Neurotoxicity Profiling of Aluminum Salt-Based Nanoparticles as Adjuvants for Therapeutic Cancer Vaccine.

Therapeutic vaccines containing aluminum adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects. However, the neurotoxicity of aluminum adjuvants with different physicochemical properties has not been completely elucidated. In this study, a library of engineered aluminum oxyhydroxide (EAO) and aluminum hydroxyphosphate (EAHP) nanoparticles was synthesized to determine their neurotoxicity in vitro. It was demonstrated that the surface charge of EAHPs and size of EAOs did not affect the cytotoxicity in N9, bEnd.3, and HT22 cells; however, soluble aluminum ions trigger the cytotoxicity in three different cell lines. Moreover, soluble aluminum ions induce apoptosis in N9 cells, and further mechanistic studies demonstrated that this apoptosis was mediated by mitochondrial reactive oxygen species generation and mitochondrial membrane potential loss. This study identifies the safety profile of aluminum-containing salts adjuvants in the nervous system during therapeutic vaccine use, and provides novel design strategies for their safer applications. SIGNIFICANCE STATEMENT: In this study, it was demonstrated that engineered aluminum oxyhydroxide and aluminum hydroxyphosphate nanoparticles did not induce cytotoxicity in N9, bEnd.3, and HT22 cells. In comparation, soluble aluminum ions triggered significant cytotoxicity in three different cell lines, indicating that the form in which aluminum is presenting may play a crucial role in its safety. Moreover, apoptosis induced by soluble aluminum ions was dependent on mitochondrial damage. This study confirms the safety of engineered aluminum adjuvants in vaccine formulations.

Hsa_circ_0008673 Promotes Breast Cancer Progression by MiR-578/GINS4 Axis.

BACKGROUND: Circular RNAs (circRNAs) play a crucial role in breast cancer (BC) development. This study aimed to explore the new potential mechanism of hsa_circ_0008673 in BC. MATERIALS AND METHODS: Hsa_circ_0008673, microRNA-578 (miR-578) and recombinant human GINS complex subunit 4 (GINS4) abundances were measured via quantitative real-time PCR or western blot. Cell proliferation, metastasis, angiogenesis and apoptosis were assessed via EdU assay, transwell assay, tube formation assay, and flow cytometry. The interactions among hsa_circ_0008673, miR-578 and GINS4 were tested via dual-luciferase reporter analysis and RNA pull-down assay. Animal studies were performed to assess the effect of hsa_circ_0008673 on BC tumor growth. RESULTS: Hsa_circ_0008673 level was increased in BC tissues and cells. Hsa_circ_0008673 silencing repressed BC cell growth, metastasis and angiogenesis, as well as hampered BC tumor growth. Hsa_circ_0008673 acted as miR-578 sponge, and miR-578 targeted GINS4. Furthermore, hsa_circ_0008673 modulated GINS4 expression through sponging miR-578. Additionally, miR-578 inhibitor or GINS4 overexpression could reverse the inhibitory effect of hsa_circ_0008673 silencing on BC cell progression. CONCLUSION: Hsa_circ_0008673 might promote BC progression via modulating miR-578/GINS4 pathway.

Self-assembled aluminum oxyhydroxide nanorices with superior suspension stability for vaccine adjuvant.

The suspension stability of aluminum-based adjuvant (Alum) plays an important role in determining the Alum-antigen interaction and vaccine efficacy. Inclusion of excipients has been shown to stabilize antigens in vaccine formulations. However, there is no mechanistic study to tune the characteristics of Alum for improved suspension stability. Herein, a library of self-assembled rice-shaped aluminum oxyhydroxide nanoadjuvants i.e., nanorices (NRs), was synthesized through intrinsically controlled crystallization and atomic coupling-mediated aggregations. The NRs exhibited superior suspension stability in both water and a saline buffer. After adsorbing hepatitis B surface antigen (HBsAg) virus-like particles (VLPs), human papillomavirus virus (HPV) VLPs, or bovine serum albumin, NR-antigen complexes exhibited less sedimentation. Further mechanistic study demonstrated that the improved suspension stability was due to intraparticle aggregations that led to the reduction of the surface free energy. By using HBsAg in a murine vaccination model, NRs with higher aspect ratios elicited more potent humoral immune responses. Our study demonstrated that engineered control of particle aggregation provides a novel material design strategy to improve suspension stability for a diversity of biomedical applications.