Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Objective To analyze the expression and clinical treatment and prognosis assessment significance of FAM83H-AS1 in breast cancer by bioinformatics analysis.Methods The expression of FAM83H-AS1 in various cancer types was analyzed in the Cancer Genome Atlas(TCGA)database by R language.Additionally the expression in breast cancer was examined by Gene Expression Profiling Interactive Analysis(GEPIA)online database.Survival data were downloaded from TCGA to analyze the correlation between FAM83H-AS1 expression levels and prognosis among breast cancer patients.GEPIA and Kaplan-Meier Plotter were used for dual verification.Clinical information was obtained from TCGA for further analysis on the relationship between FAM83H-AS1 and clinical characteristics.And the relationship between FAM83H-AS1 and tumor microenvironment,immunodetection point-related genes and tumor mutation burden(TMB)was analyzed using R language.Gene set enrichment analysis(GSEA)was performed.Results The expression of FAM83H-AS1 was abnormal in many cancers,particularly exhibiting a significant increase in breast cancer.High expression of FAM83H-AS1 is associated with significantly reduced overall survival in breast cancer patients.Furthermore,the expression level of FAM83H-AS1 varies among breast cancer patients with different clinical stages.FAM83H-AS1 exhibits negative correlation with stromal cell score and immune cell score in breast cancer samples,and correlated with immune detection point-related gene.TMB radar map results suggest that the expression of FAM83H-AS1 in breast cancer is positively correlated with tumor mutational burden.GSEA revealed a positive correlation between the expression of FAM83H-AS1 and the function of mismatch repair.Conclusion FAM83H-AS1 is highly expressed in breast cancer,and is related to poor prognosis.Its expression correlates with clinicopathological stage,tumor microenvironment and TMB of breast cancer patients.Furthermore,FAM83H-AS1 exhibits associations with certain immune checkpoint-related genes and mismatch repair genes.These findings provide a important theoretical basis for clinical treatment,prognosis prediction and development of gene-target drugs.