Targeted delivery of bio-active molecules to mitochondria using mesoporous silica nanoparticles for anti-cancer applications

The biological applications of mesoporous silica nanoparticles (MSNPs) in drug delivery and bio-imaging applications have been developing for decades. The continuous developments in this field are achieved by virtue of the attractive properties of MSNPs such as large surface area and volume, tunable particle and pore size and easy surface functionalization. However, the conventional MSNPs based drug delivery systems are mainly focusing on delivering drug molecules to target cells. More specific delivery applications such as sub-cellular delivery based on MSNPs have not been fully investigated and developed. In choosing the target of sub-cellular delivery of MSNPs, mitochondria appear to be a good candidate. As an important organelle in almost all living cells, mitochondria have many features that make them the possible and attractive target for cancer treatment. Such features involve energy production, cellularmetabolism and apoptotic signal transduction. In view of that, my primary research focus during Ph.D study is design, fabrication and characterization of MSNP-based system in targeted delivery of anticancer drugs to mitochondria for anticancer study as well as overcoming drug resistance. In Chapter 2, in order to validate the application of MSNPs in sub-cellular delivery, we fabricated and characterized the obtained well-ordered MSNPs. By conjugating mitochondria targeting ligand, mitochondria targeted MSNPs were obtained and characterized. Doxorubicin (DOX) was loaded into MSNPs and the mitochondria targeting property was demonstrated by the co-localization study of mitochondria and fluorescent MSNPs or DOX loaded MSNPs. In addition, the anticancer effect of DOX loaded MSNPs was further investigated. After proving that the availability of MSNPs in sub-cellular drug delivery, we further chose one mitochondria specific hydrophobic anticancer drug, α-Tocopheryl Succinate (α-TOS) as payload to be delivered by MSNPs with reduced particle size. In Chapter 3, we applied α-TOS as effective mitochondria specific anticancer drug and its hydrophobicity drawback could be overcome by MSNPs. Thus, the anticancer effectiveness of α-TOS was maximized by MSNPs after targeted delivery to mitochondria. The maximized anticancer effectiveness of α-TOS was demonstrated by cytotoxicity study. In addition, the α-TOS loaded MSNPs with mitochondria targeting property also showed effectiveness in inducing programmed cell death, further validating the application potential of MSNPs in sub-cellular drug delivery. In order to broaden the biological application of mitochondria targeted MSNPs system, their application in overcoming drug resistance was further investigated. In Chapter 4, we aim to change the target site of DOX molecules intracellularly from nucleus DNAs to mitochondria DNAs (mtDNAs) to overcome DOX resistance. After targeted delivery of DOX molecule to mitochondria, such delivered DOX molecules were found to be able to induce the decrease in ATP supply and depletion of mitochondrial membrane potential, leading to the dysfunction of P-glycoprotein (P-gp) on cell membrane which is responsible for DOX efflux, and the induction of apoptosis. As such, the current research may be helpful in providing new insight in developing MSNPs in sub-cellular drug delivery and their applications in anticancer treatment including overcoming drug resistance.​Doctor of Philosophy (SPMS