An anticancer drug delivery system based on surfactant-templated mesoporous silica nanoparticles

Abstract

Three types of surfactant-templated mesoporous silica nanoparticles (Surf@MSNs) of 150–660 nm in diameter were developed as anticancer drug delivery systems. The Surf@MSNs exhibit the high drug (surfactant) loading capacities, the sustained drug (surfactant) release profiles and the high and long-term anticancer efficacy. The effects of the Surf@MSNs concentration, the type of the contained surfactants and the incubation time on the cytotoxicity and proliferative activity of MCF-7 cells were evaluated. A common anticancer drug CPT-11 was also loaded into surfactant-free MSNs (CPT@MSNs) and used as a reference for estimating the anticancer efficacies of Surf@MSNs. Surfactant-extracted MSNs exhibited neglectable cytotoxicity to MCF-7 cell, and free surfactants exhibited higher cytotoxicity than free CPT-11 at the same concentration. The endocytosis enhanced the drug uptake by MCF-7 cells and the anticancer efficacies of Surf@MSNs and CPT@MSNs, and more surfactants would be released in a longer term, which led to the more significant enhancement of the cytotoxicity, than CPT-11 with the process of incubation. Among the investigated Surf@MSNs, CTAB-contained MSNs (CTAB@MSNs) show remarkably higher long-term anticancer efficacy than CPT-11-loaded surfactant-free MSNs (CPT@MSNs), even at very low concentrations of 2–15 μg mL⁻¹.

Introduction

Surfactants are widely used in detergents, household cleaning products and in the food, mining, oil and textile industries. Most surfactants are cytotoxic because they are able to damage biological membranes and induce the release of intracellular enzymes [1], [2]. Generally, the cytotoxicity of the different types of surfactants was in an order of cationic > anionic > nonionic [3]. Triton X-100, a common nonionic surfactant, is slightly toxic but severely irritative [4], [5]. However, cationic surfactant CTAB is a known component of the broad-spectrum antiseptic and antibiotic cetrimide used as a tumoricidal irritant in colorectal cancer surgery and a scolicidal adjunct to hydatid cyst operations [6]. CTAB has demonstrated anticancer properties in vitro and in vivo by targeting tumor mitochondria [7], [8], [9], and quaternary ammonium derivatives have also been reported to show enhanced anticancer activity compared to their parent compounds [10], [11]. Very recently, Emma Ito and his co-workers have identified pure CTAB as a potential cancer-specific compound against head and neck cancer (HNC) cell lines with the minimal cytotoxicity against normal fibroblasts [12]. However, the existing reports on the cytotoxicity of surfactants were commonly based on free surfactants, the role of various surfactants in porous nanoparticles-mediated anticancer and tumoricidal activities has not been investigated extensively.

It is well known that mesoporous silica nanoparticles (MSNs) possess some excellent properties such as facile multifunctionalization, excellent biocompatibility and biodegradability, high specific surface area and pore volume, tunable pore structures and excellent physicochemical stability [13], [14], [15], [16]. Recently, it was found that PEGylated MSNs had good blood compatibility as they demonstrated minimized nonspecific binding to human serum protein (HSA), the phagocytosis of THP-1 macrophages and the hemolysis of human red blood cells (HRBCs) [17]. It was also revealed that MSNs could be effectively endocytosed, which mainly depended on their particle sizes [18], [19]. Also, MSNs are universally addressed as a major candidate for use as carriers in controlled drug delivery systems (DDSs), and in these cases, drug molecules must be loaded into MSNs after the removal of the surfactant template from the pore channel systems [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. In addition, most conventional anticancer drugs including irinotecan hydrochloride trihydrate (CPT-11), cisplatin (CDDP), taxotere (TXT), taxol (TAX), navcelbine (NVB), doxorubicin (ADM), fluorouracil (5-Fu) and methotrexate (MTX), are very expensive, while most common surfactants are very cheap and easy to be used as structure-directing agents (SDAs) to synthesize MSNs. Therefore, the development of new low-cost anticancer DDSs integrating porous nanoparticles like MSNs with various cheap surfactants like CTAB would be of great significance.

Recently, it was found both gold nanorod and mesoporous silica nanoparticles, which were synthesized by using CTAB as a structure-directing agent (SDA), displayed remarkable cytotoxicity against carcinoma cells [18], [35]. Their cytotoxicity were found to be mainly resulted from CTAB absorbed on their surface rather than nanomaterials themselves. In view of biosafety, CTAB had been either replaced with charged polyelectrolytes poly(alliamine hydrochloride) and poly(acrylic acid, sodium salt), or removed by extraction or calcination treatments. However in this work, surfactants reserved within pore channels as active drugs were expected to release chronically and steadily from MSNs, which was resulted from the physical attraction between surfactants and MSNs owing to liquid-crystal templating and cooperative self-assembly mechanisms for the formation of ordered mesoporous silica. Therefore, the as-synthesized surfactant-templated MSNs (Surf@MSNs) were investigated as a low-cost anticancer DDSs of high drug (surfactant) loading capacity, a sustained drug (surfactant) release profile, an enhanced MSNs-mediated endocytosis by cancer cells and a high anticancer efficacy.