Abstract
Introduction
Convection-enhanced delivery is to directly infuse drugs into the brain tissue through a catheter. It is a promising alternative to routine drug administration modes, e.g. intravenous administration, for bypassing the blood-brain barrier, which blocks over 98% of drugs within blood [1]. However, the effectiveness of convection-enhanced delivery remains significantly limited in clinical practice. As nerve bundles are widely present in brain white matter, the brain tissue becomes highly anisotropic, resulting in uncontrolled drug distribution [2]. How tissue anisotropy determines the drug transport and accumulation in brain has not been fully understood.
Methods
Multiphysics modelling is applied to examine the effects of brain tissue anisotropy on nanoparticlemediated convection-enhanced delivery, which has been demonstrated with the improved treatment effectiveness as compared to plain drugs [3]. The model consists of three interlinked modules [4], including the fluid mechanics module for enhanced interstitial fluid flow, the solid mechanics module for brain tissue deformation and the drug transport module to describe drug migration by convection and diffusion, drug release from nanoparticles, binding with proteins, cell uptake and drug elimination due to capillary drainage, metabolic reactions and physical degradation. A comprehensive parametric study is performed to examine the effects of tissue anisotropy on drug transport and accumulation. Treatment effectiveness is evaluated in terms of distribution volume where the drug concentration is above LD90.
Results & Discussion
The delivery using nanoparticles with different drug release rates are studied. Results show that the penetration depth and distribution volume can be significantly improved by reducing the nanoparticle release rate. The drug penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. Moreover, the delivery outcomes of nanoparticles with a lower release rate is more sensitive to tissue anisotropy. Large distribution volumes can be achieved when the tissue is less anisotropic for carmustine.
Conclusions
Outcomes of convection-enhanced delivery of nanoparticle-encapsulated carmustine are highly sensitive to tissue anisotropy, and the sensitivity also depends on the drug release rate. These findings indicate that the treatment needs to be well designed by considering both the factors of the orientation of local nerve bundles and the release dynamics of nanoparticles. Results obtained in this study could be further validated in experiments and applied as a guide for the design of this therapy to delivery drugs in brain.
References
1. Zhou J. et al. PNAS 2013; 110: 11751-11756.
2. Raghavan R. et al. Neurosurgical focus 2006; 20.4: E12.
3. Zhan W. C-H Wang. Journal of controlled release 2018; 285: 212-219.
4. Zhan W. D Dini. F Rodriguez y Baena. Drug delivery 2019; 26(1): 773-781
Convection-enhanced delivery is to directly infuse drugs into the brain tissue through a catheter. It is a promising alternative to routine drug administration modes, e.g. intravenous administration, for bypassing the blood-brain barrier, which blocks over 98% of drugs within blood [1]. However, the effectiveness of convection-enhanced delivery remains significantly limited in clinical practice. As nerve bundles are widely present in brain white matter, the brain tissue becomes highly anisotropic, resulting in uncontrolled drug distribution [2]. How tissue anisotropy determines the drug transport and accumulation in brain has not been fully understood.
Methods
Multiphysics modelling is applied to examine the effects of brain tissue anisotropy on nanoparticlemediated convection-enhanced delivery, which has been demonstrated with the improved treatment effectiveness as compared to plain drugs [3]. The model consists of three interlinked modules [4], including the fluid mechanics module for enhanced interstitial fluid flow, the solid mechanics module for brain tissue deformation and the drug transport module to describe drug migration by convection and diffusion, drug release from nanoparticles, binding with proteins, cell uptake and drug elimination due to capillary drainage, metabolic reactions and physical degradation. A comprehensive parametric study is performed to examine the effects of tissue anisotropy on drug transport and accumulation. Treatment effectiveness is evaluated in terms of distribution volume where the drug concentration is above LD90.
Results & Discussion
The delivery using nanoparticles with different drug release rates are studied. Results show that the penetration depth and distribution volume can be significantly improved by reducing the nanoparticle release rate. The drug penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. Moreover, the delivery outcomes of nanoparticles with a lower release rate is more sensitive to tissue anisotropy. Large distribution volumes can be achieved when the tissue is less anisotropic for carmustine.
Conclusions
Outcomes of convection-enhanced delivery of nanoparticle-encapsulated carmustine are highly sensitive to tissue anisotropy, and the sensitivity also depends on the drug release rate. These findings indicate that the treatment needs to be well designed by considering both the factors of the orientation of local nerve bundles and the release dynamics of nanoparticles. Results obtained in this study could be further validated in experiments and applied as a guide for the design of this therapy to delivery drugs in brain.
References
1. Zhou J. et al. PNAS 2013; 110: 11751-11756.
2. Raghavan R. et al. Neurosurgical focus 2006; 20.4: E12.
3. Zhan W. C-H Wang. Journal of controlled release 2018; 285: 212-219.
4. Zhan W. D Dini. F Rodriguez y Baena. Drug delivery 2019; 26(1): 773-781
| Original language | English |
|---|---|
| Number of pages | 1 |
| Publication status | Published - 6 Sept 2021 |
| Event | BioMedEng21 - Sheffield, United Kingdom Duration: 6 Sept 2021 → 7 Sept 2021 |
Conference
| Conference | BioMedEng21 |
|---|---|
| Country/Territory | United Kingdom |
| City | Sheffield |
| Period | 6/09/21 → 7/09/21 |