Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans.

A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev-Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5-8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting.

In-vitro respiratory drug absorption models possess nominal functional P-glycoprotein activity.

OBJECTIVES: The P-glycoprotein (P-gp) efflux pump is known to be present within several major physiological barriers including the brain, kidney, intestine and placenta. However, the function of P-gp in the airways of the lung is unclear. The purpose of this study was to use the highly specific P-gp inhibitor GF120918A to investigate the activity of the P-gp transporter in the airways to determine whether P-gp could influence inhaled drug disposition. METHODS: P-gp activity was measured as a change in digoxin transport in the presence of GF120918A in normal human bronchial epithelial (NHBE) cells, Calu-3 cell layers and the ex-vivo rat lung. KEY FINDINGS: The efflux ratios (ERs) in NHBE and Calu-3 cells were between 0.5 and 2, in contrast to 10.7 in the Caco-2 cell control. These low levels of GF120918A-sensitive polarised digoxin transport were measured in the absorptive direction in NHBE cells (ER = 0.5) and in the secretory direction in Calu-3 cells (ER = 2), but only after 21 days in culture for both cell systems and only in Calu-3 cells at passage > 50. The airspace to perfusate transfer kinetics of digoxin in the ex-vivo rat lung were unchanged in the presence of GF120918A. CONCLUSIONS: These results demonstrated that although low levels of highly culture-dependent P-gp activity could be measured in cell-lines, these should not be interpreted to mean that P-gp is a major determinant of drug disposition in the airways of the lung.