Dendritic Cell Targeted Therapy Utilising Porous Silicon Nanoparticles for the Induction of Immunological Tolerance

Abstract

The work depicted in this thesis, explores the use of drug loaded porous silicon nanoparticles (pSiNP) targeted to dendritic cells both in vitro and in vivo. Paper one explores the in vitro application of rapamycin loaded, DC-SIGN pSiNP to induces a maturation resistant, tolerogenic state within human monocyte derived DC. Furthermore, it explores the poor stimulatory ability of these tolerogenic DC within an allogeneic immune system. The study concluded that nanoparticles functionalised with DC-SIGN antibody, were capable of tracking to human monocyte derived DC expeditiously compared to their isotype counterparts. DC-SIGN pSiNP were also able to release their payload and induce a tolerogenic state in DC in vitro. Paper two develops the work from paper one exploring the in vivo tracking capability of the nanoparticle within both murine and non-human primate animal models. Within mice, the functionalisation of the pSiNP with antibodies permitting targeting to DC (CD11c receptor) significantly enhanced their tracking abilities to splenic DC populations, compared to isotype pSiNP. Within both murine and nonhuman primate animal models, a serendipitous discovery was the enhanced kidney tracking abilities of the DC targeting pSiNP. This opens the door for the development of potentially new drug delivery methods more localised to the kidneys. Following in vivo tracking experiments, paper two explored the ability of drug and peptide loaded nanoparticle to enhance regulatory T-cell populations in vivo by targeting DC. It was concluded that the CD11c pSiNP were capable of significantly increasing the number of splenic regulatory T-cells when compared to the control animals, which did not receive pSiNP. These two papers identify a novel strategy for promoting drug delivery to a scarce cell population and the ability to promote regulatory T-cell generation in vivo without ex vivo modification of DC, which is more commonly seen today. The results show promise for future development of an enhanced drug delivery method to modify the immune system.