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Two-dimensional (2D) nanocrystals are promising for optoelectronic and microelectronic technologies. However, the performance of 2D nanocrystal light-emitting diodes (LEDs) remains limited. Here, exciton dynamics are rationally controlled by both shell engineering and device engineering, obtaining colloidal quantum well LEDs (CQW-LEDs) with superior performance. The formation of CQW films on charge transport layers shows an excellent photoluminescence quantum yield of 76.63%. An unreported relationship among Auger lifetime, electron confinement energy, and external quantum efficiency (EQE) in 2D nanocrystal devices is directly observed. The optimized CQW-LEDs possess a maximum power efficiency of 6.04 lm W−1 and a current efficiency of 9.20 cd A−1, setting record efficiencies for 2D nanocrystal red LEDs. Additionally, a remarkable EQE of 13.43% has been achieved, accompanied by an exceptionally low efficiency roll-off. Significantly, EQE for flexible CQW-LEDs is 42-fold higher than the previous best results. Furthermore, active-matrix CQW-LEDs on printed circuit boards are developed. The findings not only unlock new possibilities for controlling exciton dynamics but also provide an alternative strategy to achieve high-performance 2D nanocrystal based applications. [ABSTRACT FROM AUTHOR]

Magnetic particles that can be precisely controlled under a magnetic field and transduce energy from the applied field open the way for innovative cancer treatment. Although these particles represent an area of active development for drug delivery and magnetic hyperthermia, the in vivo anti-tumor effect under a low-frequency magnetic field using magnetic particles has not yet been demonstrated. To-date, induced cancer cell death via the oscillation of nanoparticles under a low-frequency magnetic field has only been observed in vitro. In this report, we demonstrate the successful use of spin-vortex, disk-shaped permalloy magnetic particles in a low-frequency, rotating magnetic field for the in vitro and in vivo destruction of glioma cells. The internalized nanomagnets align themselves to the plane of the rotating magnetic field, creating a strong mechanical force which damages the cancer cell structure inducing programmed cell death. In vivo, the magnetic field treatment successfully reduces brain tumor size and increases the survival rate of mice bearing intracranial glioma xenografts, without adverse side effects. This study demonstrates a novel approach of controlling magnetic particles for treating malignant glioma that should be applicable to treat a wide range of cancers.

UNLABELLED: There is strong clinical interest in using neural stem cells (NSCs) as carriers for targeted delivery of therapeutics to glioblastoma. Multimodal dynamic in vivo imaging of NSC behaviors in the brain is necessary for developing such tailored therapies; however, such technology is lacking. Here we report a novel strategy for mesoporous silica nanoparticle (MSN)-facilitated NSC tracking in the brain via SPECT. METHODS: (111)In was conjugated to MSNs, taking advantage of the large surface area of their unique porous feature. A series of nanomaterial characterization assays was performed to assess the modified MSN. Loading efficiency and viability of NSCs with (111)In-MSN complex were optimized. Radiolabeled NSCs were administered to glioma-bearing mice via either intracranial or systemic injection. SPECT imaging and bioluminescence imaging were performed daily up to 48 h after NSC injection. Histology and immunocytochemistry were used to confirm the findings. RESULTS: (111)In-MSN complexes show minimal toxicity to NSCs and robust in vitro and in vivo stability. Phantom studies demonstrate feasibility of this platform for NSC imaging. Of significance, we discovered that decayed (111)In-MSN complexes exhibit strong fluorescent profiles in preloaded NSCs, allowing for ex vivo validation of the in vivo data. In vivo, SPECT visualizes actively migrating NSCs toward glioma xenografts in real time after both intracranial and systemic administrations. This is in agreement with bioluminescence live imaging, confocal microscopy, and histology. CONCLUSION: These advancements warrant further development and integration of this technology with MRI for multimodal noninvasive tracking of therapeutic NSCs toward various brain malignancies.

Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 μm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma.

The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation.

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as GliomaFF. We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.

PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is demonstrated to be capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd(3+) contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, it is demonstrated that TAT-Au NPs are capable of delivering Gd(3+) chelates for enhanced brain tumor imaging with a prolonged retention time of Gd(3+) when compared to the free Gd(3+) chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging.

A 3-step glioblastoma-tropic delivery and therapy method using nanoparticle programmed self-destructive neural stem cells (NSCs) is demonstrated in vivo: 1) FDA-approved NSCs for clinical trials are loaded with pH-sensitive MSN-Dox; 2) the nanoparticle conjugates provide a delayed drug-releasing mechanism and allow for NSC migration towards a distant tumor site; 3) NSCs eventually undergo cell death and release impregnated MSN-Dox, which subsequently induces toxicity towards surrounding glioma cells.