摘要
低氧肿瘤细胞的特征是缺乏氧气从血液供应减少对周围组织产生的,并且是实体肿瘤作为快速的细胞生长的结果一个共同的特点。低氧肿瘤是既耐癌症转移/侵袭性形式的化疗和的预测,并作为结果,癌治疗靶向于缺氧发展是至关重要的。一种这样的靶向策略是低氧激活前药(HAP),它可以优先低氧肿瘤区域内松开化疗剂的开发。此靶向策略是通过附着低氧激活触发器化疗剂和下缺氧条件来实现,所述试剂(效应)被释放到肿瘤,而其余的完好在正常组织,并留下非缺氧细胞损坏。总体而言,这种策略可以通过浓缩内低氧肿瘤环境中的药物,同时降低了周围的传统药物对氧正常细胞中的分布全身副作用和毒性问题实现比常规小分子化学治疗增加的治疗益处。在这篇综述中,我们将介绍设计一个有效的HAP,如前药的作用机制,影响HAP(即还原电位)的合理设计元素,和HAP的激活酶时应该考虑的因素。作为本说明的一部分,我们将利用选择的例子在文献中以加强这些因素的影响,并进行案例的新有害空气污染物的智能设计,导致新的缺氧靶向化疗剂的开发
关键词: 低氧,前体药物,靶向化疗,生物还原剂,抗肿瘤剂
Current Medicinal Chemistry
Title:Hypoxia Activated Prodrugs: Factors Influencing Design and Development
Volume: 22 Issue: 37
Author(s): Dinghua Liang, Graham H. Miller and Geoffrey K. Tranmer
Affiliation:
关键词: 低氧,前体药物,靶向化疗,生物还原剂,抗肿瘤剂
摘要: Hypoxia in tumor cells is characterized by a lack of oxygen resulting from reduced blood supply to the surrounding tissue, and is a common characteristic of solid tumors as a consequence of rapid cell growth. Hypoxia in tumors is a predictor of both resistance to chemotherapy and of a metastatic/aggressive form of cancer, and as a result, development of cancer therapies which target hypoxia is of vital importance. One such targeting strategy is the development of hypoxia-activated prodrugs (HAP) which can preferentially release chemotherapeutic agents within hypoxic tumor regions. This targeting strategy is accomplished by attaching a hypoxia activated trigger to a chemotherapeutic agent and under oxygen-poor conditions, the agent (effector) is released into the tumor, while remaining intact in normal tissue, and leaving non-hypoxic cells undamaged. Overall, this strategy can achieve an increased therapeutic benefit over conventional small molecule chemotherapeutic treatments by concentrating the drugs within hypoxic tumor environments, while simultaneously reducing the side-effects and toxicity issues that surround the systemic distribution of traditional drugs on normoxic cells. In this review, we will describe the factors that should be considered when designing an effective HAP, such as the mechanism of prodrug action, the elements that influence the rational design of HAP (i.e. reduction potential), and the activating enzymes of HAP. As part of this description, we will utilize select examples from the literature to reinforce these factors, and make a case for the intelligent design of new HAPs, leading to the development of novel hypoxia targeting chemotherapeutic agents.
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Cite this article as:
Dinghua Liang, Graham H. Miller and Geoffrey K. Tranmer , Hypoxia Activated Prodrugs: Factors Influencing Design and Development, Current Medicinal Chemistry 2015; 22 (37) . https://dx.doi.org/10.2174/0929867322666151021111016
DOI https://dx.doi.org/10.2174/0929867322666151021111016 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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