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Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas
摘要： Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132H cells. Next, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence.
关键词： 5-ALA,glioma,oncology,fluorescence,brain tumors,IDH1,NADPH
更新于2025-09-23 15:22:29
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Targeting Glioma with a Dual Mode Optical and Paramagnetic Nanoprobe across the Blood-brain Tumor Barrier
摘要： In brain tumors, delivering nanoparticles across the blood-tumor barrier presents major hurdles. A clinically relevant MRI contrast agent, GdDOTA and a near-infrared (NIR) fluorescent dye, DL680 were conjugated to a G5 PAMAM dendrimer, thus producing a dual-mode MRI and NIR imaging agent. Systemic delivery of the subsequent nano-sized agent demonstrated glioma-specific accumulation, probably due to the enhanced permeability and retention effect. In vivo MRI detected the agent in glioma tissue, but not in normal contralateral tissue; this observation was validated with in vivo and ex vivo fluorescence imaging. A biodistribution study showed the agent to have accumulated in the glioma tumor and the liver, the latter being the excretion path for a G5 dendrimer-based agent.
关键词： Tumor blood-brain barrier,MRI,Dual modality,Glioma,Optical imaging
更新于2025-09-23 15:21:21
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EXTH-77. LIGAND CONJUGATED QUANTUM DOTS FOR THE DETECTION OF CANCER STEM CELLS AND EXOSOMES
摘要： High grade astrocytomas and other metastatic brain cancers possess high tumor invasive and infiltrating properties making them difficult to detect and treat. In our study we demonstrate the unique and selective uptake of a variant of interleukin 13 (TQM13) conjugated quantum dots in glioma in an in vitro and in vivo model. As IL13Rα2 and EGFRVIII are known to be expressed in invasive and therapeutically resistant forms of glioma tumors, the cell lines expressing these receptors were targeted using ligand conjugated quantum dots. Monolayer and spheroidal cell culture models of glioma stem cells were utilized for demonstrating the receptor specific uptake of the targeted quantum dots. To demonstrate the in vivo specificity of the IL13Rα2 receptor targeted quantum dots, the quantum dots were injected intraperitoneally in an intracranial glioma tumor mouse model. After sacrificing the mice, the tumor sections were analyzed for the accumulation of quantum dots using 2-photon fluorescence microscopy. The interaction of exosomes with ligand conjugated quantum dots to alter the tumor cell binding was also verified in a cell culture model. For this purpose, we utilized exosomes derived from a glioma patient derived cell line and Jurkat T cell line. Our in vitro binding study indicated an effective binding of the tumor targeted quantum dots to the cancer stem cells expressing IL13Rα2 and EGFRVIII. The 2-photon fluorescence microscopy confirms a perinuclear accumulation of quantum dots in the tumor region in the in vivo model. The exosome bound quantum dots showed either increased or decreased uptake by the glioma cells depending on the source of the exosomes and the cell lines under investigation.
关键词： quantum dots,EGFRVIII,exosomes,IL13Rα2,glioma
更新于2025-09-23 15:19:57
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Lessons Learned in Using Laser Interstitial Thermal Therapy for Treatment of Brain Tumors: A Case Series of 238 Patients from a Single Institution
摘要： Background: Laser interstitial thermal therapy (LITT) is a novel, minimally invasive alternative to craniotomy, and as with any new technology, comes with a learning curve. Objective: We present our experience detailing the evolution of this technology in our practice in one of the largest patient cohorts to date regarding LITT in neuro-oncology. Methods: We reviewed 238 consecutive brain tumor patients treated with LITT at our institution. Data on patient, surgery and tumor characteristics, and follow-up were collected. Patients were categorized into two cohorts: Early (<2014, 100 patients) and Recent (>2015, 138 patients). Median follow up for the entire cohort was 8.4 months. Results: The indications for LITT included gliomas (70.2%), radiation necrosis (21.0%), and metastasis (8.8%). Patient demographics stayed consistent between the two cohorts, with the exception of age (Early: 54.3, Recent: 58.4, p=0.04). Operative time (6.6 versus 3.5, p<0.001) and number of trajectories (53.1% versus 77.9% with 1 trajectory, p<0.001) also decreased in the Recent cohort. There was a significant decrease in permanent motor deficits over time (15.5 versus 4.4%, p=0.005) and 30-day mortality (4.1% versus 1.5%) also decreased (not statistically significant) in Recent cohort. In terms of clinical outcomes, poor preoperative KPS (≤70) were significantly correlated with increased permanent deficits (p=0.001) and decreased overall survival (p<0.001 for all time points). Conclusions: We observed improvement in operative efficiency and permanent deficits over time and also patients with poor preoperative KPS achieved suboptimal outcomes with LITT. As many other treatment modalities, patient selection is very important in this procedure.
关键词： Stereotactic Laser Ablation,Radiation Necrosis,Tumor,Glioblastoma,Glioma,Minimally-Invasive
更新于2025-09-23 15:19:57
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c(RGDyk)-modified nanoparticles encapsulating quantum dots as a stable fluorescence probe for imaging-guided surgical resection of glioma under the auxiliary UTMD
摘要： Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of –10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.
关键词： quantum dots,ultrasound-targeted microbubble destruction,nanoparticles,Glioma,BBB
更新于2025-09-23 15:19:57
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Application of Raman Spectroscopy for Analysis of Carbon Nanotube Distribution in Living Cells
摘要： We have used Raman spectroscopy combined with confocal microscopy to study suspensions of single-wall and double-wall carbon nanotubes of different lengths and also multiwall carbon nanotubes. We have shown that the intensity of the G mode in the Raman spectrum of carbon nanotubes is directly proportional to the nanotube concentration, the exposure time, the exciting radiation power, and depth of focus in the transparent sample under study. We have established that the Raman spectra of longer carbon nanotubes (~1 μm) are characterized by higher intensity of the G mode compared with short carbon nanotubes (~250–450 nm). The dependences obtained were used to determine the local intracellular concentration of carbon nanotubes within the waist of the exciting laser beam, with the aim of mapping the carbon nanotube distribution inside the cells.
关键词： carbon nanotubes,local concentration,Raman spectroscopy,intracellular distribution,glioma cells
更新于2025-09-19 17:15:36
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The Role of Laser Interstitial Thermal Therapy in Surgical Neuro-Oncology: Series of 100 Consecutive Patients
摘要： BACKGROUND: Laser interstitial thermal therapy (LITT) is an adjuvant treatment for intracranial lesions that are treatment refractory or in deep or eloquent brain. Initial studies of LITT in surgical neuro-oncology are limited in size and follow-up. OBJECTIVE: To present our series of LITT in surgical neuro-oncology to better evaluate procedural safety and outcomes. METHODS: An exploratory cohort study of all patients receiving LITT for brain tumors by a single senior neurosurgeon at a single center between 2013 and 2018. Primary outcomes included extent of ablation (EOA), time to recurrence (TTR), local control at 1-yr follow-up, and overall survival (OS). Secondary outcomes included complication rate. Outcomes were compared by tumor subtype. Predictors of outcomes were identified. RESULTS: A total of 91 patients underwent 100 LITT procedures; 61% remain alive with 72% local control at median 7.2 mo follow-up. Median TTR and OS were 31.9 and 16.9 mo, respectively. For lesion subtypes, median TTR (months, not applicable [N/A] if <50% rate observed), local control rates at 1-yr follow-up, and median OS (months) were the following: dural-based lesions (n = 4, N/A, 75%, 20.7), metastases (n = 45, 55.9, 77.4%, 16.9), newly diagnosed glioblastoma (n = 11, 31.9, 83.3%, 32.3), recurrent glioblastoma (n = 14, 5.6, 24.3%, 7.3), radiation necrosis (n = 20, N/A, 67.2%, 16.4), and other lesions (n = 6, 12.3, 80%, 24.4). TTR differed by tumor subtype (P = .02, log-rank analysis). EOA predicted local control (P = .009, multivariate proportional hazards regression); EOA > 85% predicted longer TTR (P = .006, log-rank analysis). Complication rate was 4%. CONCLUSION: Our series of LITT in surgical neuro-oncology, 1 of the largest to date, further evidences its safety and outcomes profile.
关键词： Outcomes,Brain tumor,Laser,Metastasis,Treatment,Glioma
更新于2025-09-11 14:15:04
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Polymethine Thiopyrylium Fluorophores with Absorption beyond 1000 nm for Biological Imaging in the Second Near-infrared Sub-window
摘要： Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by indocyanine green structure, a series of polymethine dyes with both absorption and emission in NIR-II window have been developed for NIR-II imaging, providing the feasibility to directly compare optical imaging in NIR-IIa (1300-1400 nm) sub-window under 1064 nm excitation with that in NIR-II window under 808 nm excitation. The signal-background ratio (SBR) and tumor to normal tissue ratio (T/NT) achieved great improvement under 1064 nm excitation in the imaging of mouse blood pool and U87 glioma tumors. Our study not only introduces a broadband emission fluorophore for both NIR-II and NIR-IIa imaging, but also reveals the advantages of NIR-II excitation over NIR-I in in vivo imaging.
关键词： Molecular imaging,U87MG glioma tumor,Polymethine thiopyrylium salts,Second near-infrared window
更新于2025-09-10 09:29:36
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Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response
摘要： To determine whether the Ganzfeld ERG photopic negative response (PhNR), an assay of inner retinal activity, is altered in childhood optic glioma (OPG). Seventeen pediatric patients with a diagnosis of OPG, established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria, were enrolled. The examination protocol included determination of visual acuity (VA), fundus examination, retinal nerve fiber layer (RNFL) measurement with spectral-domain optical coherence tomography (SD-OCT) and photopic ERG. Fifteen normal children served as control group. Ten of the 17 OPG patients were retested 1 to 3 months after the first examination. Photopic ERGs were recorded after 10 minutes of light adaptation in response to a Ganzfeld flash presented on a steady light–adapting background. Amplitude and peak-time of b-wave and PhNR were measured. Compared with normal values, PhNR amplitude was significantly reduced (P < 0.0001) in the OPG group. Peak-time of PhNR as well as b-wave amplitude and peak-time were similar in both patients and controls. Losses of PhNR were found in patients with involvement of either anterior or retro-chiasmatic optic pathways. Linear regression analysis showed significant positive correlation between RNFL thickness and PhNR amplitude (r2 ? 0.34, P ? 0.008). Mean percentage test–retest difference for PhNR amplitude and peak-time was 12% and 6%, respectively. These findings indicate that flash ERG PhNR can detect a loss of inner retinal function in childhood OPGs supporting the use of this technique, as an adjunct to standard psychophysical and electrophysiological tests, to monitor visual function in OPG.
关键词： photopic negative response,optical coherence tomography,ganglion cells,optic pathways glioma,neurofibromatosis
更新于2025-09-10 09:29:36
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Photothermal Therapy Employing Gold Nanoparticle- Loaded Macrophages as Delivery Vehicles: Comparing the Efficiency of Nanoshells Versus Nanorods
摘要： Macrophages (Ma) loaded with gold-based nanoparticles, which convert near infrared light to heat, have been studied as targeted transport vectors for photothermal therapy (PTT) of tumors. The purpose of the experiments reported here was to compare the efficacy of gold-silica nanoshells (AuNS) and gold nanorods (AuNR) in macrophage-mediated PTT. Photothermal therapy efficacy was evaluated in hybrid glioma spheroids consisting of human glioma cells and either AuNS- or AuNR-loaded Ma, designated MaNS and MaNR, respectivly. Spheroids were irradiated for 10 minutes with light from an 810-nm diode laser at irradiances ranging from 0 to 28 W/cm2. Photothermal therapy efficacy was determined from spheroid growth over a 14-day period. The uptake by Ma of pegylated AuNR (3.9 ± 0.9 %) was twice that of pegylated AuNS (7.9 ± 0.7%). Hybrid spheroids consisting of a 5:1 ratio of glioma cells to loaded Ma exhibited significant growth inhibition with MaNS when subjected to irradiances of 7 W/cm2 or greater. In contrast, no significant growth inhibition was observed for the MaNR hybrid spheroids at this 5:1 ratio, even at the highest irradiance investigated (28 W/cm2). Although AuNR were taken up by Ma in larger numbers than AuNS, MaNS were shown to have greater PTT efficacy compared to MaNR for equivalent numbers of loaded Ma.
关键词： photothermal therapy,glioma,murine macrophages,gold-silica nanoshells,gold nanorods
更新于2025-09-09 09:28:46