TfR-T12 short peptide and pH sensitive cell transmembrane peptide modified nano-composite micelles for glioma treatment via remodeling tumor microenvironment.

Two kinds of amphiphilic block copolymers of TfR-T12-PEG-PLGA and TATH7-PEG-PLGA were synthesized to self-assembly nano-composite micelles for encapsulating paclitaxel and imiquimod synchronously. TfR-T12 peptide modified nano-composite micelles can pass through BBB in a TfR-mediated way to achieve targeted delivery of chemotherapeutic drugs, and pH sensitive TATH7 peptide modified nano-composite micelles enhanced uptake efficiency more significantly under pH 5.5 medium than pH 7.4 medium. The results of pharmacodynamic evaluation in vivo showed that the nano-composite micelles had achieved good anti-tumor effect in subcutaneous and normotopia glioma models, and effectively prolonged the life cycle of tumor-bearing mice. The nano-composite micelles regulated the immunosuppression phenomenon of tumor microenvironment significantly, and promoted the M1 polarization of TAMs, then enhanced the proliferation and activation of CD8+ T cells in tumor microenvironment. It comes to conclusion that the nano-composite micelle achieves the purpose of effective treatment of glioma by chemotherapy combined with immunotherapy.

Transferrin Receptor-Targeted PEG-PLA Polymeric Micelles for Chemotherapy Against Glioblastoma Multiforme.

BACKGROUND: The safe and efficient delivery of chemotherapeutic agents is critical to glioma therapy. However, chemotherapy for glioma is extremely challenging because the blood-brain barrier (BBB) rigorously prevents drugs from reaching the tumor region. MATERIALS AND METHODS: TfR-T12 peptide-modified PEG-PLA polymer was synthesized to deliver paclitaxel (PTX) for glioma therapy. TfR was significantly expressed on brain capillary endothelial cells and glioma cells; therefore, TfR-T12 peptide-modified micelles can cross the BBB system and target glioma cells. RESULTS: TfR-T12-PEG-PLA/PTX polymeric micelles (TfR-T12-PMs) could be absorbed rapidly by tumor cells, and traversed effectively the BBB monolayers. TfR-T12-PMs can effectively inhibit the proliferation of U87MG cells in vitro, and TfR-T12-PMs loaded with paclitaxel presented better antiglioma effect with prolonged median survival of nude mice-bearing glioma than the unmodified PMs. CONCLUSION: The TfR-T12-PMs could effectively overcome the BBB barrier and accomplish glioma-targeted drug delivery, thus validating its potential in improving the therapeutic outcome in multiforme.

The natural compound Cirsitakaoside enhances antiviral innate responses against vesicular stomatitis virus in vitro and in vivo.

Cirsitakaoside, isolated and purified from the stems and leaves of Premna szemaoensis and Macaranga denticulata, is a natural compound with potential anti-inflammatory effects. However, the role of Cirsitakaoside in antiviral activity and the underlying mechanism remains largely unknown. In this study, we aimed to identify whether Cirsitakaoside has antiviral activity and investigated the underlying mechanisms. Mouse peritoneal macrophages were pretreated with Cir or DMSO, and then infected by Vesicular Stomatitis Virus (VSV) for indicated hours, Q-PCR and ELISA were used to detect the expression of interferons and pro-inflammatory cytokines, immunoblot assay were employed to investigate the involved signaling pathway in the antiviral effects of Cirsitakaoside. Furthermore, mice infected with VSV were used to investigate the antiviral activities of Cirsitakaoside in vivo. Our study demonstrated that Cirsitakaoside could promote type I IFN expression and inhibit pro-inflammatory cytokines such as IL-6 and TNF-α production in mouse peritoneal macrophages infected by VSV. Suppressive viral replication effects of Cirsitakaoside were observed on VSV-infected mouse peritoneal macrophages as well. Furthermore, Cirsitakaoside significantly increased the VSV-triggered phosphorylation of TBK1, IRF3 and reduced the phosphorylation of IκBα and p65 in mouse peritoneal macrophages. in vivo, the results showed that Cirsitakaoside-treated mice were more resistant to VSV infection by producing more IFN-ß and less pro-inflammatory cytokines. Our study indicates that Cirsitakaoside is a good candidate for the treatment of viral infection and inflammation-related diseases.