The Origin of Ion-Pairing and Redissociation of Ionic Liquid

We address the possible occurrence of a minimum extent of dissociation (α) of ionic liquid (IL) in IL–solvent mixtures. This phenomenon, known as the redissociation of IL, is responsible for many interesting composition-dependent properties in such mixtures. A thermodynamic model is developed to provide a semiquantitative prediction on the change of α with solvent concentration. It is found that the occurrence of minimum α coincides with the occurrence of a maximum in the mean activity coefficient of dissociated ions, indicating better solvation of free, dissociated ions both with decreasing and increasing solvent concentration. The favorable solvation of free ions is found to change from long-range ion–solvent dielectric polarization to ion–ion-pair dielectric polarization with decreasing solvent concentration. Therefore, the composition dependence of the IL solution dielectric constants, determined from that of the ion-pair and the solvent, is found to be the most important factor for the presence of redissociation in IL solutions

Reactive Oxygen Species Responsive Nanoprodrug to Treat Intracranial Glioblastoma

Chemotherapy for intracranial gliomas is hampered by limited delivery of therapeutic agents through the blood brain barrier (BBB). An optimal therapeutic agent for brain tumors would selectively cross the BBB, accumulates in the tumor tissue and be activated from an innocuous prodrug within the tumor. Here we show brain tumor-targeted delivery and therapeutic efficacy of a nanometer-sized prodrug (nanoprodrug) of camptothecin (CPT) to treat experimental glioblastoma multiforme (GBM). The CPT nanoprodrug was prepared using spontaneous nanoemulsification of a biodegradable, antioxidant CPT prodrug and α-tocopherol. The oxidized nanoprodrug was activated more efficiently than nonoxidized nanoprodrug, suggesting enhanced therapeutic efficacy in the oxidative tumor microenvironment. The <i>in vitro</i> imaging of U-87 MG glioma cells revealed an efficient intracellular uptake of the nanoprodrug <i>via</i> direct cell membrane penetration rather than <i>via</i> endocytosis. The <i>in vivo</i> study in mice demonstrated that the CPT nanoprodrug passed through the BBB and specifically accumulated in brain tumor tissue, but not in healthy brain tissue and other organs. The accumulation preferably occurred at the periphery of the tumor where cancer cells are most actively proliferating, suggesting optimal therapeutic efficacy of the nanoprodrug. The nanoprodrug was effective in treating subcutaneous and intracranial tumors. The nanoprodrug inhibited subcutaneous tumor growth more than 80% compared with control. The median survival time of mice implanted with an intracranial tumor increased from 40.5 days for control to 72.5 days for CPT nanoprodrug. This nanoprodrug approach is a versatile method for developing therapeutic nanoparticles enabling tumor-specific targeting and treatment. The nontoxic, tumor-specific targeting properties of the nanoprodrug system make it a safe, low cost, and versatile nanocarrier for pharmaceuticals, imaging agents, and diagnostic agents

Behavioral testing of motor function using Open Field Test and Rotorod.

<p>(a) The number of ambulatory movements over the course of one hour in the Open Field Test (OFT) was reduced for the mice in the IV group. (b) The number of rearing movements in the OFT was not significantly different between groups. (c) Rotorod performance demonstrates that all mice were able to balance on a rotating rod for similar amounts of time. Statistical comparison was performed using a two tailed Student’s t-test, with a level of p = 0.05 considered significant.</p

Comparing accumulation for IV and IP administration.

<p>The injection of nanoprodrug either IV or IP results in similar accumulation in animals with TBI, while normal animals given nanoprodrug and TBI animals do not show any background flourescence. Brains are oriented with the rostral portion toward the top of the image.</p

Enhanced Permeability and Retention (EPR) at the site of TBI.

<p>This schematic illustrates the difference between healthy brain and injured brain in terms of the structural organization of the blood vessels and how this influences drug delivery. In normal tissue, the blood brain barrier is intact and the nanoprodrug does not penetrate into the tissue. An injured vessel becomes leaky, and the disruption of the blood brain barrier allows for uptake and accumulation of the nanoprodrug particles.</p

The COX system regulates blood flow and platelet activity.

<p>The COX1 enzyme acts in platelets to activate thromboxane A2, which leads to vasoconstriction and enhanced platelet aggregation. The COX2 enzyme acts in endothelial cells to stimulate vasorelaxation and platelet inhibition.</p

Disorganized vascular structures at the region of nanoprodrug uptake.

<p>Representative images from two brains showing nanoprodrug uptake on the left column and CD31 staining of vascular endothelial cells on the right. Outside of the TBI region, vascular structures exist in normal tubular arrangements, but these are disorganized within the region of injury. The nuclei are stained with DAPI are displayed in blue. <i>Scale bar,</i> 50 <i>µ</i>m.</p

Nanoprodrug preparation and characterization.

<p>This chemical schematic shows the molecular structures of the individual ibuprofen molecule, the Ibu₂TEG complex consisting of two ibuprofen molecules jointed by a tetraethylene glycol (TEG) spacer, the anti oxidant α-tocopherol, and the hydrophobic 1-octadecanethiol which is joined to Cy5.5 after emulsification. The final product is represented on the right hand side of the schematic.</p