Brain and bone cancer targeting by a ferrofluid composed of superparamagnetic iron-oxide/silica/carbon nanoparticles (earthicles)

Abstract

Despite the advances in molecularly targeted therapies, delivery across the blood-brain barrier (BBB) and the targeting of brain tumors remains a challenge. Like brain, bone is a common site of metastasis and requires therapies capable of discerning the tumor from its healthy cellular milieu. To tackle these challenges, we made a variation on the previously proposed concept of the earthicle and fabricated an aqueous, surfactant-free ferrofluid containing superparamagnetic iron oxide nanoparticles (SPIONs) coated with silicate mesolayers and carbon shells, having 13 nm in size on average. Nanoparticles were synthesized hydrothermally and characterized using a range of spectroscopic, diffractometric, hydrodynamic and electron microscopy techniques. The double coating on SPIONs affected a number of physicochemical and biological properties, including colloidal stability and cancer targeting efficacy. Nanoparticles decreased the viability of glioblastoma and osteosarcoma cells and tumors more than that of their primary and non-transformed analogues. They showed a greater preference for cancer cells because of a higher rate of uptake by these cells and a pronounced adherence to cancer cell membrane. Even in an ultralow alternate magnetic field, nanoparticles generated sufficient heat to cause tumor death. Nanoparticles in MDCK-MDR1 BBB model caused mislocalization of claudin-1 at the tight junctions, underexpression of ZO-1 and no effect on occludin-1 and transepithelial resistance. Nanoparticles were detected in the basolateral compartments and examination of LAMP1 demonstrated that nanoparticles escaped the lysosome, traversed the BBB transcellularly and localized to the optic lobes of the third instar larval brains of Drosophila melanogaster. The passage was noninvasive and caused no adverse systemic effects to the animals. In conclusion, these nanoparticulate ferrofluids preferentially bind to cancer cells and, hence, exhibit a greater toxicity in these cells compared to the primary cells. They are also effective against solid tumors in vitro, can cross the BBB in Drosophila, and are nontoxic based on the developmental studies of flies raised in ferrofluid-infused media. Statement of SignificanceWe demonstrate that a novel, hydrothermally synthesized composite nanoparticle-based ferrofluid is effective in reducing the viability of osteosarcoma and glioblastoma cells in vitro, while having minimal effects on primary cell lines. In 3D tumor spheroids, nanoparticles greatly reduced the metastatic migration of cancer cells, while the tumor viability was reduced compared to the control group by applying magnetic hyperthermia to nanoparticle-treated spheroids. Both in vitro and in vivo models of the blood-brain barrier evidence the ability of nanoparticles to cross the barrier and localize to the brain tissue. These composite nanoparticles show great promise as an anticancer biomaterial for the treatment of different types of cancer and may serve as an alternative or addendum to traditional chemotherapies.