Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs
Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs
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DOI：
10.1002/smll.200700005
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发表时间：
2007-08-01
期刊：
影响因子：
13.3
通讯作者：
Tamanoi, Fuyuhiko
中科院分区：
文献类型：
--
作者：
Lu, Jie;Liong, Monty;Tamanoi, Fuyuhiko
癌症治疗的一个关键障碍和挑战涉及大多数疏水性治疗性抗癌药物的有效生物相容性递送系统的有限可用性。提高药物的水溶性是特别重要的，因为药物在水性介质中的低溶解度阻碍了药物通过静脉内途径给药的能力。由于许多重要的抗癌剂具有较差的水溶性，因此开发不使用有机溶剂的这些分子的新型递送系统受到了极大的关注。纳米粒子提供了巨大的潜力和有前途的方法来将治疗剂递送到靶向器官或细胞中，并且它们已经被积极开发用于癌症治疗。[1，2]我们已经将代表性的疏水性抗癌药物喜树碱（CPT）掺入荧光介孔二氧化硅纳米颗粒（FMSN）的孔中，并将药物递送到各种人类癌细胞中以诱导细胞死亡，这一过程表明介孔二氧化硅纳米颗粒可用作克服许多抗癌药物不溶性问题的载体。CPT及其衍生物被认为是世纪最有前途的抗癌药物之一。[3]虽然研究已经证明了它们对胃癌，[4]结肠癌，[5]颈癌，[6]和膀胱癌，[7]以及乳腺癌[8]和小细胞肺癌[9]和白血病[10]的有效性，但CPT在人体中的临床应用迄今尚未实现，因为药物的水溶性差需要改变理化特性。由于需要配制CPT的水溶性盐（即用于静脉注射的碱性溶液），导致分子发生化学修饰，抗ACHTUNGTRENNUNG肿瘤活性丧失，药物毒理学特征发生显著变化。[10-13]虽然衍生物如伊立替康已经产生了良好的临床效果，[14]伊立替康对癌细胞的细胞毒性远低于CPT（10%），CPT仍然是最有效的化合物。[15]在各种药物递送系统中，介孔二氧化硅材料[16]具有用于递送水不溶性药物的几个有吸引力的特征。这些颗粒具有大的表面积和多孔的内部，可以用作储存疏水药物的储库。可以定制孔径和环境以选择性地储存不同的目标分子，[17，18]同时可以调整颗粒的大小和形状以最大化细胞摄取。与基于聚合物的纳米颗粒不同，这些坚固的无机材料可以耐受许多有机溶剂。[19]硅基材料已成功地用作药物递送载体，[20，21]基因转染试剂，[22]细胞标记物，[23]和分子载体。[24]在这里，我们描述了在水溶液中高度稳定的荧光介孔二氧化硅纳米颗粒的制备及其用于递送疏水性抗癌药物CPT的用途。FMSNs的制备通过使用碱催化的溶胶-凝胶过程中在高温下与修改公布的程序。[23在典型的合成中，首先用3-氨丙基三乙氧基硅烷（APTS）在乙醇中处理异硫氰酸荧光素（FITC）。然后在80 ℃下将混合物与原硅酸四乙酯沿着加入到十六烷基三-ACHTUNGTRENNUNG甲基溴化铵溶液中。通过将纳米颗粒浸泡在酸性甲醇中从孔中除去表面活性剂，其成功通过傅里叶变换红外光谱法（FTIR;参见支持信息...
A critical obstacle and challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. It is particularly important to improve the aqueous solubility of drugs, as low drug solubility in aqueous media hampers the ability of drugs to be administered through the intravenous route. Since many important anticancer agents have poor water solubility, the development of novel delivery systems for these molecules without the use of organic solvents has received significant attention. Nanoparticles offer great potential and a promising approach to deliver therapeutic agents into targeted organs or cells and they have been actively developed for application in cancer therapy.[1, 2] We have incorporated a representative hydrophobic anticancer drug, camptothecin (CPT), into the pores of fluorescent mesoporous silica nanoparticles (FMSNs) and delivered the drug into a variety of human cancer cells to induce cell death, a procedure suggesting that the mesoporous silica nanoparticles might be used as a vehicle to overcome the insolubility problem of many anticancer drugs. CPT and its derivatives are considered to be among the most promising anticancer drugs of the 21st century.[3] Although studies have demonstrated their effectiveness against carcinomas of the stomach,[4] colon,[5] neck,[6] and bladder,[7] as well as breast [8] and small-cell lung cancers,[9] and leukemia,[10] in vitro, clinical application of CPT in humans has not been achieved to date because the poor water solubility of the drug requires changes to the physicochemical characteristics. The need to formulate water-soluble salts of CPT (that is, alkaline solutions for intravenous injections) led to chemical modifications of the molecule with loss of anti-ACHTUNGTRENNUNGtumor activity and significant alterations in the toxicological profile of the drug.[10–13] Although derivatives such as irinotecan have produced good clinical results,[14] irinotecan was shown to have far lower cytotoxicity to cancer cells than CPT (10%), and CPT remains the most potent compound.[15]Among a variety of drug-delivery systems, mesoporous silica materials [16] have several attractive features for use in the delivery of water-insoluble drugs. These particles have large surface areas and porous interiors that can be used as reservoirs for storing hydrophobic drugs. The pore size and environment can be tailored to selectively store different molecules of interest,[17, 18] while the size and shape of the particles can be tuned to maximize cellular uptake. Unlike polymer-based nanoparticles, these robust inorganic materials can tolerate many organic solvents.[19] Silica-based materials have been successfully used as drug-delivery vectors,[20, 21] gene transfection reagents,[22] cell markers,[23] and carriers of molecules.[24] Here, we describe the preparation of fluorescent mesoporous silica nanoparticles that are highly stable in aqueous solution and their use for the delivery of the hydrophobic anticancer drug CPT. The FMSNs were prepared by using a base-catalyzed sol–gel process at high temperature with a modification of published procedures.[23, 25, 26] In a typical synthesis, fluorescein isothiocyanate (FITC) was first treated with 3-aminopropyltriethoxysilane (APTS) in ethanol. The mixture was then added, along with tetraethylorthosilicate, to cetyltri-ACHTUNGTRENNUNGmethylammonium bromide solution at 808C. The surfactants were removed from the pores by refluxing the nanoparticles in acidic methanol, the success of which was confirmed by Fourier transform infrared spectroscopy (FTIR; see Supporting Information …