Multiphysics modeling of chitosan nanocarrier thrombolysis in human arterial occlusion: insights into carrier retention and dosing strategy

Abstract

Objectives To develop a human-scale multiphysics model for comparative evaluation of thrombolytic nanocarrier performance and dosing strategies under clinically relevant arterial conditions. Methods We coupled a systemic pharmacokinetic-pharmacodynamic model with one-dimensional convection-diffusion-reaction transport in an occluded artery, incorporating platelet-triggered tissue plasminogen activator (tPA) release and formulation-specific effective binding to activated platelet sites. Twenty-two scenarios varied thrombus composition, nanocarrier formulation, and dosing regimen. Results PNC produced shorter predicted recanalization times than free tPA in platelet-rich thrombi when activated platelet density was sufficient to sustain triggered release. Matched-diffusivity comparisons indicated that diffusivity alone was insufficient to explain the formulation-dependent differences in intrathrombic retention and thrombolytic efficacy. These differences were associated with the combined formulation-specific binding, release, transport, and pharmacokinetic parameters represented in the model. A single low-dose PNC bolus containing 10% of the standard tPA dose achieved recanalization times comparable to those of standard-dose free tPA under the bolus-plus-infusion regimen while producing substantially less modeled systemic fibrinogen depletion. Conclusions The coupled model provides a quantitative framework for comparing thrombolytic nanocarrier behavior and dosing strategies under the specified human-scale arterial conditions and may help guide further preclinical evaluation of targeted thrombolytic nanocarriers.