ABSTRACT
Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Central Nervous System , Drug Delivery Systems/methods , Lymphoma, B-Cell/drug therapy , Molecular Targeted Therapy/methods , Rituximab/pharmacology , Animals , Brain , Chemokine CXCL13/drug effects , Chemokine CXCL13/metabolism , Disease Models, Animal , Lymphatic Metastasis/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Mice , Nanocapsules , Receptors, CXCR5/drug effects , Receptors, CXCR5/metabolism , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Postoperative cognitive dysfunction (POCD) is a neurodegenerative disorder with impairment of cognition. Sevoflurane anesthesia has been found to lead to CD and microRNAs (miRNAs) were reported to affect cognitive function. This study investigates the neuroprotective effect against sevoflurane anesthesia-induced CD. METHODS: HE staining was used to detect the pathological change of hippocampal neuron. Morris water maze test was used to analyze latency time, platform crossing and swimming speed. Quantitative real-time PCR (qRT-PCR) and western blotting were performed to examine the mRNA and protein expression of miR-410-3p, IL-6, TNF-α, IL-1ß and C-X-C motif chemokine receptor 5 (CXCR5). Dual-luciferase reporter assay was used to detect the relationship between miR-410-3p and CXCR5. RESULTS: MiR-410-3p was downregulated in sevoflurane anesthesia-induced rats and cells and act as a suppressor in sevoflurane anesthesia-induced hippocampal neuron apoptosis and inflammation. Furthermore, miR-410-3p was identified to bind with CXCR5. Further analysis showed that CXCR5 expression was increased by sevoflurane treatment, whereas was repressed by miR-410-3p overexpression. Moreover, miR-410-3p could inhibit sevoflurane anesthesia-induced hippocampal neuron apoptosis by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. CONCLUSION: These data indicated that miR-410-3p exhibited its neuroprotective effect on sevoflurane anesthesia-induced CD by targeting CXCR5 via PI3K/Akt signaling pathway. Our study may potentially provide a new light on the pathogenesis and therapeutic method for sevoflurane anesthesia-induced CD.
Subject(s)
Anesthesia/adverse effects , Cognitive Dysfunction/drug therapy , MicroRNAs/pharmacology , Neuroprotective Agents/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Sevoflurane/pharmacology , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/pathology , Disease Models, Animal , Down-Regulation , Hippocampus/pathology , Inflammation , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Male , MicroRNAs/genetics , Neurons/drug effects , Postoperative Cognitive Complications , Rats , Receptors, CXCR5/drug effects , Receptors, CXCR5/metabolism , Receptors, Chemokine/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We recently showed that B cells reduce CNS inflammation in mice with experimental allergic encephalomyelitis (EAE). Here, we demonstrate that adoptively transferred CD5/CD19+ B cells protect against EAE severity. Furthermore, we show that glatiramer acetate (GA), a therapeutic for relapsing multiple sclerosis treatment, amplifies this effect. Transfer of GA-conditioned B cells leads to increased production of immunoregulatory cytokines and reduced CNS inflammation, as well as decreased expression of the chemokine receptor, CXCR5, and elevated BDNF expression in the CNS. Thus B cells can protect against EAE, and GA augments this effect in maintaining immune homeostasis and controlling EAE disease progression.
