Synthesis of pore expanded silica nanoparticles and their applications for the delivery of biomolecular drugs

Abstract

Nanotechnology has been utilized to overcome the existing problem in biomedical area. Various nanomaterials have been investigated for the enhanced therapeutic effect with reduced side effect and accurate diagnosis with the non-invasive imaging technique. However there are several prerequisites to translocate the developed material into clinical applications such as synthetic reproducibility, easiness in large scale synthesis and surface modification, biocompatibility, and cost-effectiveness. In this respect, mesoporous silica nanoparticles (MSN) have attracted lots of interests due to their biocompatibility, synthet-ic advantages, robust structure under modification and storage, easiness in surface modification, cost effec-tiveness, and tunable particle size. In addition, the porosity enables the smart delivery of drugs to the target-ed site, which is the major goal of drug delivery system. Modulating the opening and closing the gate in the external or internal stimuli responsive manner allows the spatio-temporal control of the drug releases. However the conventionally synthesized MSN has been mainly utilized for the small molecular drug delivery due to the pore size limitation. Even though there has been growing interests in biomolecular drugs such as DNA, siRNA, and protein for the treatment of incurable disease, their stability in the blood circulation has limited the therapeutic efficacy in vivo. Hence we investigated the facile synthesis of MSNs possessing ultra large pore and utilized them for the application in the delivery of biomolecular drugs. Firstly, the synthesis of MSN possessing ultra large pore was successfully done through facile and scalable procedure by the treatment of TMB (trimethylbenzene). Using the prepared particle, the gene delivery effi-ciency was investigated in vitro and in vivo to develop the cancer therapeutics based on RNAi. It is demon-strated that our materials could deliver siRNA molecules inside cells and induce the remarkable knockdown of target gene in the sequence specific manner in the cell level as well as tumor xenograft model. In addition, pore sizes were tuned to develop the transfection tool eliciting optimal knockdown. It seemed that pore size influenced on the protection of loaded cargo from being degraded by the presence of nuclease and maxi-mum knockdown time point. Secondly, it is demonstrated that MSN possessing ultra large pore could serve as an efficient protein delivery vehicle for the intracellular delivery of various types of proteins. Proteins vary in sizes and surface property, thus the universal protein delivery vehicle is not commercially available on the contrary to gene transfection agent. Our material showed significant efficiency in intracellular delivery of various types of proteins in terms of various sizes and pI values. Thirdly, multifunctional nanoparticle was developed based MSN possessing large pore enabling the simulta-neous therapy and diagnosis. The synthesized particle showed considerable gene knockdown efficiency. In addition, it was also carried out the successful imaging in both MRI and fluorescence imaging. In summary, it is demonstrated MSN possessing ultra large pore could serve as not only a useful tool for the intracellular delivery of biomolecular drugs but also a potential imaging modality.