Multiscale Kinetic Modeling of Liposomal Doxorubicin Delivery Quantifies the Role of Tumor and Drug‐Specific Parameters in Local Delivery to Tumors

Abstract

Nanoparticle encapsulation has been used as a means to manipulate the pharmacokinetic (PK) and safety profile of drugs in oncology. Using pegylated liposomal doxorubicin (PLD) vs. conventional doxorubicin as a model system, we developed and experimentally validated a multiscale computational model of liposomal drug delivery. We demonstrated that, for varying tumor transport properties, there is a regimen where liposomal and conventional doxorubicin deliver identical amounts of doxorubicin to tumor cell nuclei. In mice, typical tumor properties consistently favor improved delivery via liposomes relative to free drug. However, in humans, we predict that some tumors will have properties wherein liposomal delivery delivers the identical amount of drug to its target relative to dosing with free drug. The ability to identify tumor types and/or individual patient tumors with high degree of liposome deposition may be critical for optimizing the success of nanoparticle and liposomal anticancer therapeutics.

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

“…Doxorubicin cellular transport is modeled on the basis of published work (34,35). Free doxorubicin partitions into the outer leaflet of the plasma membrane, characterized by association rate constant k f_ol , cell surface area (based on cell radius, assuming spherical cells), and a partition coefficient.…”

Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology

“…This exercise suggested that inhibitors of TrkA kinase may be an interesting approach for novel pain medications, but highlights that achieving saturating inhibition may require higher unbound plasma drug concentrations than might be expected according to simple pharmacological theory. Data-validated systems pharmacology models such as described in this study (and in other areas such as central nervous system diseases [33], oncology [34], osteoporosis [35], endometriosis [9] and safety [36]) could be of great utility in drug discovery.…”

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…If this relationship holds true in a larger population, it would suggest that deposition may be a dominant factor for response to nal-IRI in certain tumor types. The importance of lesion permeability for liposomal delivery has been shown in preclinical tumor models (15,16).…”

“…A sensitivity analysis found that pharmacokinetic properties and permeability of the tumor vasculature to nal-IRI positively affected duration of SN-38 in tumors. Liposomal deposition in tumors was also found to be a rate-limiting step for drug delivery to cells for other long-circulating liposomes (16). It has previously been shown that tumor deposition of a liposomal contrast agent correlated with treatment outcome to a liposomal drug in a rat xenograft model (17).…”