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.