Solid
tumors frequently metastasize to bone and induce bone destruction leading to severe
pain, fractures, and other skeletal-related events (SREs). Osteoclast inhibitors such as
bisphosphonates delay SREs but do not prevent skeletal complications or improve overall survival. Because
bisphosphonates can cause adverse side effects and are contraindicated for some patients, we sought an alternative
therapy to reduce
tumor-associated bone destruction. Our previous studies identified the
transcription factor Gli2 as a key regulator of
parathyroid hormone-related protein (
PTHrP), which is produced by bone metastatic
tumor cells to promote osteoclast-mediated bone destruction. In this study, we tested the treatment effect of a Gli antagonist
GANT58, which inhibits Gli2 nuclear translocation and
PTHrP expression in
tumor cells. In initial testing,
GANT58 did not have efficacy in vivo due to its low water solubility and poor bioavailability. We therefore developed a micellar nanoparticle (NP) to encapsulate and colloidally stabilize
GANT58, providing a fully aqueous, intravenously
injectable formulation based on the
polymer poly(propylene sulfide)135-b-poly[(oligoethylene glycol)9 methyl
ether acrylate]17 (PPS135-b-POEGA17). POEGA forms the hydrophilic NP surface while PPS forms the hydrophobic NP core that sequesters
GANT58. In response to
reactive oxygen species (ROS), PPS becomes hydrophilic and degrades to enable drug release. In an intratibial model of
breast cancer bone
metastasis, treatment with GANT58-NPs decreased bone lesion area by 49% (p<.01) and lesion number by 38% (p<.05) and resulted in a 2.5-fold increase in trabecular bone volume (p<.001). Similar results were observed in intracardiac and intratibial models of breast and
lung cancer bone
metastasis, respectively. Importantly, GANT58-NPs reduced
tumor cell proliferation but did not alter mesenchymal stem cell proliferation or osteoblast mineralization in vitro, nor was there evidence of cytotoxicity after repeated in vivo treatment. Thus, inhibition of Gli2 using GANT58-NPs is a potential
therapy to reduce bone destruction that should be considered for further testing and development toward clinical translation.