Department of Mechanical Engineering, Imperial College London, South Kensington Campus, London, United Kingdom.
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore.
J Control Release. 2018 Sep 10;285:212-229. doi: 10.1016/j.jconrel.2018.07.006. Epub 2018 Jul 17.
Convection enhanced delivery is promising to overcome the blood brain barrier. However, the treatment is less efficient in clinic due to the rapid elimination of small molecular drugs in brain tumours. In this study, numerical simulation is applied to investigate the convection enhanced delivery of liposome encapsulated doxorubicin under various conditions, based on a 3-D brain tumour model that is reconstructed from magnetic resonance images. Treatment efficacy is evaluated in terms of the tumour volume where the free doxorubicin concentration is above LD90. Simulation results denote that intracerebral infusion is effective in increasing the interstitial fluid velocity and inhibiting the fluid leakage from blood around the infusion site. Comparisons with direct doxorubicin infusion demonstrate the advantages of liposomes in enhancing the doxorubicin accumulation and penetration in the brain tumour. Delivery outcomes are determined by both the intratumoural environment and properties of therapeutic agents. The treatment efficacy can be improved by either increasing the liposome solution concentration and infusion rate, administrating liposomes in the tumour with normalised microvasculature density, or using liposomes with low vascular permeability. The delivery is less sensitive to liposome diffusivity in the examined range (E-11~E-7 cm/s) as convective transport is dominative in determining the liposome migration. Drug release rate is able to be optimised by keeping a trade-off between enhancing the drug penetration and providing sufficient free doxorubicin for effective cell killing. Results from this study can be used to improve the regimen of CED treatments.
递增强化输送有望克服血脑屏障。然而，由于小分子药物在脑肿瘤中的快速消除，该治疗方法在临床上的效果较差。在这项研究中，基于从磁共振图像重建的三维脑肿瘤模型，应用数值模拟来研究脂质体包裹阿霉素在各种条件下的递增强化输送。根据游离阿霉素浓度高于 LD90 的肿瘤体积来评估治疗效果。模拟结果表明，脑内输注可有效增加间质液速度并抑制输注部位周围血液中的液体渗漏。与直接阿霉素输注的比较表明，脂质体在增强脑肿瘤中阿霉素的积累和渗透方面具有优势。输送结果取决于肿瘤内环境和治疗剂的性质。通过增加脂质体溶液浓度和输注率、在具有正常微血管密度的肿瘤中给予脂质体、或使用血管通透性低的脂质体，可以提高治疗效果。在研究范围内（E-11~E-7 cm/s），脂质体扩散性对输送的敏感性较低，因为对流传输在决定脂质体迁移方面占主导地位。通过在增强药物渗透和提供足够的游离阿霉素以有效杀死细胞之间取得平衡，可以优化药物释放率。本研究的结果可用于改进 CED 治疗方案。
