Drug delivery system composed of mesoporous silica and hollow mesoporous silica nanospheres for chemotherapeutic drug delivery

Abstract

Mesoporous silica nanoparticles (MSN) and hollow mesoporous silica nanoparticles (HMSN) of the size of ∼200 nm have been synthesized from iron silicate via selective etching of iron oxide and were used to deliver a prominent anticancer drug doxorubicin under external stimuli. The facile synthesis of MSN and HMSN involves synthesis of iron silicate coated by iron oxide and silica in a layer by layer (LbL) fashion followed by selective etching of iron oxide under mild conation. Among all the particles, HMSN has less surface area (100 m²/g) and larger pore size (4.62 nm). We demonstrated that both MSN and HMSN release the drug over a period of 4 h under external stimuli (acidic pH). The release profile reveals that HMSN release comparatively less amount of drug as compared to MSN. This could be attributed to the larger pore volume (0.52 cc/g) of MSN as compared to HMSN (0.20 cc/g). The particles neither show any cytotoxicity towards the HeLa cells up to 350 μg/ml nor any morphological change to the nucleus of the cells. The cytotoxicity value was much higher compared to the literature reports on MSN. This implies a better biocompatibility of the particles prepared through this methodology.

Introduction

Controlled and site specific delivery along with zero premature releases are the essential conditions for a drug delivery system of chemotherapeutic drugs ((e.g. Taxol, Doxorubicin, Camptothecin etc.) as they are very toxic to the healthy cells [1]. To achieve this goal several drug delivery systems (liposomes, polymer capsules, hydrogels, nanogels, nanoparticles etc) have been discovered in the last few decades and already been approved by FDA [2,3]. Recently, mesostructured materials have attracted the scientists due to their various interesting properties including high surface area, porous structure, tunable pore size, thermal stability etc. for the loading and delivery of chemotherapeutics in a controlled manner under external stimuli [[4], [5], [6]].

The last few years have witnessed tremendous development in the design and synthesis of hollow and micro/nanostructured materials and their application in various fields [7,8].Among various hollow and micro/mesostructured materials mesoporous silica nanoparticles (MSN) [9]gained substantial attention from chemists and biologists because of their low toxicity, high biocompatibility, uniform mesopores, easy drug loading, high loading capacity, and ability to release the encapsulated guest under different external stimuli [[10], [11], [12], [13]].Due to theenormous applications of MSN, various synthetic routes have been discovered during the last few years for the synthesis of mesoporous silica with different morphologies and controllable pore size [[14], [15], [16], [17]]. Out of all methodologies two traditionally and most widely used preparation methods of MSN are soft template and hard template methods [18,19].

In case of soft template method; templating agents such as vesicles, emulsion (e.g. oil in water, air in water), polymer micelles are used [[20], [21], [22]].This method involves some complex chemical steps. It is difficult to maintain the uniform size distribution, shell thickness, core size, of the prepared MSN due to the low stability and poor uniformity of the soft templates in solution [[20], [21], [22]].To overcome these problems, another approach was developed which is known as hard templating methods [[23], [24], [25]]. In this case, a sacrificial hard template is used. Mesoporous silica is formed around the template followed by removal of the core. Generally inorganic or polymeric beads are used as sacrificial templates in this method. Although this method can produce MSN but it is difficult to prepare the sacrificial template. The removal of the template is also multistep procedure and need more time [[23], [24], [25]].

Although various procedures have been developed throughout the years for the etching of the template core, selective etching of the template core remains one of the favorite methods to the chemist [26]. In this method, a specific portion is selectively etched by the application of acidic/basic solution or by calcinations [26]. Recently, cationic surfactant assisted selective etching using cetyltrimethyl ammonium bromide (CTAB) have been developed by Zheng and co-workers to prepare MSN [27]. Besides hard template and soft template approaches, there are some other methods by which mesoporous silica can be prepared. A wet chemical based route was developed by Yu and coworkers to prepare hollow silica spheres [28]. RuisongGuo and co-workers have prepared hollow mesoporous silica using a cationic surfactant cetyltrimethylammonium chloride (CTAC) [29]. Hollow mesoporous silica spheres were also prepared under hydrothermal treatment using acidic conditions by Wang and coworkers [30].A sol-gel route followed by distillation-precipitation polymerization was employed to prepare a core shell anatasetitania/hollow silica spheres where hollow silica spheres were shell and anatasetitania act as a core [31].A one pot synthetic route was also applied by Binyang Du and coworkers [32]to prepare hollow silica spheres using thermo responsive polymer.

Although several routes have been discovered through several years by various groups but still new routes which will be more straightforward, more economical and easily scalable to the industrial level so that it can be employed for practical application are necessary for the synthesis of MSN and HMSN.

Keeping all these in mind, herein, we report a straightforward and a simple procedure for the synthesis of mesoporous silica and hollow mesoporous silica from mesoporous iron silicate via selective etching of the core under acidic conditions (Scheme 1). Recently mesoporous zinc silicate has been prepared by Kangtaek Lee and co-workers [33] by using well known layer by layer technology. We adopted this methodology with slight modification [33].First, we prepared iron silicate and a simple acid treatment etched iron oxide selectively and produced mesoporous silica (MSN). The size of the synthesized mesoporous silica was around 200 nm with pore diameter of 3.6–4.2 nm. Then we coated this iron silicate by iron oxide followed by silica using a layer by layer (LbL) technique [34].Due to the wide range of material choice, simple methodology, versatility, LbL method becomes one of the prominent technology for coating [[35], [36], [37], [38]]. After the coating, hollow mesoporous silicananospheres (HMSN) were prepared by acid treatment which selectively etched iron oxide. The size of the hollow mesoporous silica was 200–300 nm with pore diameter of 3.6–4.6 nm. We explored these as delivery system of a prominent anticancer drug doxorubicin which is one kind of anthracyclin antibiotic extensively used for the treatment of solid tumors, breast, prostate, uterus, ovary, stomach, and liver tumors [39].We have shown the release of the drug from MSN and HMSNunder external stimuli (pH).

We have also studied the cytotoxicity and cellular uptake of the prepared MSN and HMSN. It has been found that MSNand HMSN, prepared by this method shows good biocompatibility and can release the drug over a period of 4 h. Overall this manuscript describes a new facile method to prepare mesoporous silica and hollow mesoporous silica and their application in chemotherapeutic delivery. We hope this study will help further in the future development of preparation of MSN and HMS and their application as drug delivery vehicles.