements, and an MRI perfusion scan failed to provide an explanation for the asymmetric presentation. Although various hypotheses have been proposed regarding the mechanism underlying the occurrence of chorea, some scenarios still remain unexplained. Further investigation on the pathophysiology of chorea in SLE may be warranted to clarify its prognosis.

Deciphering the genetic basis of resistome and virulome diversity among multidrug-resistant Mycoplasma hominis.

Mycoplasma hominis, a commensal bacterium that commonly inhabits the genital tract, leading to infections in both the genitourinary and extragenital regions. However, the antimicrobial resistance and pathogenic mechanisms of M. hominis isolated from extra-urogenital cystic abscess is largely unknown. This study reports the genomic epidemiological characteristics of a M. hominis isolate recovered from a pelvic abscess sample in China. Genomic DNA was extracted and sequenced using Illumina HiSeq X Ten platform. De novo assembly was performed and in silico analysis was accomplished by multiple bioinformatics tools. For phylogenomic analysis, publicly available M. hominis genomes were retrieved from NCBI GenBank database. Whole genome sequencing data showed that the genome size of M. hominis MH4246 was calculated as 679,746 bp, with 558 protein-coding sequences and a G + C content of 26.9%. M. hominis MH4246 is resistant to fluoroquinolones and macrolides, harboring mutations in the quinolone resistance-determining regions (QRDRs) (GyrA S153L, ParC S91I and ParE V417I) and 23S rRNA gene (G280A, C1500T, T1548C and T2218C). Multiple virulence determinants, such as tuf, hlyA, vaa, oppA, MHO_0730 and alr genes, were identified. Phylogenetic analysis showed that the closest relative of M. hominis MH4246 was the strain MH-1 recovered from China, which differed by 3490 SNPs. Overall, this study contributes to the comprehension of genomic characteristics, antimicrobial resistance patterns, and the mechanisms underlying the pathogenicity of this pathogen.

Human Embryonic Stem-Cell-Derived Exosomes Repress NLRP3 Inflammasome to Alleviate Pyroptosis in Nucleus Pulposus Cells by Transmitting miR-302c.

Recent studies have shown that the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is extensively activated in the process of intervertebral disc degeneration (IVDD), leading to the pyroptosis of nucleus pulposus cells (NPCs) and the exacerbation of the pathological development of the intervertebral disc (IVD). Exosomes derived from human embryonic stem cells (hESCs-exo) have shown great therapeutic potential in degenerative diseases. We hypothesized that hESCs-exo could alleviate IVDD by downregulating NLRP3. We measured the NLRP3 protein levels in different grades of IVDD and the effect of hESCs-exo on the H2O2-induced pyroptosis of NPCs. Our results indicate that the expression of NLRP3 was upregulated with the increase in IVD degeneration. hESCs-exo were able to reduce the H2O2-mediated pyroptosis of NPCs by downregulating the expression levels of NLRP3 inflammasome-related genes. Bioinformatics software predicted that miR-302c, an embryonic stem-cell-specific RNA, can inhibit NLRP3, thereby alleviating the pyroptosis of NPCs, and this was further verified by the overexpression of miR-302c in NPCs. In vivo experiments confirmed the above results in a rat caudal IVDD model. Our study demonstrates that hESCs-exo could inhibit excessive NPC pyroptosis by downregulating the NLRP3 inflammasome during IVDD, and miR-302c may play a key role in this process.

Promoting college students' systems thinking in asynchronous discussions: Encouraging students initiating questions.

Introduction: Systems thinking is one of the most important thinking skills for medical students. Most of the studies focused on designing technological-rich learning environments which usually take several weeks or months to implement. However, the occurring of COVID-19 health crisis does not allow extensive period of time to implement classroom interventions. How to support students' systems thinking in fully online environments remains an issue. This study examines if encouraging students initiating questions on asynchronous discussion forum supports their systems thinking development. Methods: Twenty-two junior students participated in this study. We compared if and how students developed systems thinking when they were encouraged asking questions in asynchronous discussion forums in one unit with another unit in which traditional method was used. Multiple analytical methods were applied in this study, including, social network analysis, epistemic network analysis, inferential statistical analysis and qualitative analysis. Results: Quantitative results showed that all students improved systems thinking compared with traditional teaching unit among which leader students improved most. Further analysis on students' discussion posts suggested leader students asked high systems thinking level questions and provided high level responses. Epistemic network analysis unpacked how leader, regular and peripheral students engaged in initiating questions and providing responses differently. Discussion: This study provides methodological and practical contributions. Methodologically, this study extends prior methods of applying network analysis beyond its original preservice teacher training contexts; practically, this study provides strategies to practitioners to support students' asynchronous forum discussions.

Agricultural production structure and inequality of educational development in China.

Unbalanced regional development in China has always been the focus of the government's attention. Agricultural development in China's main agricultural regions is characterized by relatively obvious features, which are mainly manifested in the excessive concentration of agricultural production on one crop or a few agricultural products. Whether this trend of concentration will help to improve the inequalities in China's educational development is an important question for this study. Based on China's population, education and agricultural data over the past 20 years, this paper provides an in-depth analysis of educational inequalities in five typical agricultural-producing provinces by calculating indicators such as the rationalization index of agricultural production structures, the average number of years of schooling of residents and the Gini coefficient of education, in order to analyze the essential reasons for the development of education inequality in major agricultural producing areas. The results show that the urban-rural gap is an important factor affecting the equality of educational development in the main agricultural production areas; the reduction of the rationalization index of agricultural production structure can promote the improvement of inequality in educational development and narrow the urban-rural educational development gap; it also shows that the improvement of specialization in major agricultural producing areas is conducive to reducing educational inequality in major agricultural producing provinces; these conclusions provide a useful reference for narrowing the urban-rural education gap in the main agricultural production areas.

Temozolomide hexadecyl ester targeted plga nanoparticles for drug-resistant glioblastoma therapy via intranasal administration.

Introduction: Temozolomide (TMZ) is the first-line drug for glioblastoma (GBM), but it is limited in clinical use due to the drug resistance, poor brain targeting, and side effects. Temozolomide hexadecyl ester (TMZ16e), a TMZ derivative with high lipophilicity, membrane permeability, and high anti-glioma properties, has the potential to reverse drug resistance. In this study, anti-ephrin type-A receptor 3 (EphA3) modified TMZ16e loaded nanoparticles (NPs) were prepared for targeted GBM therapy via intranasal administration to deliver TMZ16e to the brain, treat drug-resistant glioma effectively, and reduce peripheral toxicity. Methods: TMZ16e loaded NPs were prepared by emulsion solvent evaporation method followed by modified with anti-EphA3 (anti-EphA3-TMZ16e-NPs). In vitro evaluations were performed by an MTT assay and flow cytometry analysis. The orthotopic nude mice models were used to evaluate the anti-glioma effect in vivo. Additionally, we investigated the anti-drug resistant mechanism by western blot analysis. Results: The particle size of the prepared NPs was less than 200 nm, and the zeta potential of TMZ16e-NPs and anti-EphA3-TMZ16e-NPs were -23.05 ± 1.48 mV and -28.65 ± 1.20mV, respectively, which is suitable for nasal delivery. In vitro studies have shown that anti-EphA3 modification increased the cellular uptake of nanoparticles in T98G cells. The cytotoxicity in the anti-EphA3-TMZ16e-NPs treated group was significantly higher than that of the TMZ16e-NPs, TMZ16e, and TMZ groups (p < 0.01), and the cell cycle was blocked. Western blotting analysis showed that the TMZ16e-loaded NPs were able to effectively downregulate the expression level of O6-methylguanine-deoxyribonucleic acid-methyltransferase (MGMT) protein in T98G cells and reverse drug resistance. In vivo studies showed that the median survival time of tumor-bearing nude mice in the anti-EphA3-TMZ16e-NPs group was extended to 41 days, which was 1.71-fold higher than that of the saline group and the TUNEL staining results of the brain tissue section indicated that the TMZ16e-loaded NPs could elevate apoptosis in T98G cells. Conclusion: In conclusion, the TMZ16e-loaded NPs can be effectively delivered to the brain and targeted to gliomas, exhibiting better anti-glioma activity, indicating they possess great potential in the treatment of drug-resistant glioma.

A New Instrument Combines Cognitive and Social Functioning Items for Detecting Mild Cognitive Impairment and Dementia in Parkinson's Disease.

Background: The commonly used screening tests for Parkinson's disease (PD) are the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), both of which only focus on cognitive function. A composite assessment that considers both cognitive and social dysfunction in PD would be helpful in detecting mild cognitive impairment (MCI) and PD dementia (PDD). Objective: We aimed to simplify the commonly used tools and combine cognitive and social functioning tests to detect early MCI and PDD. Materials and Methods: A total of 166 participants (84 PD patients and 82 healthy) were recruited who completed the MMSE, MoCA, PD social functioning scale (PDSFS), clock drawing test, activities of daily living, comprehensive neuropsychological assessment (e.g., executive, attention, language, memory, and visuospatial functions), and movement disorder society (MDS)-unified PD rating scale. According to the MDS diagnostic criteria, the patients were grouped into PD-nonMCI, PD-MCI, or PDD. Results: To detect PD-MCI, the optimal cut-off scores for the simplified MoCA and the combined test were 9 and 35. The discrimination values measured by the area under the receiver operating characteristic curve (AUC) of the two tests were 0.767 (p < 0.001) and 0.790 (p < 0.001). When the simplified MoCA was 7 or the combined test 30, the patients would be classified as having PDD. The AUCs of the two tests were 0.846 (p < 0.001) and 0.794 (p = 0.003). Conclusion: We suggest considering both cognitive and social functions when detecting PD-MCI and PDD.

The etiology of poststroke-depression: a hypothesis involving HPA axis.

Approximately, one in three ischemic stroke survivors suffered from depression, namely, post-stroke depression (PSD). PSD affects functional rehabilitation and may lead to poor quality of life of patients. There are numerous explanations about the etiologies of PSD. Here, we speculated that PSD are likely to be the result of specific changes in brain pathology. We hypothesized that the stroke-induced hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis plays an important role in PSD. Stroke initiates a complex sequence of events in neuroendocrine system including HPA axis. The HPA axis is involved in the pathophysiology of depression, especially, the overactivity of the HPA axis occurs in major depressive disorder. This review summarizes the possible etiologies of PSD, focusing on the stroke-induced activation of HPA axis, mainly including the stress followed by severe brain damage and the proinflammatory cytokines release. The role of hyperactive of HPA axis in PSD was discussed in detail, which includes the role of high level corticotropin-releasing hormone in PSD, the effects of glucocorticoids on the alterations in specific brain structures, the expression of enzymes, excitotoxicity, the change in intestinal permeability, and the activation of microglia. The relationship between neuroendocrine regulation and inflammation was also described. Finally, the therapy of PSD by regulating HPA axis, neuroendocrine, and immunity was discussed briefly. Nevertheless, the change of HPA axis and the occurring of PSD maybe interact and promote on each other, and future investigations should explore this hypothesis in more depth.

Efficacy of Temozolomide-Conjugated Gold Nanoparticle Photothermal Therapy of Drug-Resistant Glioblastoma and Its Mechanism Study.

Temozolomide (TMZ) is a standard-of-care chemotherapeutic drug for the treatment of glioblastoma (GBM), but TMZ-acquired resistance limits its therapeutic effect. In this study, TMZ-loaded gold nanoparticles (TMZ@GNPs) with anti-EphA3 modification on the surface (anti-EphA3-TMZ@GNPs) were synthesized for chemical and auxiliary plasma photothermal treatment (GNPs-PPTT), aiming to overcome the problem of glioma resistance to TMZ and improve the therapeutic effects of GBM. The prepared anti-EphA3-TMZ@GNPs were spherical with a particle size of 45.88 ± 1.9 nm, and the drug loading was 7.31 ± 0.38%. In vitro, cell-culture-based experiments showed that anti-EphA3 increased the cellular uptake of GNPs in T98G cells. Upon laser irradiation, the cytotoxicity and apoptosis rate in the anti-EphA3-TMZ@GNPs-treated group were significantly higher than those in the GNPs and nonphotothermal groups (p < 0.001). The Western blot analysis showed that the GNPs-PPTT-mediated killing of tumor cells induced apoptosis by regulating the apoptotic signaling molecules and cell cycle inhibitors; the expression of MGMT significantly decreased upon p53 induction, thereby reversing drug resistance. After photothermal treatment, the survival time of the subcutaneous GBM model of nude mice in the anti-EphA3-TMZ@GNPs group was prolonged to 46 days, 1.64-fold longer as compared to that in the TMZ group. Based on H&E and TUNEL staining, GNPs-PPTT could elevate apoptosis in T98G cells. In vivo thermal imaging results showed that GNPs could enter the brain via intranasal administration and be eliminated in 2 days, indicating that GNPs are safe for brain. In conclusion, GNPs-PPTT could effectively induce apoptosis in glioma cells and reverse TMZ resistance, thereby, indicative of a promising treatment strategy for GBM.

Ultrafast Deep-Ultraviolet Laser-Induced Voltage Response of Pyrite.

Ultrafast, high-sensitivity deep-ultraviolet (UV) photodetectors are crucial for practical applications, including optical communication, ozone layer monitoring, flame detection, etc. However, fast-response UV photodetectors based on traditional materials suffer from issues of expensive production processes. Here, we focused on pyrite with simultaneously cheap production processes and ultrafast response speed. Nanoseconds photovoltaic response was observed under UV pulsed laser irradiation without an applied bias at room temperature. In addition, the response time of the laser-induced voltage (LIV) signals was ~20 ns, which was the same as the UV laser pulse width. The maximum value of the responsivity is 0.52 V/mJ and the minimum value of detectivity was about to ~1.4 × 1013 Jones. When there exists nonuniform illumination, a process of diffusion occurs by which the carriers migrate from the region of high concentration toward the region of low concentration. The response speed is limited by a factor of the diffusion of the carriers. With an increment in laser energy, the response speed of LIV is greatly improved. The high response speed combined with low-cost fabrication makes these UV photodetectors highly attractive for applications in ultrafast detection.

Developmental Traits of Impulse Control Behavior in School Children under Controlled Attention, Motor Function, and Perception.

This research surveyed the characteristics of the developmental traits of impulse control behavior in children through parent-report questionnaires. After matching for gender and attention behavior, as well as controlling for variables (motor and perception) which might confound impulse control, 710 participants (355 girls and 355 boys; grade, 1-5; age, 7-12 years) were recruited from a database of 1763 children. Results demonstrated that there was a significant difference between grade 1 and grade 5 in impulse control. Conversely, no significant differences were found when comparing other grades. The present findings indicate that a striking development of impulse control occurs from grade 4 to 5. Moreover, the plateau of impulse control development from grade 1 to 4 implies that a long transition period is needed to prepare children to develop future impulse control. In conclusion, the age-dependent maturation associated with stage-wise development is a critical characteristic of impulse control development in school age children. Further discussions are made regarding this characteristic, such as from the perspective of frontal lobe development.

A new fluorescently labeled bisphosphonate for theranostics in tumor bone metastasis.

Bone metastasis of malignant solid tumors has become one of the most serious complications, especially in breast cancer, which was particularly challenging for early detection and treatment in clinical practice. In this work, we reported a new fluorescently labeled bisphosphonate for bone metastasis detection of breast cancer. The designed probes were based on Rhodamine B and bisphosphonate as recognition group, which can specifically target hydroxyapatite (HA) existed in bone tissue. After the osteoclasts were adsorbed on the bone surface, the surrounding microenvironment was acidified, causing the HA to locally dissolve. The probe bound to the HA was then released, and realized the fluorescence turn on under acidic conditions. In vitro experiments showed that G0 was more excellent than G2 owing to shorter connecting arm. Subsequently, we proved that G0 could combine with HA rapidly and exhibit excellent response in solid state. More importantly, we established a model of bone metastasis with MDA-MB-231 cells which was similar to the clinical cases and evaluated the theranostics value of G0 prospectively, which provide the potential application prospect in clinical.

A novel fast-response and highly selective AIEgen fluorescent probe for visualizing peroxynitrite in living cells, C. elegans and inflammatory mice.

Most of the ONOO- fluorescent probes have restricted applications because of their aggregation-caused quenching (ACQ) effect, long response time and low fluorescence enhancement. Herein, we developed a novel AIEgen fluorescent probe (PE-XY) based on a benzothiazole and quinolin scaffold with high sensitivity and selectivity for imaging of ONOO-. The results indicated that probe PE-XY exhibited fast response towards ONOO- with 2000-fold enhancement of fluorescence intensity ratio in vitro. Moreover, PE-XY exhibited a relatively high sensitivity (limit of detection: 8.58 nM), rapid response (<50 s), high fluorescence quantum yield (δ = 0.81) and excellent selectivity over other analytes towards ONOO-in vitro. Furthermore, PE-XY was successfully applied to detect endogenous ONOO- levels in living HeLa cells, C. elegans and inflammatory mice with low cytotoxicity. Overall, this work provided a novel fast-response and highly selective AIEgen fluorescent probe for real-time monitoring ONOO- fluctuations in living systems.

Glutathione-responsive prodrug conjugates for image-guided combination in cancer therapy.

Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293 T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.

Synthesis and Characterization of a Series of Temozolomide Esters and Its Anti-glioma Study.

Temozolomide is a first-line therapeutic drug for glioblastoma (GBM), and it has a low solubility, short biological half-life, and resistance to drug limits in clinical applications. Therefore, it is necessary to find more effective anti-tumor drugs to overcome drug resistance and enhance its anti-glioma activity. We therefore used n-butanol, n-hexanol, n-octanol, 1-dodecanol and 1-hexadecanol to synthesize a series of temozolomide ester compounds (TMZEs) and then investigated their physicochemical properties and anti-glioma efficacy. Our results showed that TMZEs had a higher lipophilicity compared to TMZ and could stably exist in plasma and brain homogenates. TMZEs had significantly increased cytotoxicity and cellular uptake in C6 glioma cells as chain lengths increased. Additionally, the IC50 of TMZ-16E towards TMZ-resistant cells (T98G) was 85.9-fold lower than that of TMZ (p < 0.001), and Western blot results demonstrated that TMZ-16E could significantly reduce the expression of O6-methylguanine-DNA-methyltransferase (MGMT). The in vivo anti-glioma efficacy of TMZ-16E were then investigated in orthotopic and subcutaneous GBM models. TMZ-16E prolonged the survival time to 35 days in orthotopic glioma bearing rats, which was 1.94-fold longer than the survival time of rats treated with TMZ, and TMZ-16E increased tumor cell apoptosis based on TUNEL staining. Moreover, TMZ-16E (50 mg/kg) noticeably slowed the growth of T98G subcutaneous tumors by down-modulating MGMT expression in subcutaneous GBM-bearing mice, indicating that TMZ-16E could effectively reverse drug resistance. In conclusion, TMZEs improved the lipophilicity and stability of these drugs. Especially, TMZ-16E could reverse drug resistance and improve therapeutic effects of TMZ, which has clinical application potential for GBM treatment.

Intranasal Delivery of Temozolomide-Conjugated Gold Nanoparticles Functionalized with Anti-EphA3 for Glioblastoma Targeting.

Glioblastoma multiforme (GBM) is a highly lethal and aggressive tumor of the brain that carries a poor prognosis. Temozolomide (TMZ) has been widely used as a first-line treatment for GBM. However, poor brain targeting, side effects, and drug resistance limit its application for the treatment of GBM. We designed a Temozolomide-conjugated gold nanoparticle functionalized with an antibody against the ephrin type-A receptor 3 (anti-EphA3-TMZ@GNPs) for targeted GBM therapy via intranasal administration. The system can bypass the blood-brain barrier and target active glioma cells to improve the glioma targeting of TMZ and enhance the treatment efficacy, while reducing the peripheral toxicity and drug resistance. The prepared anti-EphA3-TMZ@GNPs were 46.12 ± 2.0 nm and suitable for intranasal administration, which demonstrated high safety to the nasal mucosa in a toxicity assay. In vitro studies showed that anti-EphA3-TMZ@GNPs exhibited significantly enhanced cellular uptake and toxicity, and a higher cell apoptosis ratio has been seen compared with that of TMZ (54.9 and 14.1%, respectively) toward glioma cells (C6). The results from experiments on TMZ-resistant glioma cells (T98G) demonstrated that the IC50 of anti-EphA3-TMZ@GNPs (64.06 ± 0.16 µM) was 18.5-fold lower than that of TMZ. In addition, Western blot analysis also revealed that anti-EphA3-TMZ@GNPs effectively down-modulated expression of O6-methylguanine-DNA methyltransferase and increased chemosensitivity of T98G to TMZ. The antiglioma efficacy in vivo was investigated in orthotopic glioma-bearing rats, and the results demonstrated that the anti-EphA3-TMZ@GNPs prolonged the median survival time to 42 days and increased tumor-cell apoptosis dramatically compared with TMZ. In conclusion, anti-EphA3-TMZ@GNPs could serve as an intranasal drug delivery system for efficacious treatment of GBM.