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Systemic delivery of a Gli inhibitor via polymeric nanocarriers inhibits tumor-induced bone disease.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2019 Oct; Vol. 311-312, pp. 257-272. Date of Electronic Publication: 2019 Sep 05. - Publication Year :
- 2019
-
Abstract
- 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) <subscript>135</subscript> -b-poly[(oligoethylene glycol) <subscript>9</subscript> methyl ether acrylate] <subscript>17</subscript> (PPS <subscript>135</subscript> -b-POEGA <subscript>17</subscript> ). 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.<br /> (Published by Elsevier B.V.)
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Apoptosis drug effects
Bone Neoplasms secondary
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Drug Carriers chemistry
Drug Carriers pharmacokinetics
Drug Liberation
Female
Gene Expression Regulation, Neoplastic
Humans
Mammary Neoplasms, Animal pathology
Mesenchymal Stem Cells drug effects
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Nanoparticles chemistry
Osteogenesis drug effects
Polymers administration & dosage
Polymers chemistry
Polymers pharmacokinetics
Pyridines chemistry
Pyridines pharmacokinetics
Thiophenes chemistry
Thiophenes pharmacokinetics
Zinc Finger Protein Gli2 antagonists & inhibitors
Zinc Finger Protein Gli2 genetics
Antineoplastic Agents administration & dosage
Bone Neoplasms drug therapy
Drug Carriers administration & dosage
Mammary Neoplasms, Animal drug therapy
Nanoparticles administration & dosage
Pyridines administration & dosage
Thiophenes administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 311-312
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 31494183
- Full Text :
- https://doi.org/10.1016/j.jconrel.2019.08.038