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Development of thermosensitive liposomal drug delivery formulations with actuation from superparamagnetic nanoparticle heating for the treatment of cancer


Background Formulations which can regulate the exposure of anticancer agents after administration could potentially reduce systemic side effects through several parallel mechanisms. These include minimizing drug exposure to healthy tissue by passive targeting of the delivery vehicle before significant drug release and modulating the release kinetics (and therefore tissue exposure to drug) for potential optimization of dose effectiveness. Liposomes which undergo a phase transition from an impermeable to a permeable state at temperatures slightly higher than physiological conditions would provide a method for altering release kinetics. Superparamagnetic iron oxide nanoparticles (SPIOs) in the presence of an alternating magnetic field (AMF) would generate the heating necessary for localized, elevated temperatures which trigger changes in drug release from a liposomal formulation.

Experiments and Results Methods have been developed for the formulation of liposomes with SPIOs for intravenous administration using a pH gradient dialysis method to induce magnetic separation of unloaded SPIOs from those encapsulated within liposomes. Confirmation was performed using a colorimetric iron assay and dynamic light scattering. Power generation from these SPIOs within at alternating magnetic field was also determined using a fluoroptic temperature probe. The experimental loading conditions of SPIOs encapsulated within liposomes and SPIO power generation were used to simulate liposomal heating under thermal sink conditions. The simulation provided information in regards to the mechanism of heating, bulk or nanoenvironment, required to induce changes in drug release from thermosensitive liposomes and the time such heating would take to reach steady-state. This simulation is shown in Figure 1. and indicates localized heating of the nanoenvironment is not feasible.

Initial experiments to confirm the mechanism of heat transfer have been inconclusive because of evaporative water loss and loss of sink conditions for drug release due to the small size constraints of the AMF. A flow-through system is currently under development to monitor temperature and real-time drug release in the AMF in an attempt to eliminate the problems mentioned above. The system will use a microfluidic dialysis device fabricated from a collaborative effort with Dr. Eitel in Materials Engineering. Because of the difficulty inherent in achieving bulk heating from a systemically administered formulation, this delivery platform will be explored for its use under other scenarios. One which may be suitable is the treatment of brain cancer using convection enhanced delivery (CED). Providing a strategy which localizes SPIOs and liposomes similarly, co-administration in conjunction with the homogeneous concentration profile achieved with convection-based mass transport can be used to increase SPIO concentration to provide the desired heating for drug release.

Simulations to examine the mass transport of both liposomes and SPIO using CED and the subsequent temperature profile from magnetic heating have been performed. Figure 2. shows the radial temperature profile from SPIOs after a CED infusion. To this end, thermosensitive liposomal formulations have been explored with the AR -67 as a model drug to explore drug permeability as a function of temperature. Liposomes possessing a bilayer phase transition at 41.5 °C were chosen for thermosensitive release studies as it would undergo phase transition at mildly hyperthermic conditions. Because AR-67 permeability is inversely related to pH, release studies were performed at pH 10 to slow the release, allowing it to be monitored by dialysis. Release profiles were obtained over a range of temperatures and the data was fitted to an apparent permeability release model as shown in Figure 3. While the increase in release is substantially faster above the phase transition than at physiological conditions, release kinetics at that temperature was rate-limited by the dialysis bag itself, leaving the possibility that release above the phase transition may be even faster. These studies demonstrate that the permeability of larger drug molecules has significant temperature dependence and thereby a means for controlling drug release from liposomes.

Address Goals

This research has lead to the development of thermosensitive nanoparticles for use in treating cancer. The work involved collaboration among faculty and students in chemical engineering and pharmaceutical sciences. The students were trained in multidisciplinary research related to drug delivery systems.