Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine
| Autor: | Boram Gu, Yu Huang, Emily Louise Manchester, Alun D. Hughes, Simon A. McG. Thom, Rongjun Chen, Xiao Yun Xu |
|---|---|
| Přispěvatelé: | Imperial College Healthcare NHS Trust- BRC Funding |
| Rok vydání: | 2021 |
| Předmět: |
multiphysics modelling
thrombolysis STRATEGIES Chemistry Multidisciplinary CLOT LYSIS RECANALIZATION Pharmaceutical Science THERAPY targeted drug delivery THROMBUS Fibrinolytic Agents pharmacodynamics Pharmacology (medical) Thrombolytic Therapy Pharmacology & Pharmacy ACUTE ISCHEMIC-STROKE TISSUE-PLASMINOGEN ACTIVATOR Pharmacology Science & Technology integumentary system MECHANICAL THROMBECTOMY Fibrinolysis Organic Chemistry CEREBRAL-ARTERY OCCLUSION Chemistry Nanomedicine Tissue Plasminogen Activator Physical Sciences Molecular Medicine INTRAVENOUS THROMBOLYSIS 1115 Pharmacology and Pharmaceutical Sciences Life Sciences & Biomedicine pharmacokinetics Biotechnology |
| Zdroj: | Pharmaceutical research. 39(1) |
| ISSN: | 1573-904X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink