Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid.
Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid.
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DOI：
10.3389/fonc.2015.00165
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发表时间：
2015
影响因子：
4.7
通讯作者：
Baronzio M
中科院分区：
文献类型：
--
作者：
Baronzio G;Parmar G;Baronzio M
每种用于治疗癌症的药物（化疗药物、免疫药物、单克隆抗体、纳米颗粒、放射性核素）都必须以足够的浓度通过肿瘤环境到达靶细胞，才能发挥其细胞杀伤作用。这些药物要到达目标细胞，就必须克服肿瘤微环境 (TME) 造成的许多障碍，首先是肿瘤间质液压力 (TIFP)，以及细胞外基质 (ECM) 成分的多因素增加。 TME 的主要调节因素是缺氧，它会增加生长因子的产生，例如血管内皮生长因子和血小板衍生生长因子。肿瘤细胞和骨髓募集的髓样细胞释放的这些生长因子形成异常的脉管系统，其特征是血管曲折且更具渗透性。渗漏增加与炎症副产物增加相结合，在肿瘤块内积聚液体（肿瘤间质液），最终产生压力增加（TIFP）。成纤维细胞也受到 TME 的上调，并沉积纤维，进一步增加 ECM 的密度，从而进一步恶化 TIFP。 ECM 增加的 TIFP 是充分给药的主要障碍。通过降低 TIFP 和 ECM 密度，我们可以预期肿瘤本身内的药物浓度会相应上升。在本概述中，我们将描述能够降低 TIFP 和修改 ECM 以增加肿瘤组织内药物浓度的所有方法（药物、营养制品和物理治疗方法）。
Every drug used to treat cancer (chemotherapeutics, immunological, monoclonal antibodies, nanoparticles, radionuclides) must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells, they must overcome a number of impediments created by the tumor microenvironment (TME), beginning with tumor interstitial fluid pressure (TIFP), and a multifactorial increase in composition of the extracellular matrix (ECM). A primary modifier of TME is hypoxia, which increases the production of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor. These growth factors released by both tumor cells and bone marrow recruited myeloid cells form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass (tumor interstitial fluid), ultimately creating an increased pressure (TIFP). Fibroblasts are also up-regulated by the TME, and deposit fibers that further augment the density of the ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview, we will describe all the methods (drugs, nutraceuticals, and physical methods of treatment) able to lower TIFP and to modify ECM used for increasing drug concentration within the tumor tissue.