Creation of Pure Nanodrugs and Their Anticancer Properties
Creation of Pure Nanodrugs and Their Anticancer Properties
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DOI：
10.1002/anie.201204596
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Hashida, Mitsuru
中科院分区：
文献类型：
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作者：
Kasai, Hitoshi;Murakami, Tatsuya;Hashida, Mitsuru
伊立替康(方案1)是喜树碱[1]的衍生物，目前已知是一种具有良好水溶性的主要化疗药物。[2]事实上，它是SN-38(方案1)的药用活性部分的前药，它是氨基甲酸酯部分水解形成的，具有DNA抑制活性。[3，4]如果SN-38本身能被输送到适当的位置，那将是理想的；然而，由于它在水中的溶解性很差，需要使用复杂的制剂技术。关于SN-38的药物输送，过去已经报道了一些制剂技术，例如将SN-38包裹在含有亲水性聚乙二醇的小(100 nm或更小)聚合物胶束中[5-7]，从而使颗粒在血液中有足够的保留时间，以增强细胞通透性并产生有效的滞留效果。另一方面，毫无疑问，完全由药理活性化合物组成的无载体纯纳米粒(PND)将成为下一代药物的候选药物。[8，9]已经有几个关于使用各种方法制备水溶性较差的药物化合物(如类固醇)的纳米粒的报道。[8，10，11]然而，尺寸在20 nm到100 nm之间且没有污染颗粒的PND还没有通过快速和低能量的工艺制备，关于它们的制备仍然存在一些问题。在这种背景下，我们在大约20年前发现，可以通过一种简单的再沉淀法来制备尺寸可控的有机纳米晶。在这种方法中，将化合物(溶质)的溶液快速地注入到较差的溶剂(抗溶剂)中，以引起溶质的再沉淀。用再沉淀法已经成功地制备了50多种有机染料[13]，[13]，[14]，[15，16]和[17]的纳米晶。
Irinotecan (Scheme 1) is a derivative of camptothecin [1] and is known to be currently used as a major chemotherapeutic agent with favorable water solubility.[2] It is, in fact, a prodrug of the pharmaceutically active moiety of SN-38 (Scheme 1), which is formed as a result of hydrolysis of the carbamate moiety and is active as a DNA repressor.[3, 4] It would be ideal if SN-38 could itself be delivered to appropriate locations; however, because of its poor solubility in water, sophisticated formulation technologies need to be used. With regard to drug delivery of SN-38, in the past, some formulation technologies have been reported, such as the enclosure of SN-38 in small (100 nm or less) polymer micelles [5–7] containing hydrophilic polyethylene glycol, so that the particles have a sufficient retention time in the bloodstream to enhance cell permeability and to elicit an efficient retention effect. On the other hand, there is no doubt that carrier-free pure nanodrugs (PNDs) that consist exclusively of pharmacologically active compounds will become candidates for use as the next generation of drugs.[8, 9] There have been several reports on the preparation of nanoparticles of drug compounds with poor aqueous solubility, such as steroids, by using various methods.[8, 10, 11] However, PNDs of a size of between 20 nm and 100 nm that are free of contaminant particles have not yet been prepared by a rapid and low-energy process, and several problems remain with regard to their preparation. Given this background, we discovered about 20 years ago that size-controlled organic nanocrystals can be produced by a simple reprecipitation method in which a solution of a compound (solute) is rapidly injected into a poor solvent (antisolvent) to cause reprecipitation of the solute.[12] Nanocrystals of more than 50 organic dyes,[13] including perylene,[14] polydiacetylene,[15, 16] and phthalocyanine [17] have been successfully prepared by the reprecipitation method.