Engineered Microglia Potentiate the Action of Drugs against Glioma Through Extracellular Vesicles and Tunneling Nanotubes.

Gliomas remain difficult to treat because of their metastatic and recurrent nature and the existence of the blood-brain barrier (BBB), which impedes drug delivery. Microglia, the resident macrophages in the CNS, can be recruited by gliomas and can penetrate the tumor. In this study, microglia (BV2 cells) are used as transport vectors to deliver paclitaxel for the treatment of glioma. To avoid paclitaxel toxicity in microglia, liposomes are first employed to isolate the drug from BV2 cells. Dipalmitoyl phosphatidylserine (DPPS), as an "eat me" signal, is doped into liposomes to amplify their phagocytosis by microglia. This study demonstrates that engineered microglia can cross the BBB, independently migrate toward gliomas, and transfer cargo to glioma cells. Of note, extracellular vesicles and tunneling nanotubes are found to offer unique modes of cargo transportation between microglia and glioma cells. In vivo, the engineered drug-loaded microglia has a high ability to target the brain, penetrate glioma, and suppress tumor progression, supporting the notion that the use of engineered microglia is a potential strategy for the treatment of glioma. These findings present new opportunities for exploration into the use of microglia as transport vectors to deliver therapeutic agents through specific membrane nanotubes and vesicles.

Phototherapy and anti-GITR antibody-based therapy synergistically reinvigorate immunogenic cell death and reject established cancers.

Phototherapy and immunogenic cell death (ICD) are powerful strategies to fight cancer. However, their therapeutic outcomes are diminished by immunosuppressive and hypoxia microenvironment. Herein, a photo-based, immunomodulating and hypoxia-alleviated nanosystem, PDA-ICG@CAT-DTA-1, is proposed to achieve the synergism between phototherapy and immunotherapy. Catalase (CAT) and anti-GITR antibody (DTA-1) are loaded to photothermal agent and photosensitizer composed PDA-ICG nanoparticles. The PDA-ICG@CAT-DTA-1 exhibits intrinsic local hyperthermia and enhanced ROS generation in tumor, and abrogates tumor immune suppression. It results in reduction of intratumoral FOXP3+ regulatory T cells (4.3-fold) and increase of CD4+ effector T cells (1.5-fold) compare with the control, and promotes damage associated molecular patterns generation to reinvigorate ICD effect. The potent antitumor of PDA-ICG@CAT-DTA-1 is proved in 4T1 bilateral tumor-bearing mice, with inhibition ratio of 95.1% for primary cancers and 68.7% for abscopal cancers. Our findings highlight great promise of the constructed versatility nanosystem to fix bottlenecks for cancer therapy.

Albumin-Based Nanotheranostic Probe with Hypoxia Alleviating Potentiates Synchronous Multimodal Imaging and Phototherapy for Glioma.

Highly infiltrative and invasive glioma cells obscure the boundary between tumor and normal brain tissue, making it extremely difficult to precisely diagnose and completely remove. The combination of multimodal imaging with effective treatments to diagnose precisely and guide surgery and therapy accurately is desperately needed for glioma in the brain. Here, we report a biomimetic catalase-integrated-albumin phototheranostic nanoprobe (ICG/AuNR@BCNP) to realize multimodal imaging, amplify phototherapy, and guide surgery for glioma after penetrating the blood-brain barrier, accumulating into deep-seated glioma via albumin-binding protein mediated transportation. The phototheranostic nanoprobe enabled fluorescence, photoacoustic, and infrared thermal imaging with desirable detecting depth and high signal-to-background ratio for clearly differentiating brain tumors from surrounding tissues. Meanwhile, the nanoprobe could effectively induce local hyperthermia and promote the level of singlet oxygen based on alleviated hypoxic glioma microenvironment by decomposing endogenous hydrogen peroxide to oxygen to amplify phototherapy. Thus, significant inhibition of glioma growth, extended survival time, alleviated tumor hypoxia, improved apoptosis, and antiangiogenesis effects were exhibited in several animal models including the periphery and the brain through intravenous or intratumoral injection, meanwhile with low toxicity to normal tissue. The phototherapy was also guided by the assistance of external bioluminescence, magnetic resonance, and positron emission tomography imaging. Moreover, the nanoprobe could accurately guide the glioma resection. These results suggest that the phototheranostic nanoprobe is a promising nanoplatform specifically for glioma to achieve multimodal diagnosis, effective phototherapy, and accurate imaging-guided surgery.

[Top-cited academic articles in acupuncture and moxibustion research].

OBJECTIVE: To identify the 100 top-cited articles published in journals dedicated to acupuncture & moxibustion research and analyze their characteristics so as to explore its academic state. METHODS: All the articles were collected from the China National Knowledge Infrastructure (CNKI, January 1, 1943 to December 25, 2016), Web of Science (January 1, 1950 to December 25, 2016), WANFANG Database (January 1, 1998 to December 25, 2016). The top-cited articles were selected and analyzed with regard to publication year, number of citations, journals, authors, country or region, institution, title, type and subject. RESULTS: One hundred and two articles were included, 43 Chinese articles and 59 English articles, cited between 146 and 505 times, and the average number of citation was 222. Of the 10 articles cited in the top 10, China and the United States had 4 articles respectively. These articles appeared in 44 journals, 24 articles in Chinese Acupuncture & Moxibustion, followed by 8 articles in Pain. All the articles belonged to 9 countries and regions, 47 articles from mainland China and 21 articles from the United State. Of the 14 institutes whose article number ranked at top 10, Tianjing University of TCM had 8 articles. The first authors published most papers were professor HAN Jisheng and Cherkin DC, each of whom had 4 articles. All the articles were categorized into basic science article (n=27), clinical research (n=33) and literature study (n=42). The main topics were pain diseases and brain impairment. CONCLUSIONS: This analysis of high cited articles reveals academic trends and directions of acupuncture and moxibustion. Acupuncture and moxibustion are more and more recognized by mainstream medicine in the world, but the academic dominance of China has been increasingly challenged by the United States, Germany and so on.