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Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

Transition metal oxides hold great promise as high-energy anodes in next-generation lithium-ion batteries. However, owing to the inherent limitations of low electronic/ionic conductivities and dramatic volume change during charge/discharge, it is still challenging to fabricate practically viable compacted and thick TMO anodes with satisfactory electrochemical performance. Herein, with mesoporous cobalt–boride nanoflakes serving as multifunctional bridges in ZnCo 2 O 4 micro-/nanospheres, a compacted ZnCo 2 O 4 /Co–B hybrid structure is constructed. Co–B nanoflakes not only bridge ZnCo 2 O 4 nanoparticles and function as anchors for ZnCo 2 O 4 micro-/nanospheres to suppress the severe volume fluctuation, they also work as effective electron conduction bridges to promote fast electron transportation. More importantly, they serve as Li + transfer bridges to provide significantly boosted Li + diffusivity, evidenced from both experimental kinetics analysis and density functional theory calculations. The mesopores within Co–B nanoflakes help overcome the large Li + diffusion barriers across 2D interfaces. As a result, the ZnCo 2 O 4 /Co–B electrode delivers high gravimetric/volumetric/areal capacities of 995 mAh g −1 /1450 mAh cm −3 /5.10 mAh cm −2 , respectively, with robust rate capability and long-term cyclability. The distinct interfacial design strategy provides a new direction for designing compacted conversion-type anodes with superior lithium storage kinetics and stability for practical applications. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Transition metal oxides hold great promise as high-energy anodes in next-generation lithium-ion batteries. However, owing to the inherent limitations of low electronic/ionic conductivities and dramatic volume change during charge/discharge, it is still challenging to fabricate practically viable compacted and thick TMO anodes with satisfactory electrochemical performance. Herein, with mesoporous cobalt–boride nanoflakes serving as multifunctional bridges in ZnCo 2 O 4 micro-/nanospheres, a compacted ZnCo 2 O 4 /Co–B hybrid structure is constructed. Co–B nanoflakes not only bridge ZnCo 2 O 4 nanoparticles and function as anchors for ZnCo 2 O 4 micro-/nanospheres to suppress the severe volume fluctuation, they also work as effective electron conduction bridges to promote fast electron transportation. More importantly, they serve as Li + transfer bridges to provide significantly boosted Li + diffusivity, evidenced from both experimental kinetics analysis and density functional theory calculations. The mesopores within Co–B nanoflakes help overcome the large Li + diffusion barriers across 2D interfaces. As a result, the ZnCo 2 O 4 /Co–B electrode delivers high gravimetric/volumetric/areal capacities of 995 mAh g −1 /1450 mAh cm −3 /5.10 mAh cm −2 , respectively, with robust rate capability and long-term cyclability. The distinct interfacial design strategy provides a new direction for designing compacted conversion-type anodes with superior lithium storage kinetics and stability for practical applications. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Transition metal oxides hold great promise as high-energy anodes in next-generation lithium-ion batteries. However, owing to the inherent limitations of low electronic/ionic conductivities and dramatic volume change during charge/discharge, it is still challenging to fabricate practically viable compacted and thick TMO anodes with satisfactory electrochemical performance. Herein, with mesoporous cobalt–boride nanoflakes serving as multifunctional bridges in ZnCo 2 O 4 micro-/nanospheres, a compacted ZnCo 2 O 4 /Co–B hybrid structure is constructed. Co–B nanoflakes not only bridge ZnCo 2 O 4 nanoparticles and function as anchors for ZnCo 2 O 4 micro-/nanospheres to suppress the severe volume fluctuation, they also work as effective electron conduction bridges to promote fast electron transportation. More importantly, they serve as Li + transfer bridges to provide significantly boosted Li + diffusivity, evidenced from both experimental kinetics analysis and density functional theory calculations. The mesopores within Co–B nanoflakes help overcome the large Li + diffusion barriers across 2D interfaces. As a result, the ZnCo 2 O 4 /Co–B electrode delivers high gravimetric/volumetric/areal capacities of 995 mAh g −1 /1450 mAh cm −3 /5.10 mAh cm −2 , respectively, with robust rate capability and long-term cyclability. The distinct interfacial design strategy provides a new direction for designing compacted conversion-type anodes with superior lithium storage kinetics and stability for practical applications. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

JingLun Li,1 JiaoJiao Deng,2 JinXian Yuan,1 Jie Fu,1 XiaoLing Li,2 AiPing Tong,2 YueLong Wang,2 YangMei Chen,1 Gang Guo2 1Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 2State Key Laboratory of Biotherapy and Cancer Center, and Department of Neurosurgery, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China Abstract: Spinal cord injury (SCI) commonly leads to lifelong disability due to the limited regenerative capacity of the adult central nervous system. Nanomicelles can be used as therapeutic systems to provide effective treatments for SCI. In this study, a novel triblock monomethyl poly(ethylene glycol)-poly(L-lactide)-poly(trimethylene carbonate) copolymer was successfully synthesized. Next, polymeric nanomicelles loaded with zonisamide (ZNS), a Food and Drug Administration-approved antiepileptic drug, were prepared and characterized. The ZNS-loaded micelles (ZNS-M) were further utilized for the treatment of SCI in vitro and in vivo. The obtained ZNS-M were ~50 nm in diameter with good solubility and dispersibility. Additionally, these controlled-release micelles showed significant antioxidative and neuron-protective effects in vitro. Finally, our results indicated that ZNS-M treatment could promote motor function recovery and could increase neuron and axon density in a hemisection SCI model. In summary, these results may provide an experimental basis for the use of ZNS-M as a clinically applicable therapeutic drug for the treatment of SCI in the future. Keywords: spinal cord injury, zonisamide, nanomicelles

JingLun Li,1 JiaoJiao Deng,2 JinXian Yuan,1 Jie Fu,1 XiaoLing Li,2 AiPing Tong,2 YueLong Wang,2 YangMei Chen,1 Gang Guo2 1Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 2State Key Laboratory of Biotherapy and Cancer Center, and Department of Neurosurgery, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China Abstract: Spinal cord injury (SCI) commonly leads to lifelong disability due to the limited regenerative capacity of the adult central nervous system. Nanomicelles can be used as therapeutic systems to provide effective treatments for SCI. In this study, a novel triblock monomethyl poly(ethylene glycol)-poly(L-lactide)-poly(trimethylene carbonate) copolymer was successfully synthesized. Next, polymeric nanomicelles loaded with zonisamide (ZNS), a Food and Drug Administration-approved antiepileptic drug, were prepared and characterized. The ZNS-loaded micelles (ZNS-M) were further utilized for the treatment of SCI in vitro and in vivo. The obtained ZNS-M were ~50 nm in diameter with good solubility and dispersibility. Additionally, these controlled-release micelles showed significant antioxidative and neuron-protective effects in vitro. Finally, our results indicated that ZNS-M treatment could promote motor function recovery and could increase neuron and axon density in a hemisection SCI model. In summary, these results may provide an experimental basis for the use of ZNS-M as a clinically applicable therapeutic drug for the treatment of SCI in the future. Keywords: spinal cord injury, zonisamide, nanomicelles