Drug-targeting methodologies with applications: A review.

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system.

Impact of fluid-structure interaction on direct tumor-targeting in a representative hepatic artery system.

Direct targeting of solid tumors with chemotherapeutic drugs and/or radioactive microspheres can be a treatment option which minimizes side-effects and reduces cost. Briefly, computational analysis generates particle release maps (PRMs) which visually link upstream particle injection regions in the main artery with associated exit branches, some connected to tumors. The overall goal is to compute patient-specific PRMs realistically, accurately, and cost-effectively, which determines the suitable radial placement of a micro-catheter for optimal particle injection. Focusing in this paper on new steps towards realism and accuracy, the impact of fluid-structure interaction on direct drug-targeting is evaluated, using a representative hepatic artery system with liver tumor as a test bed. Specifically, the effect of arterial wall motion was demonstrated by modeling a two-way fluid-structure interaction analysis with Lagrangian particle tracking in the bifurcating arterial system. Clearly, rapid computational evaluation of optimal catheter location for tumor-targeting in a clinical application is very important. Hence, rigid-wall cases were also compared to the flexible scenario to establish whether PRMs generated when based on simplifying assumptions could provide adequate guidance towards ideal catheter placement. It was found that the best rigid (i.e., time-averaged) geometry is the physiological one that occurs during the diastolic targeting interval.

Experimental microsphere targeting in a representative hepatic artery system.

Recent work employing the computational fluid-particle modeling of the hepatic arteries has identified a correlation between particle release position and downstream branch distribution for direct tumor-targeting in radioembolization procedures. An experimental model has been constructed to evaluate the underlying simulation theory and determine its feasibility for future clinical use. A scaled model of a generalized hepatic system with a single inlet and five outlet branches was fabricated to replicate the fluid dynamics in the hepatic arteries of diseased livers. Assuming steady flow, neutrally buoyant microspheres were released from controlled locations within the inlet of the model and the resulting output distributions were recorded. Fluid and particle transport simulations were conducted with identical parameters. The resulting experimentally and simulation-derived microsphere distributions were compared. The experimental microsphere distribution exhibited a clear dependence on injection location that correlated very strongly with the computationally predicted results. Individual branch targeting was possible for each of the five outputs. The experimental results validate the simulation methodology for achieving targeted microsphere distributions in a known geometry under constant flow conditions.

Computer modeling of controlled microsphere release and targeting in a representative hepatic artery system.

Combating liver tumors via yttrium-90 ((90)Y) radioembolization is a viable treatment option of nonresectable liver tumors. Employing clinical (90)Y microparticles (i.e., SIR-Spheres and TheraSpheres) in a computational model of a representative hepatic artery system, laminar transient 3D particle-hemodynamics were simulated. Specifically, optimal particle release positions in the right hepatic (parent) artery as well as the best temporal release window were determined for the microspheres to exit specific outlet daughter vessels, potentially connected to liver tumors. The results illustrate the influence of a curved geometry on the velocity field and the particle trajectory dependence on the spatial and temporal particle injection conditions. The differing physical particle characteristics of the SIR-Spheres and the TheraSpheres had a subtle impact on particle trajectories in the decelerating portion of the arterial pulse, i.e., when the inertial forces on the particles are weaker. Conversely, particle characteristics and inelastic wall collisions had little effect on particles released during the accelerating phase of the arterial pulse, i.e., both types of microspheres followed organized paths to predetermined outlets. Such results begin paving the way towards directing 100% of the released microspheres to specific daughter vessels (e.g., those connected to tumors) under transient flow conditions in realistic geometries via a novel drug-particle targeting methodology.