Treatment of Invasive Brain Tumors Using a Chain-like Nanoparticle

Abstract

Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By two hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof of concept for a broadly improved method for glioblastoma treatment.

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…228,243 Other alternative strategies were found in this search. Researchers developed stimuli-responsive liposomes that were able to release DOX in a controlled manner in response to an external low-power radio frequency field 209 or local temperature rise. 218 Both strategies showed an improvement of DOX delivery across the BBB and prolonged survival time of animals.…”

“…It was also demonstrated that just angiopep-2 peptide was able to target BBB and glioma cells at the same time, 219 and RGD peptide targeted both BBTB and tumor cells. 204,207,209 PDT uses photosensitizing agents, such as Photofrin, for brain tumors, along with light of appropriated wavelength to kill glioma cells. The PDT cell-killing mechanism is directly related to the production of reactive oxygen species, which leads to cell apoptosis, with minimal side effects.…”

Perspectives on Dual Targeting Delivery Systems for Brain Tumors

“…In vivo, the vascular targeting NPs with a rod shape displayed a higher accumulation in the lung and brain than that of spherical NPs. Peiris et al established chain-like NPs, which showed much higher brain tumor accumulation (Peiris et al 2015). Compared with traditional chemotherapy, the chainlike NPs delivered 18.6-fold greater drug to the brain tumor, resulting in considerably better anti-tumor effect.…”

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size

“…However, despite recent advances in targeted immunotherapeutics using biomaterials, 22,23,25,27 there is limited understanding of how carrier design simultaneously affects retention and accumulation in both the skin injection site and its dLN. Previous studies have explored the effects of biomaterial carrier size, 21,28 charge, 29,30 hydrophobicity, 31,32 and shape 33,34 on various aspects of transport, cellular uptake, and adaptive immune response.…”