Doxorubicin‐loaded nanoparticle coated with endothelial cells‐derived exosomes for immunogenic chemotherapy of glioblastoma

Abstract

Treatments of glioblastoma (GBM) have not been very effective, largely due to the inefficiency of drugs in penetrating the blood brain barrier (BBB). In this study, we investigated the potential of exosome-coated doxorubicin (DOX)-loaded nanoparticles (ENP DOX) in BBB penetration, inducing immunogenic cell death (ICD) and promoting survival of GBM-bearing mice. DOX-loaded nanoparticles (NP DOX) were coated with exosomes prepared from mouse brain endothelial bEnd.3 cells. ENP DOX cellular uptake was examined. Penetration of ENP DOX through the BBB was tested in an in vitro transwell system and a GBM mouse model. The effects of ENP DOX in inducing apoptosis and ICD were assessed. Finally, the efficacy of ENP DOX in the treatment of GBM-bearing mice was assessed. ENP DOX was taken up by bEnd.3 cells and could penetrate the BBB both in vitro and in vivo. In vitro, END DOX induced apoptosis and ICD of glioma GL261 cells. Systemic administration of ENP DOX resulted in maturation of dendritic cells, activation of cytotoxic cells, altered production of cytokines, suppressed proliferation and increased apoptosis of GBM cells in vivo and prolonged survival of GBM-bearing mice. Our findings indicate that ENP DOX may be a potent therapeutic strategy for GBM which warrants further investigation in clinical application. K E Y W O R D S blood brain barrier, doxorubicin, exosome-coated doxorubicin-loaded nanoparticle, glioblastoma, immunogenic cell death 1 | INTRODUCTION Glioblastoma (GBM) is a highly aggressive brain tumor with an extremely poor prognosis and a small rate (4%-5%) or 5-year survival. 1 Current treatments of GBM include surgeries, radiotherapy, and/or chemotherapy. These treatments not only cause severe side effects, but also only slightly improve the overall median survival (only 15 months) and 5-year survival rate. 2 Although many therapeutic strategies targeting have been developed, their application in the clinic for treatment GBM has been largely impeded due to the lack of safe and efficient drug delivery system that delivers drugs to tumor location. 3 Recent research findings suggest that, in various cancer types including GBM, human immune response has significant potential in promoting immune mediated tumor eradication and improving long term survival. 4 Recent studies have shown that anthracyclines, such as doxorubicin (DOX), not only induce apoptosis of tumor cells, but also

Polymeric Nanosystems for Immunogenic Cell Death‐Based Cancer Immunotherapy

“…To address this common issue, Yang and co‐workers prepared an exosome‐coated DOX‐loaded PEG‐PLA nanoparticles (ENP DOX ) for easy BBB penetration, high‐efficient ICD, and prolonging the life span of GBM‐bearing mice. [ 83 ] After intravenous administration, ENP DOX is supposed to cross the BBB, gather in the GBM site and trigger ICD, following by maturation of DCs and infiltration of cytotoxic T lymphocytes ( Figure 3 a). Figure 3b shows the transwell culture system that the bEnd.3 cells (treated with NP DOX and ENP DOX ) and GL261 cells were cultured in the upper layer and lower layer, respectively.…”

“…Reproduced with permission. [ 83 ] Copyright 2020, The Authors, published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.…”

“…j) The chemiluminescent ATP Determination Kit was used to accessed the release of ATP. Reproduced with permission [83]. Copyright 2020, The Authors, published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.…”

Overview of the Therapeutic Applications of Stem Cell–Derived Exosomes: A Research and Commercial Perspective

“…The average diameter of exosomes is ∼100 nm (Kalluri & LeBleu, 2020). Given their small size, exosomes have the unique opportunity to permeate the blood-brain barrier (BBB; Zhang et al, 2020;Zhu et al, 2019).…”

“…The average diameter of exosomes is ∼100 nm (Kalluri & LeBleu, 2020). Given their small size, exosomes have the unique opportunity to permeate the blood–brain barrier (BBB; Zhang et al., 2020; Zhu et al., 2019). The BBB comprises the specialized vasculature that separates the CNS from the rest of the blood in circulation (Banks, 2009).…”