Drug targeting and tumor heterogeneity.
Drug targeting and tumor heterogeneity.
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DOI：
10.1016/j.jconrel.2008.09.074
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发表时间：
2009-01-05
影响因子：
10.8
通讯作者：
Bae, You Han
中科院分区：
文献类型：
--
作者：
Bae, You Han
“导弹药物”、“神奇子弹”或报纸文章或公共杂志上出现的类似词语经常吸引普通读者和科学家，因为这些词语在某种程度上暗示着“遥远”、“寻求”和“选择性摧毁”。“药物靶向”最初用于描述与靶标癌细胞表面抗原特异的单抗(MAb)结合的抗癌药物在体内可能的作用。从那时起，一系列靶向系统被设计出来，并出现在科学论文中。这些靶向系统利用癌细胞上过度表达的营养受体或特定化学物质。这种“靶向”还给人一种印象，即这种共轭物找到的目标细胞类似于智能导弹，智能导弹可能会主动从几英里外追逐目标。情况肯定不是这样的。任何水溶性或纳米级的构建物，作为药物载体并被引入血液中，似乎不可能主动寻找远程位于实体肿瘤中的靶细胞。很可能是药物携带者碰上了漂浮的细胞，如血液隔间中的白血病细胞，这是由于碰撞的可能性。药物结合物或药物载体要到达其目标实体肿瘤部位，必须通过对流和随机扩散过程，偶然发现肿瘤血管上的窗孔(开口)。这个与概率问题有关的过程被称为“被动定位”和“增强渗透率(EP)”[1]。EP对肿瘤部位载体聚集的影响可能由一个相反的力主导：静水压力，在肿瘤细胞外空间略高于正常组织/器官。传统的肿瘤靶向方法分为被动靶向和主动靶向，然而，主动靶向过程不能与被动靶向过程分开，因为它只有在肿瘤内被动积聚后才发生。长期流通的资产一直都很有价值。更长的循环时间肯定会增加携带者在血管上发现大开口的可能性。在血液循环过程中，结合的药物应该留在载体中，以便在目标部位提供足够高的浓度。如果药物在载体到达治疗部位之前过早释放，可能无助于肿瘤部位的药物积聚。
“Missile drug,”“Magic bullet” or similar words found in newspaper articles or public magazines have often fascinated general readers and scientists for the reason that these words in some way implicate ‘remote,’‘seeking’and ‘selective destruction.’“Drug targeting” was initially used to describe the possible in vivo action of an anticancer drug conjugated to a monoclonal antibody (mAb) which is specific to a surface antigen on target cancer cells. Since then, a range of targeting systems were devised and appeared in scientific papers. These targeting systems exploit over-expressed receptors of nutrients or specific chemistry on cancer cells. The ‘targeting’has also given an impression that such conjugates find target cells similar to a smart missile, which may actively chase its target from miles away. This is certainly not the case.It is seemingly not possible that any water-soluble or nano-sized construct, designed as a drug carrier and introduced into the blood stream, will actively seek target cells that are remotely sitting in solid tumors. It is likely that the drug carriers stumble on floating cells such as leukemic cells in the blood compartment by a probability of collision. To reach its target solid tumor site, a drug conjugate or drug carrier must find the fenestraes (openings) on the tumor blood vessels by chance through convectional flow and random diffusional process. This process, which is linked to probability issues, is called ‘passive targeting’coupled with ‘enhanced permeability (EP)’[1]. The EP effect on carrier accumulation at tumor sites may be dominated by an opposite force; hydrostatic pressure, which is slightly higher in tumor extracellular space than in normal tissues/organs. Traditionally, tumor targeting approaches are classified into ‘passive targeting’and ‘active targeting’; however, the active targeting process cannot be separated from the passive because it occurs only after passive accumulation in tumors. Long-circulating property has always been valuable. A longer circulation time definitely improves the probability for a carrier to find large openings on the blood vessels. During circulation in the blood stream, the incorporated drug should remain in the carrier to give high enough concentrations at the target sites. If premature release of drug occurs before the carrier reaches therapeutic sites, it may not help in drug accumulation at the tumor sites.
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影响因子：
10.8
作者：
Maeda, H;Wu, J;Hori, K
通讯作者：
Hori, K
影响因子：
6.4
作者：
Hartmann, Lynn C.;Keeney, Gary L.;Low, Philip S.
通讯作者：
Low, Philip S.
影响因子：
10.8
作者：
Hwang, Ho-Young;Kim, In-San;Kim, Yong-Hee
通讯作者：
Kim, Yong-Hee
DOI：
10.1073/pnas.95.8.4607
发表时间：
1998-04-14
影响因子：
11.1
作者：
Hobbs, SK;Monsky, WL;Jain, RK
通讯作者：
Jain, RK