Mesoporous silica nanoparticles (MSNs) have attracted substantial attention for their application in drug delivery and biomedicine. MSNs have been established as a promising and novel drug delivery vehicle due to their unique structural properties, such as high surface area, large pore volume, tunable pore diameter, and narrow pore size distribution. Furthermore, they provide the possibility to include various surface functions and are biocompatible. For efficient drug delivery using mesoporous silica nanocarriers, their physicochemical characteristics should be controlled to predict their behavior under physiological conditions. The surface function on the particles determines their fate in the physiological environment. Further, the surface functionalization needs to be tailored according to the cargo molecule to be delivered. In this thesis, various surface functionalization strategies of MSNs employing different polymers and lipids were utilized to fabricate novel drug delivery nanocarriers for hydrophobic and hydrophilic drugs, in order to improve the efficacy of poorly aqueous soluble drugs and to achieve sustained or triggered drug release. Adequate surface functionalizations provide colloidal stability and reduce protein adsorption on the particle surface. By the application of zwitterionic coating on the MSN surface, protein adsorption on the particle surface can be diminished. For intravenous delivery, first passive targeting (extravasation) of nanoparticles at the tumor site is required and then active targeting to cancer cells using small molecular targeting ligands can be achieved, which provides the advantage of lowering the dose and reducing the side effects imparted on healthy cells. In this thesis, MSNs were designed for active cellular targeting using glucose and folic acid as targeting ligands, and further loaded with anticancer drug molecules. Therapeutic efficacy of the drug molecules were significantly improved using MSNs compared to free drug in vitro and in vivo. For oral drug delivery, the drug molecule should be protected from degradation in the gastrointestinal (GI) tract and permeability through the mucus layer needed to be improved. In this thesis, MSNs were functionalized by polymeric surface grafts, which has facilitated drug transport through the mucosal barrier and enhanced intestinal cellular internalization. Drug targeting in different parts of the intestine could be tuned by surface modifications, and polyethylene glycosylation (PEGylation) of nanoparticles in combination with polyethylene imine (PEI) as particle surface coating enhanced the internalization of MSNs into intestinal epithelial cells. For the delivery of hydrophilic anticancer molecules after intravenous administration requires protection from non-specific uptake in healthy cells. In this thesis, hydrophilic molecules were loaded in MSNs, which were further coated with lipid bilayer for intracellular drug delivery. MSNs provided delivery to cancer cells without any observed toxicity to normal cells in vivo. The thesis reports the importance of a) surface modification needed with respect to the properties of the cargo molecules, and b) appropriate evaluation of biophysicochemical interactions of nanocarriers for their future drug delivery applications. This knowledge can facilitate the development of nanomedicines with desired properties for cancer therapy with reduced side effects.
|Tila||Julkaistu - 2016|
|OKM-julkaisutyyppi||G5 Tohtorinväitöskirja (artikkeli)|