Vuk Uskoković
Department of Mechanical and Aerospace Engineering, University of California, Irvine, CA, USA
Despite the advances in molecularly targeted therapies, delivery across the blood-brain barrier (BBB) and the targeting of brain tumors remains a challenge. To tackle these challenges, we made a variation on the previously proposed concept of the earthicle [1,2] and fabricated an aqueous, surfactant-free ferrofluid containing superparamagnetic iron oxide nanoparticles coated with silicate mesolayers and carbon shells, having 13 nm in size on average [3]. The nanoparticulate ferrofluids preferentially bind to brain cancer cells and, hence, exhibit a greater toxicity in these cells compared to the primary cells. In 3D tumor spheroids, nanoparticles greatly reduce the metastatic migration of cancer cells, while the tumor viability gets reduced compared to the control group by applying magnetic hyperthermia to nanoparticle-treated spheroids. In a MDCK-MDR1 blood-brain barrier model, the nanoparticles cause mislocalization of claudin-1 at the tight junctions, underexpression of ZO-1 and no effect on occludin-1 and transepithelial resistance. In spite of preserving the integrity of the blood-brain barrier, the nanoparticles traverse it transcellularly and get localized to the optic lobes of the third instar larval brains of Drosophila melanogaster. Examination of LAMP1 demonstrated that nanoparticles escape the lysosome during their noninvasive passage across the blood-brain barrier, causing no adverse systemic effects to the animals. All in all, both in vitro and in vivo models of the blood-brain barrier evidence the ability of these composite nanoparticles to cross the blood-brain barrier and localize to the brain tissue. In conclusion, 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. Their other applications, including magnetic hyperthermia [4] and targeted magnetic separation of cancer cells and other biological entities [5] are currently under investigation.
References:
[1] Vuk Uskoković, Victoria M. Wu – “Astromimetics: The Dawn of a New Era for (Bio)Materials Science?”, Nanobiomedicine 5, 1 - 5 (2018).
[2] Vuk Uskoković, Sebastian Pernal, Victoria M. Wu – “Earthicle: The Design of a Conceptually New Type of Particle”, ACS Applied Materials and Interfaces 9 (2) 1305 – 1321 (2017).
[3] Victoria M. Wu, Eric Huynh, Sean Tang, Vuk Uskoković – “Brain and Bone Cancer Targeting by a Ferrofluid Composed of Superparamagnetic Iron-Oxide/Silica/Carbon Nanoparticles (Earthicles)”, Acta Biomaterialia 88, 422 – 447 (2019).
[4] Vuk Uskoković, Eric Huynh, Sean Tang, Sonja Jovanović, Victoria M. Wu – “Colloids or Powders: Which Nanoparticle Formulations Do Cells Like More?” Colloids and Surfaces B: Biointerfaces 181, 39 - 47 (2019).
[5] Vuk Uskoković, Sean Tang, Victoria M. Wu – “Targeted Magnetic Separation of Biomolecules and Cells using Earthicle-Based Ferrofluids”, Nanoscale 11, 11236 – 11253 (2019).
