Enhanced permeability and retention of macromolecular drugs in solid tumors: A royal gate for targeted anticancer nanomedicines
Enhanced permeability and retention of macromolecular drugs in solid tumors: A royal gate for targeted anticancer nanomedicines
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DOI：
10.1080/10611860701539584
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发表时间：
2007-01-01
影响因子：
4.5
通讯作者：
Greish, Khaled
中科院分区：
文献类型：
--
作者：
Greish, Khaled
在过去的二十年里，癌症已经上升到世界上许多国家的第一或第二位。大多数传统抗癌化疗药物固有的一个主要限制是它们缺乏肿瘤选择性。实现对实体肿瘤的选择性药物靶向的一种方法是利用肿瘤血管的异常，即多血管形成；异常的血管结构；广泛产生的血管渗透因子刺激肿瘤组织内的渗出，以及缺乏淋巴引流。前田及其同事在主动和选择性地将抗癌药物输送到肿瘤组织方面对肿瘤血管异常进行了广泛的研究，特别是确定了大分子药物在实体肿瘤中的增强渗透性和滞留效应(EPR效应)。由于其大分子尺寸，纳米大分子抗癌药物静脉注射(i.v.)逃脱了肾脏的清除。通常情况下，它们不能穿透正常血管紧密的包膜连接，但它们可以渗入肿瘤血管，并被困在肿瘤附近。随着时间的推移，由于实体瘤缺乏有效的淋巴引流，肿瘤浓度将积累到血浆浓度的数倍以上，是基于EPR的选择性抗癌药物输送的理想应用。这一原理的确立加速了用于肿瘤靶向化疗的各种聚合物偶联物和聚合物胶束以及多功能纳米颗粒的开发。事实上，这种肿瘤组织中选择性的高局部浓度的纳米抗癌药物在临床前和临床环境中都被证明具有优越的治疗效果和最小的副作用。在这篇综述中，将详细讨论EPR效应的机制和涉及的因素，以及通过EPR效应进行肿瘤靶向的纳米药物的独特性。
Over the past two decades cancer has ascended the causes of human death to be number one or two in many nations world wide. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Maeda and his colleagues have extensively studied tumor vascular abnormalities in terms of active and selective delivery of anticancer drugs to tumor tissues, notably defining the enhanced permeability and retention effect (EPR effect) of macromolecular drugs in solid tumors. Due to their large molecular size, nanosized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Often they can not penetrate the tight enclothelial junctions of normal blood vessels, but they can extravasate in tumour vasculature and become trapped in the tumor vicinity. With time the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor; an ideal application for EPR-based selective anticancer drug delivery. Establishing this principle hastened development of various polymer conjugates and polymeric micelles as well as multifunctional nanoparticles for targeted cancer chemotherapy. Indeed this selective high local concentration of nanosized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings.In this review the mechanisms and factors involved in the EPR effect, as well as the uniqueness of nanoscale drugs for tumor targeting through EPR effect, will be discussed in detail.