Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine

• Published in: Pharmaceutical research Vol. 39; no. 1; pp. 41 - 56
• Main Authors: Gu, Boram, Huang, Yu, Manchester, Emily Louise, Hughes, Alun D., Thom, Simon A. McG, Chen, Rongjun, Xu, Xiao Yun
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2022; Springer; Springer Nature B.V
• Subjects: Analysis; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood platelets; Computer applications; Dosage; Fibrin; Fibrinolysis; Fibrinolytic Agents - pharmacology; Health aspects; Mathematical models; Medical Law; Nanomedicine; Nanotechnology; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Platelets; Research Paper; Risk assessment; Simulation; Simulation methods; t-Plasminogen activator; Thrombolysis; Thrombolytic drugs; Thrombolytic Therapy - methods; Tissue plasminogen activator; Tissue Plasminogen Activator - pharmacology; Tissue Plasminogen Activator - therapeutic use; pharmacokinetics; thrombolysis; targeted drug delivery; multiphysics modelling; pharmacodynamics
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-021-03161-2

Purpose This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated. Methods The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV. Results Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots. Conclusions Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.