An Imaging-Driven Model for Liposomal Stability and Circulation

Abstract

Simultaneous labeling of the drug compartment and shell of delivery vehicles with optical and positron emission tomography (PET) probes is developed and employed to inform a physiologically-based pharmacokinetic model. Based on time-dependent estimates of the concentration of these tracers within the blood pool, reticulo-endothelial system (RES) and tumor interstitium, we compare the stability and circulation of long-circulating and temperature-sensitive liposomes. We find that rates of transport to the RES for long-circulating and temperature-sensitive particles are 0.046 and 0.19 hr−1, respectively. Without the application of exogenous heat, the rates of release from the long-circulating and temperature-sensitive particles circulating within the blood pool are 0.003 and 0.2 hr−1, respectively. Prolonged life-time in circulation and slow drug release from liposomes result in a significantly greater drug area under the curve for the long-circulating particles. Future studies will couple these intrinsic parameters with exogenous heat-based release. Finally, we develop a transport constant for the transport of liposomes from the blood pool to the tumor interstitium, which is on the order of 0.01 hr−1 for the Met-1 tumor system.

Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines

“…This was accomplished by conjugating a chelating agent, AmBaSar, onto the ELP prior to radiolabeling with 64 Cu. In contrast to the classical method of obtaining blood samples to deduce pharmacokinetics, this imaging modality allows for the application of image-driven pharmacokinetic modeling[83]. These studies confirmed that a low molecular weight soluble ELP (<40 kDa) was cleared rapidly by the kidney, and that high molecular weight soluble ELPs (>70 kDa) were retained in the blood for long enough to generate an EPR-based enhancement in a breast cancer xenograft model.…”

A systematic study of temperature sensitive liposomal delivery of doxorubicin using a mathematical model

“…is varied over a range of 0.1-10 folds of its baseline value, which is sufficient to cover the parameter values reported in the literature [17,18]. Comparisons of temporal profiles of obtained with the baseline value and the lower and upper bounds are shown in Figure 5(a).…”

The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

“…Following administration of a drug encapsulated into drug delivery system, drug disposition is not constant and cannot be described by a single volume of distribution parameter. Pharmacokinetics of drugs incorporated in delivery systems can be described using sophisticated distribution mechanism-based PK models, such as PBPK models [10,55] that can incorporate processes of tissue diffusion and drug release from the delivery system [56,57].…”