Radio Frequency-Activated Nanoliposomes for Controlled Combination Drug Delivery

This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance ((31)P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.