Fabrication of doxorubicin and chlorotoxin-linked Eu-Gd2O3 nanorods with dual-model imaging and targeted therapy of brain tumor

It is urgent to find a technology accurately to better diagnose and treat to brain tumor.Eu-doped Gd2 O3 nanorods(Eu-Gd2 O3 NRs)with paramagnetic and fluorescent properties were conjugated with doxorubicin(Dox)and chlorotoxin(CTX)via PEGylation,hydrazone bond and sulfur bond(named as CTXNRs-Dox),and these NRs could release more Dox in lower pH environment.The results of cell experiments indicated that CTX-NRs-Dox had obvious targeting and toxic effects on U251 cells,as well as good fluorescence imaging behavior.The orthotopic glioma-transplanted mice models were constructed via the intracranial injection of glioma cells(U87 MG).The result of experiments after the tail-vein injection of the prepared NRs suggested that CTX-NRs-Dox could target to brain tumors via the long-time blood circulation,leading to their obvious contrast enhancement of MR imaging of the intracranial tumor and their significant inhibitory effect on the growth and metastasis of brain tumors.A mechanism of synergistic effect of CTX-NRs-Dox on targeting and inhabiting the brain tumor was proposed.Our research suggested that CTX-NRs-Dox had potential application prospect in the detection and treatment of glioma.     

Harnessing the Potential Synergistic Interplay Between Photosensitizer Dark Toxicity and Chemotherapy

The combination of photodynamic therapy and taxol- or platinum-based chemotherapy (photochemotherapy) is an effective and promising cancer treatment. While the mechanisms of action of photochemotherapy are actively studied, relatively little is known about the cytotoxicity and molecular alterations induced by the combination of chemotherapy and photosensitizers without light activation in cancer cells. This study investigates the interplay between the photosensitizer benzoporphyrin derivative (BPD) without light activation and cisplatin or paclitaxel in two glioblastoma lines, U87 and U251. The combination effect of BPD and cisplatin in U87 cells is slightly synergistic (combination index, CI = 0.93), showing 1.8- to 2.6-fold lower half-maximal inhibitory concentrations (IC₅₀) compared to those of individual drugs. In contrast, combining BPD and paclitaxel is slightly antagonistic (CI = 1.14) in U87 cells. In U251 cells, the combinations of BPD and cisplatin or paclitaxel are both antagonistic (CI = 1.24 and 1.34, respectively). Western blotting was performed to investigate changes in the expression levels of YAP, TAZ, Bcl-2 and EGFR in U87 and U251 cells treated with BPD, cisplatin and paclitaxel, both as monotherapies and in combination. Our study provides insights into the molecular alterations in two glioma lines caused by each monotherapy and the combinations, in order to inform the design of effective treatments.     

Anticancer Effect of Cathelicidin LL-37, Protegrin PG-1, Nerve Growth Factor NGF,and Temozolomide: Impact on the Mitochondrial Metabolism,Clonogenic Potential,and Migration of Human U251 Glioma Cells

Glioblastoma (GBM) is one of the most aggressive and lethal malignancy of the central nervous system. Temozolomide is the standard of care for gliomas, frequently results in resistance to drug and tumor recurrence. Therefore, further research is required for the development of effective drugs in order to guarantee specific treatments to succeed. The aim of current study was to investigate the effects of nerve growth factor (NGF), human cathelicidin (LL-37), protegrin-1 (PG-1), and temozolomide on bioenergetic function of mitochondria, clonogenicity, and migration of human U251 glioma cells. Colony formation assay was used to test the ability of the glioma cells to form colonies in vitro. The U251 glioma cells migration was evaluated using wound-healing assay. To study the mitochondrial metabolism in glioma cells we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) using a Seahorse XF cell Mito stress test kit and Seahorse XF cell Glycolysis stress kit, respectively. We revealed that LL-37, NGF, and TMZ show strong anti-tumorigenic activity on GMB. LL-37 (4 μM), TMZ (155 μM), and NGF (7.55 × 10⁻³ μM) inhibited 43.9%–60.3%, 73.5%–81.3%, 66.2% the clonogenicity of glioma U251 cells for 1–2 days, respectively. LL-37 (4 μM), and NGF (7.55 × 10⁻³ μM) inhibited the migration of U251 glioma cells on the third and fourth days. TMZ also inhibited the migration of human glioma U251 cells over 1–3 days. In contrast, PG-1 (16 μM) stimulated the migration of U251 glioma cells on the second, fourth, and sixth days. Anti-mitogenic and anti-migration activities of NGF, LL-37, and TMZ maybe are relation to their capacity to reduce the basal OCR, ATP-synthetase, and maximal respiration of mitochondria in human glioma U251 cells. Glycolysis, glycolytic capacity and glycolytic spare in glioma U251 cells haven`t been changed under the effect of NGF, LL-37, PG-1, and TMZ in regard to control level. Thus, LL-37 and NGF inhibit migration and clonogenicity of U251 glioma cells, which may indicate that these compounds have anti-mitogenic and anti-migration effects on human glioma cells. The study of the mechanisms of these effects may contribute in the future to the use of NGF and LL-37 as therapeutic agents for gliomas.     

Deferoxamine Iron Chelation Increases δ-Aminolevulinic Acid Induced Protoporphyrin IX in Xenograft Glioma Model

Exogenous administration of δ-aminolevulinic acid (δ-ALA) leads to selective accumulation of protoporphyrin IX (PpIX) in brain tumors, and has shown promising results in increasing extent of resection in fluorescence-guided resection (FGR) of brain tumors. However, this approach still suffers from heterogeneous staining and so some tumor margins may go undetected because of this variation in PpIX production. The aim of this study was to test the hypothesis that iron chelation therapy could increase the level of fluorescence in malignant glioma tumors. Mice implanted with xenograft U251-GFP glioma tumor cells were given a 200 mg kg⁻¹ dose of deferoxamine (DFO), once a day for 3 days prior to δ-ALA administration. The PpIX fluorescence observed in the tumor regions was 1.9 times the background in animal group without DFO, and 2.9 times the background on average, in the DFO pre-treated group. A 50% increase in PpIX fluorescence contrast in the DFO group was observed relative to the control group (t-test P-value = 0.0020). These results indicate that iron chelation therapy could significantly increase δ-ALA-induced PpIX fluorescence in malignant gliomas, pointing to a potential role of iron chelation therapy for more effective FGR of brain tumors.     

Formation of metal chelates in solid state reaction between 8-hydroxyquinoline and carbonates of cadmium and zinc

The solid state reactions between 8-hydroxyquinoline (8-HQ) and CdCO₃ and ZnCO₃ have been studied. The Brounshtein-Ginstling rate equation is followed in both cases. The activation energy for CdCO₃-8-HQ and ZnCO₃-8-HQ are respectively 92.3 ± 3.3 and 86.6 ± 0.6 kJ mole⁻¹. The reaction products were characterized by elemental analysis, X-ray diffraction, and IR studies. Metal (Zn and Cd) carbonates and 8-HQ react in 1:2 molar ratio and the reaction proceeds via surface migration of 8-HQ.     

Treatment of Human Glioblastoma U251 Cells with Sulforaphane and a Peptide Nucleic Acid (PNA) Targeting miR-15b-5p: Synergistic Effects on Induction of Apoptosis

Glioblastoma multiforme (GBM) is a lethal malignant tumor accounting for 42% of the tumors of the central nervous system, the median survival being 15 months. At present, no curative treatment is available for GBM and new drugs and therapeutic protocols are urgently needed. In this context, combined therapy appears to be a very interesting approach. The isothiocyanate sulforaphane (SFN) has been previously shown to induce apoptosis and inhibit the growth and invasion of GBM cells. On the other hand, the microRNA miR-15b is involved in invasiveness and proliferation in GBM and its inhibition is associated with the induction of apoptosis. On the basis of these observations, the objective of the present study was to determine whether a combined treatment using SFN and a peptide nucleic acid interfering with miR-15b-5p (PNA-a15b) might be proposed for increasing the pro-apoptotic effects of the single agents. To verify this hypothesis, we have treated GMB U251 cells with SFN alone, PNA-a15b alone or their combination. The cell viability, apoptosis and combination index were, respectively, analyzed by calcein staining, annexin-V and caspase-3/7 assays, and RT-qPCR for genes involved in apoptosis. The efficacy of the PNA-a15b determined the miR-15b-5p content analyzed by RT-qPCR. The results obtained indicate that SFN and PNA-a15b synergistically act in inducing the apoptosis of U251 cells. Therefore, the PNA-a15b might be proposed in a “combo-therapy” associated with SFN. Overall, this study suggests the feasibility of using combined treatments based on PNAs targeting miRNA involved in GBM and nutraceuticals able to stimulate apoptosis.     

Controllable Assembly and Properties of Brain Targeting Peptides with Tetrahedral Framework Nucleic Acids北大核心CSCD

In this study,the armed tetrahedral DNA nanostructures（TDN）are designed to bind single or three complementary strands of armed chain（1-ANG-TDN,3-ANG-TDN）which is modified with angiopep-2 or other brain targeting peptides（TAT,TGN）. We compare the cell viability and cellular uptake of 1-ANG-TDN or 3-ANG-TDN in brain capillary endothelial（bEnd. 3）cells and Uppsala 87 malignant glioma（U87） cells. In addition,the cell viability and cellular uptake of ANG-TDN,TAT-TDN and TGN-TDN in bEnd. 3 cells are investigated respectively. The results show that these probes are not cytotoxic to bEnd. 3 cells and U87 cells at concentrationsbelow 100 nmol/L. After being incubated with bEnd. 3cells for 0. 5 h,the cellular uptake of 3-ANG-TDN is higher than that of 1-ANG-TDN（P<0. 01）. After being incubated with U87 cells for 1h,the cellular uptake of 3-ANG-TDN is higher than that of 1-ANG-TDN（P<0. 01）. After 2 h,there is no obvious difference in cellular uptake between 1-ANG-TDN and 3-ANG-TDN. ANG-TDN,TAT-TDN and TGN-TDN are up-taken by bEnd. 3 cells much more than TDN（P<0. 01）. However,there isno statistical difference among ANG-TDN,TAT-TDN and TGN-TDN（P>0. 05）. These results indicate that the targeting of ANG-TDN probe can be improved by increasing the number of peptides or prolonging the co-incubation time. This discovery providesareference for the multifunctional modification of tetrahedral framework nucleic acid. When a single peptidelinked with TDN achieves the brain targeting,other sites of TDN can be modified by other functional groups to expand the structure and function. Tetrahedral framework nucleic acids can be used not only as an assembly platform for ANG peptides,but also for the assembly of other brain-targeting peptides （TAT and TGN）to design brain-targeting probes. © 2022, Science Press (China). All rights reserved.     

Cancer Cell Membrane-Coated Nanosuspensions for Enhanced Chemotherapeutic Treatment of Glioma

Effective intracerebral delivery is key for glioma treatment. However, the drug delivery system within the brain is largely limited by its own adverse physical and chemical properties, low targeting efficiency, the blood–brain barrier and the blood–brain tumor barrier. Herein, we developed a simple, safe and efficient biomimetic nanosuspension. The C6 cell membrane (CCM) was utilized to camouflaged the 10-hydroxycamptothecin nanosuspension (HCPT-NS) in order to obtain HCPT-NS/CCM. Through the use of immune escape and homotypic binding of the cancer cell membrane, HCPT-NS/CCM was able to penetrate the blood–brain barrier and target tumors. The HCPT-NS is only comprised of drugs, as well as a small amount of stabilizers that are characterized by a simple preparation method and high drug loading. Similarly, the HCPT-NS/CCM is able to achieve targeted treatment of glioma without any ligand modification, which leads it to be stable and efficient. Cellular uptake and in vivo imaging experiments demonstrated that HCPT-NS/CCM is able to effectively cross the blood–brain barrier and was concentrated at the glioma site due to the natural homing pathway. Our results reveal that the glioma cancer cell membrane is able to promote drug transport into the brain and enter the tumor via a homologous targeting mechanism.     

Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein

The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson''s disease (PD). The intracytoplasmic deposition of α-synuclein aggregates and Lewy bodies, often found in PD and other α-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of α-synuclein aggregates in neuronal cytoplasm causes numerous autonomous changes in neurons. However, it can also affect the neighboring cells through transcellular transmission of the aggregates. Indeed, a progressive spreading of Lewy pathology among brain regions has been hypothesized from autopsy studies. We tested whether inhibition of the autophagy/lysosome pathway in α-synuclein-expressing cells would increase the secretion of α-synuclein, subsequently affecting the α-synuclein deposition in and viability of neighboring cells. Our results demonstrated that autophagic inhibition, via both pharmacological and genetic methods, led to increased exocytosis of α-synuclein. In a mixed culture of α-synuclein-expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular α-synuclein transmission. This increase in protein transmission coincided with elevated apoptotic cell death in the recipient cells. These results suggest that the inefficient clearance of α-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated α-synuclein exocytosis, thereby promoting α-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology.     

CoFe2O4 nano-particles functionalized with 8-hydroxyquinoline for dispersive solid-phase micro-extraction and direct fluorometric monitoring of aluminum in human serum and water samples

A simple dispersive solid-phase micro-extraction method based on CoFe₂O₄ nano-particles (NPs) functionalized with 8-hydroxyquinoline (8-HQ) with the aid of sodium dodecyl sulfate (SDS) was developed for separation of Al(III) ions from aqueous solutions. Al(III) ions are separated at pH 7 via complex formation with 8-HQ using the functionalized CoFe₂O₄ nano-particles sol solution as a dispersed solid-phase extractor. The separated analyte is directly quantified by a spectrofluorometric method at 370 nm excitation and 506 nm emission wavelengths. A comparison of the fluorescence of Al(III)–8-HQ complex in bulk solution and that of Al(III) ion interacted with 8-HQ/SDS/CoFe₂O₄ NPs revealed a nearly 5-fold improvement in intensity. The experimental factors influencing the separation and in situ monitoring of the analyte were optimized. Under these conditions, the calibration graph was linear in the range of 0.1–300 ng mL⁻¹ with a correlation coefficient of 0.9986. The limit of detection and limit of quantification were 0.03 ng mL⁻¹ and 0.10 ng mL⁻¹, respectively. The inter-day and intra-day relative standard deviations for six replicate determinations of 150 ng mL⁻¹ Al(III) ion were 2.8% and 1.7%, respectively. The method was successfully applied to direct determine Al(III) ion in various human serum and water samples.     

Theoretical studies on structures and reactivity of 8-hydroxyquinoline and its one-water complex in the ground and excited states

In this Letter, MP2, DFT and CASSCF calculations were carried out to investigate proton transfer reactions of 8-hydroxyquinoline (8-HQ) and its one-water complex (8-HQ-H₂O). Since the forward reactions from the normal form (N) to the tautomer form (T) in the ground state have a considerable barrier and the reverse processes nearly have no barrier, the tautomerization reactions from N to T proceed with little probability in the ground state of 8-HQ and 8-HQ-H₂O. After photoexcitation, the excited-state proton transfer reactions proceed very easily for both 8-HQ and 8-HQ-H₂O, which are mainly responsible for lack of fluorescence for 8-HQ in aqueous solution.     

Cytotoxicity of Amino-BODIPY Modulated via Conjugation with 2-Phenyl-3-Hydroxy-4(1H)-Quinolinones

The combination of cytotoxic amino-BODIPY dye and 2-phenyl-3-hydroxy-4(1H)-quinolinone (3-HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino-BODIPY dye and 3-HQ derivative can be monitored by ratiometric fluorescence or by the OFF-ON effect of the amino-BODIPY dye. A similar cytotoxic activity is observed when the amino-BODIPY dye and 3-HQ derivative are connected through a non-cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening.     

Comparative study of 8-hydroxyquinoline derivatives as chelating reagents for flow-injection preconcentration of cobalt in a knotted reactor

8-Hydroxyquinoline (HQ), 2-methyl-8-hydroxyquinoline (CH₃-HQ), 5,7-dichloro-2-methyl-8-hydroxyquinoline (Cl₂-CH₃-HQ), 5,7-dibromo-8-hydroxyquinoline (Br₂-HQ), 5-sulfo-7-iodo-8-hydroxyquinoline (ferron) and 5-sulfo-8-hydroxyquinoline (SO₃H-HQ) were compared as chelating reagents for on-line sorption preconcentration of cobalt in a knotted reactor (KR) precoated with the reagent. The results obtained with the different HQ derivatives reveal those properties of the chelating reagent responsible for the processes taking place in the KR. The influence of hydrophobicity, acidity, stability of the cobalt chelate and type of substituents in the HQ ring system on the separate steps of the flow injection (FI) preconcentration procedure are discussed. According to the performance characteristics of the different HQ derivatives, the most important parameters for on-line preconcentration in a KR are the hydrophobicity of the reagent and the stability of the chelate complex with the analyte.     

Drastically enhanced cycle life of Co-B alloy electrode by 8-hydroxyquinoline at elevated temperature

The effect 8-hydroxyquinoline (8-HQ) additive in electrolyte on the cyclic stability of Co-B alloy electrode was investigated at elevated temperature (55 °C). Charge–discharge measurements show that 8-HQ can drastically enhance the cycle life of Co-B alloy electrode. Specifically, in the electrolyte containing 0.028 M 8-HQ additive, the discharge capacity of Co-B alloy electrode after 100 cycles are still up to 385.8 mAh/g at 55 °C. However, for the electrode in 8-HQ-free electrolyte, its discharge capacity is sharply decreased to only 138.5 mAh/g after 100 cycles. ICP-OES, XRD and ATR/FT-IR measurements were used to clarify the reason of the improvement in the cyclic stability. These results show that beneficial effect of 8-HQ on cycle life of Co-B alloy electrode can be attributed to the formation of insoluble complex (8-HQ)₂Co(II)·2H₂O protective layer that can suppress the dissolution of Co(OH)₂ into electrolyte at elevated temperature.     

Thermal behaviour of intercalated 8-hydroxyquinoline (oxine) in montmorillonite clay

The composite montmorillonite-8-hydroxyquinoline (Swy-1-8-HQ) was prepared by two different processes and studied by using thermogravimetric analysis (TG/DTG and DSC), as well as helpful techniques as fluorescence in the UV-visible region and X-ray diffraction. The composites developed fluorescent appearance, however with quantum poor efficiency and they exhibited distinct TG and DSC thermal behavior. The fluorescence data of spectra associated to the TG/DT curves allowed to suggest that the 8-HQ was present in the composites in two different circumstances: 1 - intercalated in the interlayer spaces (Swy-1-8-HQ2), rigidly associated to the substrate feasible as a monolayer with the aromatic rings parallel to the silica layer; and/or, 2 - adsorbed on the surface (Swy-1-8-HQ1), either as a bilayer formation or tilting of the molecules to the silicate layer sheet. All results confirmed above are in agreement with X-ray diffraction patterns, once the interlayer space increases when 8-HQ is incorporated. The experimental results confirm the formation of the composites in agreement with the method used in the preparation. This revised version was published online in August 2006 with corrections to the Cover Date.     

Analysis of U87 glioma cells by dielectrophoresis

Glioblastoma multiforme is the most aggressive and invasive brain cancer consisting of genetically and phenotypically altering glial cells. It has massive heterogeneity due to its highly complex and dynamic microenvironment. Here, electrophysiological properties of U87 human glioma cell line were measured based on a dielectrophoresis phenomenon to quantify the population heterogeneity of glioma cells. Dielectrophoretic forces were generated using a gold-microelectrode array within a microfluidic channel when 3 V_pp and 100, 200, 300, 400, 500 kHz, 1, 2, 5, and 10 MHz frequencies were applied. We analyzed the dielectrophoretic behavior of 500 glioma cells, and revealed that the crossover frequency of glioma cells was around 140 kHz. A quantifying dielectrophoretic movement of the glioma cells exhibited three distinct glioma subpopulations: 50% of the glioma cells experienced strong, 30% of the cells were spread in the microchannel by moderate, and the rest of the cells experienced very weak positive dielectrophoretic forces. Our results demonstrated the dielectrophoretic spectra of U87 glioma cell line. Dielectrophoretic responses of glioma cells linked population heterogeneity to membrane properties of glioma cells rather than their size distribution in the population.     

Silylation Improves the Photodynamic Activity of Tetraphenylporphyrin Derivatives In Vitro and In Vivo

The effects of silyl and hydrophilic groups on the photodynamic properties of tetraphenylporphyrin (TPP) derivatives have been studied in vitro and in vivo. Silylation led to an improvement in the quantum yield of singlet oxygen sensitization for both sulfo and carboxy derivatives, although the silylation did not affect other photophysical properties. Silylation also improved the cellular uptake efficiency for both sulfo and carboxy derivatives, enhancing the in vitro photodynamic activity of the photosensitizer in U251 human glioma cells. The carboxy derivative (SiTPPC₄) was found to show higher cellular uptake efficiency and in vitro photodynamic activity than the corresponding sulfo derivative (SiTPPS₄), which indicates that the carboxy group is a more promising hydrophilic group than the sulfo group in the silylated porphyrin. SiTPPC₄ was found to show high selective accumulation efficiency in tumors, although almost no tumor selectivity was observed for the nonsilylated porphyrin. The concentration of SiTPPC₄ in tumors was 13 times higher than that in muscle 12 h after drug administration. We also studied tumor response after treatment and found that silylation enhanced in vivo photodynamic activity significantly. SiTPPC₄ shows higher photodynamic activity than NPe6 with white light irradiation.