Marine microplastics enhance release of arsenic in coastal aquifer during seawater intrusion process.

Microplastics (MPs), omnipresent contaminants in the ocean, could be carried by seawater intrusion into coastal aquifers, which might affect the fate of heavy metals existing in aquifers. Herein, we investigated the release behavior of arsenic (As) in coastal aquifers during MPs-containing seawater intrusion by applying laboratory experiment and numerical simulation. We found that seawater with marine MPs enhanced the release of As in aquifers, especially for dissolved As(V) and colloidal As. Negatively charged MPs competed with As(V) for the adsorption sites on iron (hydr)oxides in aquifers, resulting in the desorption of As(V). In addition, MPs could promote the release of Fe-rich colloids by imparting negative charge to its surface and providing it with sufficient repulsive force to detach from the matrix, thereby leading to the release of As associated with Fe-rich colloid. We also developed a modeling approach that well described the transport of As in coastal aquifer under the impact of MPs, which coupled variable density flow and kinetically controlled colloids transport with multicomponent reactive transport model. Our findings elucidated the enhancement of MPs on the release of As in aquifers during seawater intrusion, which provides new insights into the risk assessment of MPs in coastal zones.

Janus plasmonic-aggregation induced emission nanobeads as high-performance colorimetric-fluorescent probe of immunochromatographic assay for the ultrasensitive detection of staphylococcal enterotoxin B in milk.

Herein, a colorimetric-fluorescent hybrid bifunctional nanobead with Janus structure (J-cf-HBN) was synthesized via one-pot microemulsification. Oleylamine-coated AuNPs and aggregation-induced emission luminogens (AIEgens) were suggested as building blocks to obtain high-performance colorimetric-fluorescent signals. The as-prepared J-cf-HBNs were used as a signal amplification probe to construct an immunochromatographic assay (J-cf-HBNs-ICA) platform for the ultrasensitive detection of staphylococcal enterotoxin B (SEB) in milk samples. Owing to the rational spatial distribution of AuNPs and AIEgens, the J-cf-HBNs present a highly retained photoluminescence and enhanced colorimetric signals. Combined with a pair of highly affinitive anti-SEB antibodies, the J-cf-HBN-ICA platform enabled the fast naked-eye visualization and fluorescent quantitative detection of SEB in various milk matrices. Given the advantages of the dual-mode high-performance J-cf-HBNs, the proposed strip achieved a high sensitivity for SEB qualitative determination with a visual limit of detection (LOD) of 1.56 ng mL-1 and exhibited ultrasensitivity for SEB quantitative detection with a LOD of 0.09 ng mL-1, which is 139-fold lower than that of ELISA using same antibodies. In conclusion, this work provides new insights into the construction of multimode immunochromatographic methods for food safety detection in the field.

Unlocking the growth potential: harnessing the power of synbiotics to enhance cultivation of Pleurotus spp. / é‡Šæ”¾ç”Ÿé•¿æ½œåŠ›ï¼šåˆ©ç”¨åˆç”Ÿå ƒçš„åŠ›é‡åŠ å¼ºä¾§è€³å±žæ¤ç‰©ç§æ¤.

The oyster mushroom (Pleurotus spp.) is one of the most widely cultivated mushroom species globally. The present study investigated the effect of synbiotics on the growth and quality of Pleurotus ostreatus and Pleurotus pulmonarius. Different synbiotics formulations were applied by spraying mushroom samples daily and measuring their growth parameters, yield, biological efficiency, proximate composition, mineral content, total phenolic content (TPC), and diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity. Results demonstrated that the most significant yield of oyster mushrooms was harvested from synbiotics sprayed with inulin and Lactobacillus casei (56.92 g). Likewise, the highest biological efficiency obtained with a similar synbiotic was 12.65%. Combining inulin and L. casei was the most effective method of improving the mushrooms' growth performance and nutrient content in both samples. Furthermore, synbiotics that combined inulin and L. casei resulted in the highest TPC (20.550 mg gallic acid equivalent (GAE)/g dry extract (DE)) in white oyster mushrooms (P. ostreatus). In comparison, in grey mushroom (P. pulmonarius) the highest TPC was yielded by L. casei (1.098 mg GAE/g DE) followed by inulin and L. casei (1.079 mg GAE/g DE). The DPPH results indicated that the oyster mushroom could be an efficient antioxidant. The results revealed that applying synbiotics improved the mushrooms' quality by increasing their antioxidant capacity with higher amounts of phenolic compounds and offering better health benefits with the increased levels of mineral elements. Together, these studies demonstrated the potential of using synbiotics as a biofertilizer, which is helpful for mushroom cultivation; therefore, it might solve the challenge of inconsistent quality mushroom growers face.

Aggregation-induced emission nanoparticles facilitating multicolor lateral flow immunoassay for rapid and simultaneous detection of aflatoxin B1 and zearalenone.

Herein we developed a multicolor lateral flow immunoassay (LFIA) test strip for rapid and simultaneous quantitative detection of aflatoxin B1 (AFB1) and zearalenone (ZEN). Three differently colored aggregation-induced emission nanoparticles (AIENPs) were designed as LFIA signal tags, with red and green AIENPs for targeting AFB1 and ZEN at the test line, and yellow AIENPs for indicating the validity of the test strip at the control (C) line. After surface functionalization with antibodies, the developed AIENP-based multicolor LFIA allows simultaneous and accurate quantification of AFB1 and ZEN using an independent C-line assisted ratiometric signal output strategy. The detection limits of AFB1 and ZEN were 6.12 and 26 pg/mL, respectively. The potential of this method for real-world applications was well demonstrated in corn and wheat. Overall, this multicolor LFIA shows great potential for field screening of multiple mycotoxins and can be extended to rapid and simultaneous monitoring of other small molecule targets.

Global trends of targeted therapy for hepatocellular carcinoma: A bibliometric and visualized study from 2008 to 2022.

BACKGROUND: Hepatocellular carcinoma (HCC) is an exceedingly prevalent malignancy with an exceptionally poor prognosis. Targeted therapy is an effective treatment option for patients with advanced HCC. However, there have been no bibliometric analyses of targeted therapies for HCC. METHODS: This study aimed to assess the current status and future directions of targeted therapy for HCC to provide future scholars with clearer research contents and popular themes. Methods: Literature on targeted therapy for HCC from 2008 to 2022 was obtained from the Web of Science (WoS) and assessed using bibliometric methodology. Additionally, the VOS viewer was applied in the visualization study to conduct bibliographic coupling, co-authorship, co-citation, and co-occurrence analyses of publications. RESULTS: A total of 10,779 papers were subsequently selected. Over the past 15 years, there has been a progressive increase in the number of publications on an annualized basis. China released the most publications in the field, whereas the United States had the highest H-index. Cancers published the most papers. Fudan University had the greatest sway in this area. Studies could be divided into 5 clusters: "Gene and expression research," "Mechanism study," "Nanoparticle study," "Targeted drug research," and "Clinical study." CONCLUSIONS: In the upcoming years, more papers on targeted therapy for HCC are expected to be released, demonstrating the potential for this topic to flourish. Particularly, "Clinical study" is the following trendy topic in this field. Other research subfields may likewise exhibit a continuous tendency towards balanced development.

Integrin αvß3 and EGFR dual-targeted [64Cu]Cu-NOTA-RGD-GE11 heterodimer for PET imaging in pancreatic cancer mouse model.

PURPOSE: Radiolabeled heterodimeric peptide has emerged as a highly promising targeting strategy for PET imaging due to their superior properties. RGD and GE11 are two peptides binding to receptor integrin αvß3 and EGFR, respectively, which both overexpress in many different types of tumors. This study focuses on the synthesis and evaluation of a RGD and GE11-containing heterodimeric radiotracer [64Cu]Cu-NOTA-RGD-GE11 for PET imaging of tumors that simultaneously overexpress integrin αvß3 and EGFR. PROCEDURES: [64Cu]Cu-NOTA-RGD-GE11 was prepared by the conjugation of RGD-PEG4-NOTA-N3 and GE11-PEG4-BCN via metal-free click chemistry, followed by radiolabeling with 64Cu. Cell uptake and efflux studies, saturation binding assay, the animal PET/CT and biodistribution studies were conducted to characterize the biological properties of [64Cu]Cu-NOTA-RGD-GE11. RESULTS: [64Cu]Cu-NOTA-RGD-GE11 was synthesized with a radiochemical purity of >97 % and molar activity of 23 GBq/µmol at the end of synthesis. [64Cu]Cu-NOTA-RGD-GE11 showed moderate hydrophilicity, good stability in mouse serum and high specific uptake by the human pancreatic cancer cell line (BxPC3) in the in vitro studies. Compared to the two monomeric counterparts [64Cu]Cu-NOTA-RGD and [64Cu]Cu-NOTA-GE11, [64Cu]Cu-NOTA-RGD-GE11 demonstrated significantly improved tumor uptakes (e.g. 4.63 ± 0.25 %ID/g vs 1.24 ± 0.18 %ID/g and 0.77 ± 0.13 %ID/g, 2 h after injection, p < 0.05) in the subsequent in vivo evaluation in mice bearing BxPC3 xenograft. Tumor uptake could be blocked in the presence of both non-radioactive c(RGDyK) and GE11 peptides, indicating good tumor specificity of [64Cu]Cu-NOTA-RGD-GE11 in vivo. CONCLUSION: The results suggested that the as-developed [64Cu]Cu-NOTA-RGD-GE11 could serve as a potential PET tracer for the noninvasive imaging of integrin αvß3 and EGFR expression in tumors.

Highly Sensitive Immunochromatographic Detection of Zearalenone Based on Ultrabright Red-Emitted Aggregation-Induced Luminescence Nanoprobes.

Highly luminescent nanospheres have been demonstrated in enhancing the sensitivity of lateral flow immunoassay (LFIA) due to their loading numerous luminescent dyes. However, the photoluminescence intensities of existing luminescent nanospheres are limited due to the aggregation-caused quenching effect. Herein, highly luminescent aggregation-induced emission luminogens embedded nanospheres (AIENPs) with red emission were introduced as signal amplification probes of LFIA for quantitative detection of zearalenone (ZEN). Optical properties of red-emitted AIENPs were compared with time-resolved dye-embedded nanoparticles (TRNPs). Results showed that red-emitted AIENPs have stronger photoluminescence intensity on the nitrocellulose membrane and superior environmental tolerance. Additionally, we benchmarked the performance of AIENP-LFIA against TRNP-LFIA using the same set of antibodies, materials, and strip readers. Results showed that AIENP-LFIA exhibits good dynamic linearity with the ZEN concentration from 0.195 to 6.25 ng/mL, with half competitive inhibitory concentration (IC50) and detection of limit (LOD) at 0.78 and 0.11 ng/mL, respectively. The IC50 and LOD are 2.07- and 2.36-fold lower than those of TRNP-LFIA. Encouragingly, the precision, accuracy, specificity, practicality, and reliability of this AIENP-LFIA for ZEN quantitation were further characterized. The results verified that the AIENP-LFIA has good practicability for the rapid, sensitive, specific, and accurate quantitative detection of ZEN in corn samples.

A labeling strategy for the three-dimensional recognition and analysis of microvascular obstruction in ischemic stroke.

Rationale: Large vessel recanalization in ischemic stroke does not always go along with tissue reperfusion, a phenomenon called "no-reflow". However, knowledge of the mechanism of no-reflow is limited because identifying microvascular obstruction across the cortex and subcortex both in clinical and experimental models is challenging. In this study, we developed a smart three-dimensional recognition pipeline for microvascular obstruction during post-ischemia reperfusion to examine the underlying mechanism of no-reflow. Methods: Transient (60 min) occlusion of the middle cerebral artery (tMCAo) in mice was induced using a filament. Two different fluorophore-conjugated tomato lectins were injected into mice via the tail vein before and after ischemia/reperfusion (I/R), respectively, one to label all blood vessels and the other to label functional blood vessels. Post-I/R microvascular obstruction was visualized using combined iDISCO+-based tissue clearing and optical imaging. Arterioles and capillaries were distinguished using whole-mount immunolabeling with an anti-αSMA antibody. Circulating neutrophils were depleted utilizing an anti-Ly6G antibody. Brain slices were immunostained with the anti-Ly6G antibody to identify co-localized blockage points and neutrophils. MATLAB software was used to quantify the capillary diameters in the ipsilateral brain from the normal and tMCAo mice. Results: Microcirculatory reperfusion deficit worsened over time after I/R. Microvascular obstruction occurred not only in arterioles but also in capillaries, with capillary obstruction associated with local capillary lumen narrowing. In addition, the depletion of circulating neutrophils mitigated reperfusion deficit to a large extent after I/R. The co-localization of blockage points and neutrophils revealed that some neutrophils plugged capillaries with coexisting capillary lumen narrowing and that no neutrophil was trapped in heaps of blockage points. Quantification of the capillary diameter showed that capillary lumen shrunk after I/R but returned to typical measurements when intravascular neutrophils were depleted. Conclusions: According to our findings, both vascular lumen narrowing and neutrophil trapping in cerebral microcirculation are the key causes of microvascular obstruction after I/R. Also, the primary contribution by neutrophils to microvascular obstruction does not occur through microemboli plugging but rather via the exacerbation of capillary lumen narrowing. Our proposed method will help monitor microcirculatory reperfusion deficit, explore the mechanism of no-reflow, and evaluate the curative effect of drugs targeting no-reflow.

Application of a novel modified Blumgart anastomosis in laparoscopic pancreaticoduodenectomy / 中国医师进修杂志

Objective:To investigate the efficacy and safety of a novel modified Blumgart pancreaticojejunostomy in laparoscopic pancreaticoduodenectomy (LPD).Methods:Between May 2021 and January 2022, 13 successive cases from Lihuili Hospital Affiliated to Ningbo University who underwent LPD were enrolled in this retrospective study. The study retrospectively analyzed the demographic characteristics, perioperative outcomes, and pathological results of these cases.Results:Twenty patients underwent LPD success-fully and one required conversion to open surgery. The operative time was (308.6 ± 61.7) min. The duration for PJ was (26.7 ± 4.3) min. The estimated blood loss was (188.1 ± 94.2) ml. The postoperative hospital stay was (14.2 ± 3.5) d. There was one case of biochemical leakage and no case of grade B or grade C pancreatic fistula.Conclusions:The new method is safe, simple and feasible. The novel method could reduce the incidence of pancreatic fistula and other complications after LPD.

Three-dimensional mapping reveals heterochronic development of the neuromuscular system in postnatal mouse skeletal muscles.

The development of the neuromuscular system, including muscle growth and intramuscular neural development, in addition to central nervous system maturation, determines motor ability improvement. Motor development occurs asynchronously from cephalic to caudal. However, whether the structural development of different muscles is heterochronic is unclear. Here, based on the characteristics of motor behavior in postnatal mice, we examined the 3D structural features of the neuromuscular system in different muscles by combining tissue clearing with optical imaging techniques. Quantitative analyses of the structural data and related mRNA expression revealed that there was continued myofiber hyperplasia of the forelimb and hindlimb muscles until around postnatal day 3 (P3) and P6, respectively, as well as continued axonal arborization and neuromuscular junction formation until around P3 and P9, respectively; feature alterations of the cervical muscle ended at birth. Such structural heterochrony of muscles in different body parts corresponds to their motor function. Structural data on the neuromuscular system of neonatal muscles provide a 3D perspective in the understanding of the structural status during motor development.

MiR-142a-3p: A novel ACh receptor transcriptional regulator in association with peripheral nerve injury.

Long-term denervation leads to the disintegration of nicotinic acetylcholine receptor (nAChR) located at the endplate structure, which translates to deficits in functional activation despite nerve repair. Because of a lack of effective measures to protect AChR expression, we explored the effect of alterations in muscular miR-142a-3p on nAChR. In this study, we constructed a model of miR-142a-3p knockdown by transfecting a miR-142a-3p inhibitor short hairpin RNA (shRNA) into C2C12 myotubes, and we injected this miR-142a-3p inhibitor shRNA into the tibialis anterior (TA) muscle in uninjured mice and in denervated mice by transecting the sciatic nerve. Our results showed that miR-142a-3p knockdown led to an increased number and area of AChR clusters in myotubes in vitro and larger neuromuscular endplates in adult mice. Furthermore, miR-142a-3p knockdown delayed the disintegration of motor endplates after denervation. Last, upon miR-142a-3p knockdown in uninjured and denervated mice, we observed an increase in the mRNA levels of five AChR subunits as well as mRNAs of genes implicated in AChR transcription and AChR clustering. Together, these results suggest that miR-142a-3p may be a potential target for therapeutic intervention to prevent motor endplate degradation following peripheral nerve injury.

In vivo tissue optical clearing assisted through-skull targeted photothrombotic ischemic stroke model in mice.

SIGNIFICANCE: Photothrombotic stroke is an important and widely used model for ischemic stroke research. However, the significant scattering of the skull during the procedure limits the light's ability to penetrate and focus on its target. Targeted photothrombosis uses surgery-based skull windows to obtain optical access to the brain, but it renders the brain's environment unnatural even before a stroke is established. AIM: To establish a targeted, controllable ischemic stroke model in mice through an intact skull. APPROACH: The in vivo skull optical clearing technique provides a craniotomy-free "optical window" that allows light to penetrate. Alongside the local photodynamic effect, we have established targeted photothrombosis without skull removal, effectively controlling the degree of thrombotic occlusion by changing the light dose. RESULTS: Ex vivo and in vivo results demonstrated that skull optical clearing treatment significantly enhanced light's ability to penetrate the skull and focus on its target, contributing to thrombotic occlusion. The skull optical clearing window was also used for continuous blood flow mapping, and the relationship between light dose and injury degree was evaluated over 14 days of monitoring. Per our findings, increasing the light dose was accompanied by more severe infarction, indicating that the model was easily controllable. CONCLUSIONS: Herein, a targeted, controllable ischemic stroke model was established by combinedly running an in vivo skull optical clearing technique and a photothrombotic procedure, avoiding unnecessary damage or environmental changes to the brain caused by surgery on the skull. Our established model should offer significant value to research on ischemic stroke.

[Research progress on soil soluble organic nitrogen]. / åœŸå£¤å¯æº¶æ€§æœ‰æœºæ°®ç ”ç©¶è¿›å±•.

Soluble organic nitrogen (SON) and inorganic N are two crucial nitrogen (N) forms in the cycling of N within terrestrial ecosystems, acting as either a "source" or a "sink" to the environmental N release. The mineralization, retention, leaching, and plant absorption of N in terrestrial ecosystems are closely related to SON. As a result, the role of SON in soil material circulation and nutrient flow has attracted much attention and has become one of the hotspots in various research fields, such as ecology, environmental science, soil science, and hydrology. We reviewed the research progress on soil SON, including the definition and quantification, the size and composition, the absorption and utilization by plants and microorganisms, the sources and influencing factors, and the transformation, migration, and leaching loss of SON. SON is a complex collection of multi-component soluble organic matter, mainly as recalcitrant components (difficult to degrade), with relatively low proportion as labile components (easily degradable). Due to the difference in the turnover time among recalcitrant and labile components, the roles of SON in N cycling and turnover cannot be fully represented by the SON quantity. Therefore, to accurately reflect the role of SON in N turnover, N uptake, and N leaching, it is necessary to establish new methods and distinguish between recalcitrant and labile SON components in future studies. When studying the role of SON in N conversion and N absorption, it is essential to focus on its labile components. When studying the contribution of soil SON to N leaching or runoff loss, it is necessary to focus on the recalcitrant components.

An Approach to Maximize Retrograde Transport Based on the Spatial Distribution of Motor Endplates in Mouse Hindlimb Muscles.

Knowledge regarding the relationship between muscles and the corresponding motor neurons would allow therapeutic genes to transport into specific spinal cord segments. Retrograde tracing technique by targeting the motor endplate (MEP), a highly specialized structure that offers direct access to the spinal motor neurons, has been used to elucidate the connectivity between skeletal muscles and the innervating motor neuron pools. However, current injection strategies mainly based on blind injection or the local MEP region might lead to an underestimation of the motor neuron number due to the uneven distribution of MEP in skeletal muscles. In this work, we proposed a novel intramuscular injection strategy based on the 3D distribution of the MEPs in skeletal muscles, applied the 3D intramuscular injection to the gastrocnemius and tibialis anterior for retrograde tracing of the corresponding motor neurons, and compared this with the existing injection strategy. The intramuscular diffusion of the tracer demonstrated that 3D injection could maximize the retrograde transport by ensuring a greater uptake of the tracer by the MEP region. In combination with optical clearing and imaging, we performed 3D mapping and quantification of the labeled motor neurons and confirmed that 3D injection could label more motor neurons than the current injection method. It is expected that 3D intramuscular injection strategy will help elucidate the connective relationship between muscles and motor neurons faithfully and becomes a promising tool in the development of gene therapy strategies for motor neuron diseases.

A combined study of 18F-FDG PET-CT and fMRI for assessing resting cerebral function in patients with major depressive disorder.

The present study investigated changes in the regional cerebral metabolic rates of glucose uptake (rCMRglc) using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and regional homogeneity (ReHo), together with resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients with major depressive disorder (MDD). In total, 18 patients with untreated MDD and 17 healthy control subjects underwent 18F-FDG PET and BOLD-fMRI scanning. The MDD patients' cerebral changes, measured as rCMRglc and ReHo values, were mapped and statistically analyzed. Compared with the control group, the patients with MDD had a decreased rCMRglc in the bilateral superior, middle and inferior frontal gyrus, in the bilateral superior and middle temporal gyrus, in the bilateral anterior cingulate cortex, in the bilateral putamen and caudate, and in the left pallidum, but an increased rCMRglc in the bilateral hippocampus and left thalamus. The ReHo values in the patient group were decreased in the bilateral superior and middle frontal gyrus, left pallidum, bilateral putamen and left anterior cingulate cortex, but increased in the right hippocampus and thalamus. No statistically significant differences were identified between decreased metabolism and ReHo brain regions of MDD patients (χ2=9.16; P=0.90) and between increased metabolism and ReHo brain regions (χ2=3.96; P=0.27), when comparing activated brain regions of PET and MRI. The standardized uptake values (SUV) of the bilateral superior, middle and inferior frontal gyrus, bilateral superior and middle temporal gyrus, bilateral putamen, the left caudate and pallidum, the left anterior cingulate cortex, and the bilateral hippocampus and thalamus were correlated with the ReHo (r=0.51-0.83; P<0.05). However, no correlation was detected between the SUV and ReHo in the right caudate and anterior cingulate cortex (r=0.41 and 0.37, respectively; P>0.05). Taken together, these results demonstrated that patients with MDD displayed characteristic patterns regarding changes of brain glucose uptake and ReHo in the resting state. Furthermore, 18F-FDG PET may be a more sensitive technique compared with BOLD-fMRI for the identification of brain lesions in patients with MDD.

Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker.

Peptides that target cancer cell surface receptors are promising platforms to deliver diagnostic and therapeutic payloads specifically to cancer but not normal tissue. IL13RA2 is a tumor-restricted receptor found to be present in several aggressive malignancies, including in the vast majority of high-grade gliomas and malignant melanoma. This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L. In the current work, we establish the in vitro and in vivo tumor binding properties of radiolabeled Pep-1L, designed for tumor imaging. We radiolabeled Pep-1L with Copper-64 and demonstrated specific cell uptake in the IL13RA2-over expressing G48 glioblastoma cell line having abundant IL13RA2 expression. [64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity. To demonstrate in vivo tumor uptake, we intravenously injected into tumor-bearing mice and demonstrated that [64Cu]Pep-1L specifically bound tumors at 24 hours, which was significantly blocked (3-fold) by pre-injecting unlabeled peptide. To further demonstrate specificity of Pep-1L towards IL13RA2 in vivo, we exploited an IL13RA2-inducible melanoma tumor model that does not express receptor at baseline but expresses abundant receptor after treatment with doxycycline. We injected [64Cu]Pep-1L into mice bearing IL13RA2-inducible melanoma tumors and performed in vivo PET/CT and post-necropsy biodistribution studies and found that tumors that were induced to express IL13RA2 receptor by doxycycline pretreatment bound radiolabeled Pep-1L 3-4 fold greater than uninduced tumors, demonstrating receptor specificity. This work demonstrates that [64Cu]Pep-1L selectively binds hIL13RA2-expressing tumors and validates Pep-1L as an effective platform to deliver diagnostics and therapeutics to IL13RA2-expressing cancers.

Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3-Targeted Liposomes.

Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood-brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for the first time that our targeted actinium-225-labeled αvß3-specific liposomes (225Ac-IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histologic studies revealed characteristic α-particle induced double strand breaks within tumors but was not significantly present in normal brain regions away from the tumor where BBB permeability was observed. These findings indicate that the enhanced vascular permeability in these distal regions did not result from direct α-particle-induced DNA damage. On the basis of these results, in addition to their direct antitumor effects, 225Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered antitumor therapeutics. Mol Cancer Ther; 16(10); 2191-200. ©2017 AACR.

IL13RA2 targeted alpha particle therapy against glioblastomas.

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.

The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution.

Although the aspect ratio (AR) play a crucial role in determining biological effects of homogeneous nanomaterials, studies available concerning how the shape contributes to biological effect of heterogeneous nanomaterials is limited. To systematically clarify the shape influence on the endocytosis, biocompatibility and biodistribution of magnetic mesoporous silica nanoparticles (M-MSNPs), three FITC-labeled M-MSNPs with different aspect ratio (AR=1, 2, and 4) were specifically designed and constructed through altering the ratios of CTAB/TEOS in a modified so-gel method. We have demonstrated that long-rod M-MSNP2 possessed higher intracellular internalization amount than the short-rod M-MSNP1 and the sphere-like M-MSNP0 in both cancer cells and normal cells due to the difference in the endocytosis pathways. However, there are no significant shape effects on biocompatibility including cytotoxicity and hemolytic rate. Moreover, biodistribution in HepG2 tumor-bearing mice showed that M-MSNPs administrated intravenously were mainly presented in reticuloendothelial system (RES) organs including liver, spleen and kidney. In particular, sphere-like M-MSNP0 were easily trapped in the liver, while long-rod M-MSP2 exhibited more retention in the spleen. It is worth noting that rod-like M-MSNPs are preferentially accumulated in tumor sites than sphere-like M-MSNPs, indicating an improved drug delivery efficacy in cancer therapy. Our findings may provide useful data for deeply understanding the interaction between the different shapes and biological behavior of M-MSNPs, which is expected to give rise to a new generation of heterogeneous M-MSNPs with significantly enhanced efficacy and safety for the cancer theranostics. STATEMENT OF SIGNIFICANCE: In this work, we systematically clarified the shape influence on the endocytosis, biocompatibility and biodistribution of homogeneous nanomaterials. We have demonstrated that rod-like magnetic mesoporous silica nanoparticles (M-MSNPs) were capable of higher intracellular internalization and tumor accumulation than sphere-like M-MSNPs, which was expected to give rise to a new generation of heterogeneous M-MSNPs with significantly enhanced efficacy and safety for the cancer theranostics.