Surface Protected Etching

Surface protected etching strategy consist of stabilization of the nanoparticle’s surface using a protective layer (polymer ligands), and then selective etching of the interior to form hollow/rattle type mesoporous structures (Tang et al., 2012). Hollow / Rattle-Type mesoporous silica nanoparticles are a new type of mesoporous silica nanoparticles with special morphology. Hollow / rattle-type mesoporous nanoparticles have low density and high specific area, which are ideal as new-generation drug delivery systems with high loading capacity and possibility of co-delivery of different kinds of drugs. Recently, hollow and rattle-type nanomaterials have been actively explored for enzyme immobilization and confined-space catalysis (Lou et al., 2008, Liu et al., 2011, Chen et al., 2010c).

Ren et al. have established that alkaline treatment of cationic poly- (dimethyldiallylammonium chloride) (PDDA) pre-coated mesoporous silica spheres can form hollow microcapsule silica nanoparticles. It was suggested that the hydroxyl ions penetrate through the protecting PDDA layer and attack the interior silica sphere to create dissolved silicate oligomers under ammonia.

The oligomers with negative charge tend to migrate and deposit onto the positively charged PDDA layer, which act as the scaffold for the formation of the final shell. Using this method a continuous and compact silica-PDDA complex shell is formed (Ren et al., 2005). Similarly, Zhang et al. have reported using poly (vinylpyrrolidone) (PVP) as surface protector and found that the solid silica sphere can be transferred to hollow / rattle-type structure under the treatment of NaBH4 at relatively mild temperature. The mechanism was deduced to be a spontaneous dissolution-regrowth process (Zhang et al., 2008d). Same group later reported the conversion of sol−gel obtained silica nanoparticles into porous nanoparticles and multi-shell rattle structures using PVP protection layer followed by NaOH etching (Zhang et al., 2008c). Zhang et al. have reported using surface protected etching to form of SiO2@SiO2 core shell rattle type structures.

They have used a PVP protecting layer on the surface of both core and shell in order to increase their relative stability against chemical etching. Upon reacting with etchant (NaOH), the silica between the two layers are removed, as a result the outer layer becomes a hollow shell since it is

protected by PVP. The core also maintains its original size due to the PVP protection layer on its surface. They have carried out the process at room temperature without additional templates (Zhang et al., 2010a).

Mesoporous Silica Coated Magnetite Nanoparticles for Drug Delivery

Mesoporous silica nanoparticles are promising candidate for drug delivery which can overcome the challenges in chemotherapy in a controllable and sustainable manner. They have the following advantages:

 Biocompatibility

 Large surface area and pore volume which offers pronounced potential for drug adsorption within the meso-channels

 Adjustable pore structure which allow control over drug loading and release kinetics

 Easily functionalised and modified surface which offers controlled and targeted drug delivery which in turn improves the drug therapeutic efficacy and reduces toxicity

 In combinations with magnetic nanoparticles allow simultaneous drug delivery and diagnostic imaging (Wang et al., 2015).

Table 1-4 highlight some of the recently developed mesoporous silica based drug delivery systems.

The major drawback related to mesoporous silica nanoparticles is related to the high surface density of silanol groups interacting with the red blood cell membrane’s phospholipid leading to hemolysis. Another disadvantage is related to metabolic changes induced by porous silica nanoparticles (Bharti et al., 2015, Wang et al., 2015). These negative aspects of mesoporous silica nanoparticles could be avoided by surface modifications of nanoparticles such as lipid or polymer coatings.

In this project, mesoporous silica nanoparticles prepared by both template based strategy using CTAB as a template and protected surface etching strategy with PVP as a protecting agent. The nanoparticles were tested for drug delivery systems using Mitomycin C and Doxorubicin as model drugs. The detailed synthesis method is explained in Section 2.4.

Table 1-4. A list of mesoporous silica based drug delivery systems. ref (Kim et al., 2008) (Uribe Madrid et al., 2015) (Wu et al., 2011) (Qiu et al., 2015)

results MCF7 cell line were used for cytotoxicity study and it was observed that cell viability and proliferation were notaffectedby nanoparticlesup to a concentration 350μg/ mL. High drug loading content of 954 mg/g where up to 81% ofloaded drug wasreleasedafter 72hours. For cytotoxicity study 4 cell lines of MCF7, SKOV3, MRC- 5, and IMR-90 were used and ~20% cytotoxicity after 48 hours of treatment with nanoparticles were observed. Folic acidwasused as targetingagent. Drugloading content of 180mg/g was achieved. HeLa and MCF7 cell lineswere used forcytotoxicitystudywhich showed around 20% cytotoxicity after 48 hours of treatment with 400μg/mLnanoparticles. Drug loaded nanoparticles exhibited significantly greater cytotoxicity than free drug. Sugarand pHdual-responsivebiocompatible nanoparticles were obtained. Up to 25% toxicity for 100 μg/mL after 48 hours was observed against HEK293T. 70% release was achieved after 2 hours in pH=2.

Model drug Doxorubicin Ibuprofen Docetaxel Rhodamine

size 53 and 45nm magnetite core with 15 and 22nm shell thickness 208 nm magnetite core with 15 to 40 nm shell 100 nm magnetite core with 35 nm shell 80 nm

Nanoparticle structure Mesoporous silica coated magnetite nanoparticles with PEG surface modification Mesoporous silica coated magnetite nanoparticles Rattle-type magnetic mesoporous silica, with PEG and folic acid (FA) surface modification Mesoporous silica coated magnetite nanoparticles with β-cyclodextrins on the outer surfaces surface

Table 1-4. Continued ref (Shao et al., 2015) (Chen et al., 2010a) (Chen et al., 2010d)

results Loading content was 20.7%. Very slow release was observed in pH 7.4 and 43% release was observed within 24 hours in pH 5.5. Cytotoxicity wascompared in HepG2 and HL-7702cells. Higher doxorubicin content observed in HepG2 cells cytoplasm. Free dox showed highercytotoxicity thandoxloaded nanoparticles during the first 24 hours of treatment, however after 48 hours both group showed similar cytotoxicity. The folate moiety on the surface was used as targeting moiety while the iron oxide core and fluorescent polymer shell tracked the process. Drug loading content was 105 μg/mg and DOX release was 84% after 18 h at 37 °C and more than 90% within 100 hours. Nanoparticleswere developed forsimultaneous MRI cell imaging and anticancer drug Delivery. Nanocapsules showed 20% drug loading content. The capability of the nanocapsules as MRI contrast agents was confirmed both in vitro and in vivo. The DOXloaded nanocapsules exhibitedhighercytotoxicity than free DOX after 24 and 72 hours at DOX concentrations lower than 20 µg/mL.

Model drug Doxorubicin Doxorubicin Doxorubicin

size 100 nm magnetite core with 50nm shell thickness 280 nm magnetite core and 25 nm mesoporous silica layer. ~100×200nm

Nanoparticle structure Mesoporous silica coated magnetite nanoparticles Mesoporous silica coated magnetite nanoparticles with fluorescent polymer chain and folic acid surface modification Hollow core/shell structured Mesoporous silica-magnetite nanoparticles

Table 1-4. Continued ref (Zhao et al., 2013b) (Yang et al., 2015) (Qiu et al., 2014)

results pHresponsive drug delivery systemwas developed. Drug loading contentof 32.8%wasobtained. Drug release from uncoated nanoparticles were rapid at both pH 4.5 and pH 7.4, reaching saturation at 10 hours. Fe3O4@mSiO2–HAp did not show any substantial release after an initial release of about 10% at pH 7, 81.6% release was observed at pH 4.5 within the first 10 hours. Nanoparticleswithenzyme-sensitive drugrelease were developed. Drug loading capacities of up to 2.16 ± 0.5 wt% was achieved.The in vitro release profile demonstrated that without GSH, less than 25% of drug was released. With the aid of GSH the release reached 45.16% after 4 hours and 94.89%, in about 24 hours. The cell viability was 86.14% after 24 hour incubation with 50µm/mL ofnanoparticles. Non-cancerous cellline (HUVEC) incubated with Dox loaded nanoparticles showed low dell death (~28.40%) due to the lack of GSH to enhance DOX release. Microwave-triggered drug delivery system were developed with mesoporous silicashell, magnetite coreandZnOInterlayer. Drug release was less than 14% after 10 hours stirring, which was enhanced to 85% with discontinuous microwave irradiation.

Model drug Ibuprofen Doxorubicin Etoposide (VP-16)

size 20 nm magnetite core and total particle size of 85nm 20 nm magnetite core and 20 nm shell thickness 170 nm magnetite core, 20 nm ZnO layer and 25 nm silica shell thickness

Nanoparticle structure Mesoporous silica coated magnetite nanoparticles with hydroxyapatite surface modification Mesoporous silica coated magnetite nanoparticles with disulfide gatekeepers Mesoporous silica coated magnetite nanoparticles with ZnO interlayer