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使用基本解方法对电穿孔参数对化疗药物细胞内化、空间均匀性和细胞毒性影响的计算机研究

In silico study about the influence of electroporation parameters on the cellular internalization, spatial uniformity, and cytotoxic effects of chemotherapeutic drugs using the Method of Fundamental Solutions.

机构信息

Grupo de Investigación E Innovación Ambiental (GIIAM), Institución Universitaria Pascual Bravo, Cl. 73 No 73A-226 (Bloque 7), Medellín, Colombia.

Grupo de Investigación de Ciencias Administrativas, Instituto Tecnológico Metropolitano - ITM, Medellín, Colombia.

出版信息

Med Biol Eng Comput. 2024 Mar;62(3):713-749. doi: 10.1007/s11517-023-02964-2. Epub 2023 Nov 21.

Abstract

Reversible electroporation is a suitable technique to aid the internalization of medicaments in cancer tissues without inducing permanent cellular damage, allowing the enhancement of cytotoxic effects without incurring in electric-driven necrotic or apoptotic processes by the presence of non-reversible aqueous pores. An adequate selection of electroporation parameters acquires relevance to reach these goals and avoid opposite effects. This work applies the Method of Fundamental Solutions (MFS) for drug transport simulations in electroporated cancer tissues, using a continuum tumor cord approach and considering both electro-permeabilization and vasoconstriction effects. The MFS algorithm is validated with published results, obtaining satisfactory accuracy and convergence. Then, MFS simulations are executed to study the influence of electric field magnitude [Formula: see text], number of electroporation treatments [Formula: see text], and electroporation time [Formula: see text] on three assessment parameters of electrochemotherapy: the internationalization efficacy accounting for the ability of the therapy to introduce moles into viable cells, cell-kill capacity indicating the faculty to reduce the survival fraction of cancer cells, and distribution uniformity specifying the competence to supply drug homogeneously through the whole tissue domain. According to numerical results, when [Formula: see text] is the reversibility threshold, a positive influence on the first two parameters is only possible once specific values of [Formula: see text] and [Formula: see text] have been exceeded; when [Formula: see text] is just the irreversibility threshold, any combination of [Formula: see text] and [Formula: see text] is beneficial. On the other hand, the drug distribution uniformity is always adversely affected by the application of electric pulses, being this more noticeable as [Formula: see text], [Formula: see text], and [Formula: see text] increases.

摘要

可逆电穿孔是一种合适的技术,可以帮助药物在癌症组织内内化,而不会造成永久性细胞损伤,在不存在不可逆水孔的情况下,增强细胞毒性作用而不会引起电驱动的坏死或凋亡过程。适当选择电穿孔参数对于实现这些目标并避免相反的效果至关重要。本工作应用基本解方法(MFS)模拟电穿孔癌症组织中的药物传输,采用连续肿瘤索模型,并考虑电穿孔和血管收缩效应。MFS 算法通过已发表的结果进行验证,获得了令人满意的准确性和收敛性。然后,进行 MFS 模拟,研究电场强度 [Formula: see text]、电穿孔处理次数 [Formula: see text] 和电穿孔时间 [Formula: see text] 对电化学治疗的三个评估参数的影响:国际化效果考虑治疗将摩尔引入活细胞的能力,细胞杀伤能力表示降低癌细胞存活率的能力,以及分布均匀性指定通过整个组织域均匀供应药物的能力。根据数值结果,当 [Formula: see text] 是可逆性阈值时,只有在超过特定的 [Formula: see text] 和 [Formula: see text] 值时,对前两个参数才有积极影响;当 [Formula: see text] 仅仅是不可逆性阈值时,任何 [Formula: see text] 和 [Formula: see text] 的组合都是有益的。另一方面,药物分布均匀性总是受到电脉冲应用的不利影响,随着 [Formula: see text]、[Formula: see text] 和 [Formula: see text] 的增加,这种影响更加明显。

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