Mathematical modelling of the use of macrophages as vehicles for drug delivery to hypoxic tumour sites
Mathematical modelling of the use of macrophages as vehicles for drug delivery to hypoxic tumour sites
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DOI：
10.1016/j.jtbi.2003.09.004
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发表时间：
2004-02-21
影响因子：
2
通讯作者：
Lewis, CE
中科院分区：
文献类型：
--
作者：
Owen, MR;Byrne, HM;Lewis, CE
差的药物递送和低的细胞增殖速率是与低氧相关的两个因素，其降低了许多化疗药物的功效。由于已知巨噬细胞特异性地向缺氧肿瘤区域迁移并定位在缺氧肿瘤区域内，因此这些问题的一个有希望的解决方案涉及基因工程巨噬细胞以执行诸如诱导细胞裂解和抑制血管生成的抗肿瘤功能。在本文中，我们概述了一种建模方法来表征巨噬细胞浸润到早期无血管实体瘤，并扩展研究这些细胞与巨噬细胞已经存在于肿瘤内的相互作用。我们研究了趋化性和趋化因子产生的作用，以及巨噬细胞作为药物输送到缺氧肿瘤部位的载体的功效。该模型基于生长的无血管肿瘤球体，其中体积充满了肿瘤细胞、巨噬细胞和细胞外物质，肿瘤细胞的增殖和死亡受到营养扩散的调节。至关重要的是，巨噬细胞占据体积，因此有助于体积平衡，因此有助于肿瘤的大小。我们还包括巨噬细胞趋化因子的氧依赖性产生，这可能导致肿瘤缺氧区域的积累。我们发现巨噬细胞趋化敏感性是巨噬细胞浸润和肿瘤大小的关键决定因素。虽然从巨噬细胞为基础的治疗的角度来看，增加浸润应该是有益的，这样的浸润实际上导致肿瘤尺寸增加。最后，我们包括代表缺氧工程巨噬细胞诱导肿瘤细胞死亡的术语。我们证明了可以实现肿瘤大小的减少，但预测完全根除需要联合治疗。我们还强调了一些违反直觉的预测，例如，肿瘤负荷的绝对和相对测量导致不同的预后结论。总之，本文说明了如何数学模型可用于研究有前途的巨噬细胞为基础的疗法。(C)2003爱思唯尔有限公司。保留所有权利。
Poor drug delivery and low rates of cell proliferation are two factors associated with hypoxia that diminish the efficacy of many chemotherapeutic drugs. Since macrophages are known to migrate specifically towards, and localize within, hypoxic tumour regions, a promising resolution to these problems involves genetically engineering macrophages to perform such anti-tumour functions as inducing cell lysis and inhibiting angiogenesis. In this paper we outline a modelling approach to characterize macrophage infiltration into early avascular solid tumours, and extensions to study the interaction of these cells with macrophages already present within the tumour. We investigate the role of chemotaxis and chemokine production, and the efficacy of macrophages as vehicles for drug delivery to hypoxic tumour sites.The model is based upon a growing avascular tumour spheroid, in which volume is filled by tumour cells, macrophages and extracellular material, and tumour cell proliferation and death is regulated by nutrient diffusion. Crucially, macrophages occupy volume, and hence contribute to the volume balance and hence the size of the tumour. We also include oxygen-dependent production of macrophage chemokines, which can lead to accumulations in the hypoxic region of the tumour. We find that the macrophage chemotactic sensitivity is a key determinant of macrophage infiltration and tumour size. Although increased infiltration should be beneficial from the point of view of macrophage-based therapies, such infiltration in fact leads to increased tumour sizes.Finally, we include terms representing the induced death of tumour cells by hypoxic engineered macrophages. We demonstrate that reductions in tumour size can be achieved, but predict that a combination of therapies would be required for complete eradication. We also highlight some counter-intuitive predictions-for example, absolute and relative measures of tumour burden lead to different conclusions about prognosis. In summary, this paper illustrates how mathematical models may be used to investigate promising macrophage-based therapies. (C) 2003 Elsevier Ltd. All rights reserved.