This study explored the possibility of utilizing iron oxide nanoparticles as a drug delivery vehicle for minimally invasive, MRI-monitored magnetic targeting of brain tumors. In vitro determined hydrodynamic diameter of ~100nm, saturation magnetization of 94 emu/g Fe and T 2 relaxivity of 43 s −1 mM −1 of the nanoparticles suggested their applicability for this purpose. In vivo effect of magnetic targeting on the extent and selectivity of nanoparticle accumulation in tumors of rats harboring orthotopic 9L-gliosarcomas was quantified with MRI. Animals were intravenously injected with nanoparticles (12 mg Fe/kg) under a magnetic field density of 0 T (control) or 0.4 T (experimental) applied for 30 minutes. MR images were acquired prior to administration of nanoparticles and immediately after magnetic targeting at 1 hour intervals for 4 hours. Image analysis revealed that magnetic targeting induced a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors (p=0.005) and a 3.6-fold enhancement in the target selectivity index of nanoparticle accumulation in glioma over the normal brain (p=0.025). In conclusion, accumulation of iron oxide nanoparticles in gliosarcomas can be significantly enhanced by magnetic targeting and successfully quantified by MR imaging. Hence, these nanoparticles appear to be a promising vehicle for glioma-targeted drug delivery.

Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.

The potentiometric response mechanism of a previously reported polymer membrane-based electrode sensitive to the polyanion heparin is established. Based on transport and extraction studies, the heparin response is attributed to a nonequilibrium change in the phase boundary potential at the sample/membrane interface. While true equilibrium polyion response, obtained for low heparin concentrations only after very long equilibration times (> 20 h), yields the expected Nernstian response slope of < 1 mV/decade, the observed large and reproducible EMF response to clinically relevant heparin concentrations (approximately 10(-7) M) during typical measurement periods (2-5 min) is ascribed to a steady-state kinetic process defined by the flux of the polyion both to the surface and into the bulk of the polymer membrane. A model describing this nonequilibrium response is presented. With this model, the uniqueness of the polymer membrane composition (e.g., very low plasticizer content, strictly controlled cationic site concentration, etc.) required to achieve analytically useful heparin response becomes clear. Practical working conditions and limitations of the sensor are discussed. To support the generality of the steady-state model proposed, corresponding EMF response data for a newly developed membrane electrode sensitive to a polycationic protein (protamine) are also presented. It is shown that the protamine-responsive membrane electrode appears to operate via the exact same kinetic mechanism as the heparin sensing system.