Treatment of glioblastoma using multicomponent silica nanoparticles.

Glioblastoma multiforme (GBM) remains highly lethal. This partially stems from the presence of brain tumor initiating cells (BTICs), a highly plastic cellular subpopulation that is resistant to current therapies. In addition to resistance, the blood-brain barrier limits the penetration of most drugs into GBMs. To effectively deliver a BTIC-specific inhibitor to brain tumors, a multicomponent nanoparticle, termed Fe@MSN, which contains a mesoporous silica shell and an iron oxide core, is developed. Fibronectin-targeting ligands direct the nanoparticle to the near-perivascular areas of GBM. After Fe@MSN particles are deposited in the tumor, an external low-power radiofrequency (RF) field triggers rapid drug release due to mechanical tumbling of the particle resulting in penetration of high amounts of drug across the blood-brain tumor interface and widespread drug delivery into the GBM. The nanoparticle is loaded with the drug 1400W, which is a potent inhibitor of the inducible nitric oxide synthase (iNOS). It is shown that iNOS is preferentially expressed in BTICs and is required for their maintenance. Using the 1400W-loaded Fe@MSN and RF-triggered release, in vivo studies indicate that the treatment disrupts the BTIC population in hypoxic niches, suppresses tumor growth and significantly increases survival in BTIC-derived GBM xenografts.