Dendritic cell-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites elicits enhanced anti-cancer immune response in glioblastoma. (October 2018)

• Record Type: Journal Article
• Authors: Li, Tong-Fei; Li, Ke; Zhang, Quan; Wang, Chao; Yue, Yuan; Chen, Zhuo; Yuan, Shen-Jun; Liu, Xin; Wen, Yu; Han, Min; Komatsu, Naoki; Xu, Yong-Hong; Zhao, Li; Chen, Xiao
• Is Part Of: Biomaterials. Volume 181(2018)
• Page Start: 35
• Page End: 52
• Publication Date: 2018-10
• Subjects: Dendritic cells -- Immunogenicity -- Glioblastoma -- Nano-DOX -- Drug delivery -- Immunogenic cell death; ATP adenosine triphosphate -- BBB blood-brain barrier -- BCA bicinchoninic acid -- 5-(N-dodecanoyl)aminofluorescein C11-fluor -- DC dendritic cells -- Mφ macrophages -- LC lymphocyte -- mDC mouse dendritic cells -- mLC mouse lymphocyte -- ICD immunogenic cell death -- CFSE 5(6)-carboxyfluorescein diacetate, succinimidyl ester -- GFP green fluorescent protein -- GCM GC-conditioned culture medium -- CRT calreticulin -- DAMPs damage-associated molecular patterns -- DOX doxorubicin -- HMGB1 high mobility group protein B1 -- HSP90 heat shock protein 90 -- FACS flow cytometry -- GBM glioblastoma -- GC glioblastoma cells -- MHC-I major histocompatibility complex I molecules -- MHC-II major histocompatibility complex II molecules -- ND-GCM Nano-DOX-treated GCM -- IL interleukin -- ELISA enzyme-linked immunosorbent assay -- Nano-DOX ND-PG-RGD-DOX -- ND nanodiamonds -- Nano-DOX-mDC Nano-DOX-loaded mDC -- PBS phosphate buffered saline -- PG polyglycerol -- RGD tripeptide of l-arginine, glycine and l-aspartic acid -- PVDF polyvinylidene fluoride -- TBST Tris Buffered Saline with Tween® 20 -- SD standard deviation -- PD-L1 programmed cell death-ligand 1 -- PDT Hypericin-based photodynamic therapy -- TME tumor microenvironment; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2018.07.035
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Glioblastoma (GBM) is the deadliest and most common type of primary brain tumor in adults with a grim prognosis despite multimodal treatments. Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic modality for GBM, whose efficacy is nonetheless fundamentally undermined by GBM-induced immunosuppression. Inducing emission of damage associated molecular patterns (DAMPs) is a highly effective strategy to subvert tumor-associated immunosuppression. The present work was carried out to explore the idea of subverting the GBM immunosuppressive microenvironment through DC-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites (Nano-DOX), a potent DAMPs inducer demonstrated by our previous study, and thereby eliciting enhanced DC-driven anti-GBM immune response. In the in-vitro work on human cell models, Nano-DOX-loaded DC were shown to be functionally viable and release cargo drug to co-cultured GBM cells (GC). Nano-DOX-treated GC displayed not only profuse DAMPs emission but also antigen release. Enhanced activation and acquisition and presentation of GC-derived antigen were then demonstrated in DC in co-culture with GC and Nano-DOX. Consistently, co-culture with GC and Nano-DOX also activated mouse bone marrow-derived DC (mDC) which in turn stimulated mouse spleen-derived lymphocytes which ultimately suppressed co-cultured GC. Next, athymic mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mDC and, 48 h later, spleen-derived lymphocytes. The presence of Nano-DOX, DAMPs emission and enhanced infiltration and activation of mDC and lymphocytes were detected in the GBM xenografts. Taken together, our results demonstrate the efficacy of DC-mediated delivery of Nano-DOX to stimulate GC immunogenicity and elicit anti-cancer immune response in the GBM. By this work, we present a novel approach with great application potential to subverting the GBM immunosuppressive microenvironment and to anti-GBM immunotherapy. Investigation has also been conducted probing the mechanisms by which Nano-DOX stimulates GC immunogenicity, which is described in a follow-up paper. Graphical abstract: Image 1