(348g) Methods for Characterizing Paramagnetic Nanoparticle-Loaded Liposomes for Remote Controlled Drug Release in Solid Tumors

Liposomal delivery systems are established formulations in the pharmaceutical industry. Evidence suggests that liposomes minimize the side effects associated with systemic administration of chemotherapeutic agents through passive targeting associated with the enhanced permeation and retention effect, making them suitable vehicles for tumor-specific drug delivery. However, better control over the liposomal release characteristics is needed in vivo. An ideal release mechanism would retain the drug within the liposome until localization at the tumor; a subsequent triggering mechanism would allow controllable drug release at the tumor site. This controlled drug delivery system would reduce adverse reactions while providing a means to produce the optimum pharmacodynamic response at the tumor site. The remote heating properties of magnetite nanoparticles in an alternating magnetic field have the potential to act as this trigger by providing the heat necessary to induce a phase change in the liposomal membrane, thereby increasing permeation and the rate of drug release.

This project focused on developing methods to characterize drug release when magnetic magnetite nanoparticles were incorporated into a liposomal drug carrier. For this delivery system, magnetic magnetite nanoparticles were synthesized using a co-precipitation method, and liposomes were formulated through an extrusion process. To make nanoparticle suspensions suitable for physiological conditions, an ultrafiltration/dialysis method was developed to control pH of the nanoparticle suspension and adjust osmolality. Loading of the magnetic nanoparticles was carried out during liposome extrusion and separation of unloaded magnetite was accomplished by decomposing particles through acidification of the external aqueous environment followed by dialysis to remove free iron in solution. Drug loading took advantage of this unique trans-bilayer pH gradient, using the conversion of a camptothecin drug molecule from its lactone to carboxylate to measure drug loading via HPLC with fluorescent detection. Dynamic Light Scattering was used to confirm particle size of the liposomes and magnetic nanoparticles. Finally, spectrophotometric analysis was used to determine the iron content inside the liposomes and verify that no unloaded magnetite was present. To ascertain changes in drug permeability, the development of a novel system to measure drug release at sink conditions in an alternating magnetic field was developed; mathematical modeling of these conditions was used to show sink conditions were maintained.