Editors' ChoiceCancer

Immunomodulation in the front, bone-binding in the back

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Science Translational Medicine  29 Jan 2020:
Vol. 12, Issue 528, eaba2917
DOI: 10.1126/scitranslmed.aba2917

Abstract

Zoledronic acid–tethered nanoparticles bind remodeling bone, polarize macrophages, and reduce osteoclasts to prevent breast cancer–induced osteolysis.

Breast cancer bone metastases are osteolytic due to the stimulation of osteoclasts by bone-residing tumor cells. This osteolysis is the primary cause of patient bone pain and increases fracture risk. Osteoclasts and tumor-associated macrophages are differentiated from a common myeloid progenitor cell, and both stimulate metastatic growth in the bone microenvironment. Although several osteoclast-targeting agents are in clinical use as treatments for bone metastases, no current treatments target the immune cells that also contribute to the progression and survival of metastases.

Pang and colleagues developed a metal nanoparticle loaded with cytosine phosphate guanosine (CpG) oligonucleotides and tethered to zoledronic acid. Nanoparticles were deposited in the bone microenvironment due to the zoledronic acid, where they stimulated immune cells. Using peritoneal macrophages, bone marrow–derived macrophages, and cell lines, the authors demonstrated that nanoparticles polarized macrophages toward an M1, proinflammatory phenotype and reduced osteoclast differentiation and resorption in vitro. Nanoparticles injected via the tail vein accumulated in tumor-bearing bone preferentially over healthy bone in mice, with fewer nanoparticles accumulating in the liver and kidney. Intraperitoneal nanoparticle delivery beginning one week after intratibial injection of human breast cancer cells resulted in increased numbers of M1 macrophages and reduced osteoclast numbers within the bone microenvironment adjacent to tumors. Nanoparticle-mediated changes in the myeloid population helped preserve bone structure and reduced tumor size in mice. Thus, treatment with the zoledronic acid–tethered CpG-loaded metal nanoparticles may slow breast cancer bone metastatic tumor growth and prevent tumor-induced osteolysis.

Zoledronic acid is used clinically for bone metastases and osteoporosis to inhibit osteoclast function (bone resorption); however, as a single agent, it does not affect tumor metastasis or immune cells. As with nanoparticle delivery in this study, other studies showed that zoledronic acid treatment alone prevents progression of bone resorption but does not improve the structure of existing degraded bone. The effect of the nanoparticles on bone-forming osteoblasts was not described in this study. The addition of an osteoblast-stimulating agent, such as teriparatide, could help induce regeneration of degraded bone, which could decrease fracture risk. Combining bone anabolic agents with the zoledronic acid–tethered immunostimulatory metal nanoparticles could potentially reduce tumor burden and induce bone remodeling, preserving skeletal integrity in patients with breast cancer–associated osteolysis.

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