Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics

Abstract

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma- versus contralateral brain-relevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting.

Figure 1

Schematic illustration of brain tumor magnetic targeting following the systemic administration of magnetic nanoparticles. Targeting can presumably be achieved due to the combination of several phenomena including passive biodistribution of the administered nanoparticles, pathophysiological peculiarities of tumor vasculature and the principles of magnetic entrapment.

Figure 2

Zero field cooled (ZFC) magnetization curve of freeze-dried G100, measured at 100 Oe. The curve exhibits a broad maximum corresponding to the blocking temperature, T_B ∼ 160K. The decay of magnetization above T_B is an indication of superparamagnetic behavior of the nanoparticles at room temperature.

Figure 3

Images illustrating extraction of nanoparticles from a stable colloidal fluid, pumped at a linear velocity of 0.05 cm/s, (A) before and (B) 10 minutes after the initiation of a 0.4T magnetic field.

Figure 4

In Vitro kinetic analysis of magnetic nanoparticle entrapment with the magnetic field (B=0.4T) at physiologically relevant linear flow velocities: ■ 0.05, Δ 0.08, ★ 0.1, and ▼ 0.2 cm/s. Solid lines represent nonlinear least squares regression fits of the data sets to the model w=a₁* t/[a₂ + t] (R²s are 0.97, 0.96, 0.98 and 0.71 for 0.05, 0.08, 0.1 and 0.2 cm/s, respectively). The inset illustrates the extent of nanoparticle capture, represented by dW, after 10 minutes of tube perfusion as a function of linear flow velocities.

Figure 5

In Vivo magnetic targeting in 9L-glioma bearing rats. (A) Typical MRI images obtained from experimental and control animals following intravenous nanoparticle administration and magnetic targeting. Hypointense region in the brain of the targeted animal reflects nanoparticle accumulation within glioma lesion. (B) Nanoparticle concentrations in excised glioma and contra-lateral brain tissues of targeted and control rats quantified by ESR spectroscopy. Data are taken from reference (19).

Figure 6

(A) Representative TEM micrograph taken of a tumor section dissected from a targeted animal. The image demonstrates the presence of entrapped magnetic nanoparticles within the glioma lesion. (B) TEM micrograph of nanoparticles obtained from a standard G100 preparation, shown for comparison.