DataVXACS NanoPaper
journal article·2019-12-24Open access

Tumor-Derived Extracellular Vesicles Breach the Intact Blood–Brain Barrier via Transcytosis

Golnaz Morad, Christopher V. Carman, Elliott J. Hagedorn, Julie R. Perlin, Leonard I. Zon, Nur Mustafaoglu, Tae-Eun Park, Donald E. Ingber, Cassandra C. Daisy, Marsha A. Moses

ACS Nano· Volume 13· Issue 12
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Source abstract

Abstract

The restrictive nature of the blood–brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown. Here, we demonstrate that tumor-derived EVs can breach the intact BBB in vivo, and by using state-of-the-art in vitro and in vivo models of the BBB, we have identified transcytosis as the mechanism underlying this process. Moreover, high spatiotemporal resolution microscopy demonstrated that the endothelial recycling endocytic pathway is involved in this transcellular transport. We further identify and characterize the mechanism by which tumor-derived EVs circumvent the low physiologic rate of transcytosis in the BBB by decreasing the brain endothelial expression of rab7 and increasing the efficiency of their transport. These findings identify previously unknown mechanisms by which tumor-derived EVs breach an intact BBB during the course of brain metastasis and can be leveraged to guide and inform the development of drug delivery approaches to deliver therapeutic cargoes across the BBB for treatment of a variety of brain diseases including, but not limited to, brain malignancies.
Source: openalex_inverted_index · Quality: baseline

Research context

Nanomaterials

OpenAlex topics: Extracellular vesicles in disease · MicroRNA in disease regulation · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Vascular Biology Program, Boston Children’s Hospital, Boston, Massachusetts 02115, United States

Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States

Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138, United States

Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United States

Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, United States

Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02115, United States

Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts 02115, United States

Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea

Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, United States

Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts 02115, United States

Funding

National Cancer Institute · Advanced Medical Research Foundation · National Institute of Diabetes and Digestive and Kidney Diseases · Breast Cancer Research Foundation

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