Date of Graduation
Doctor of Philosophy (PhD)
Progress in drug delivery approaches have not adequately translated into clinical advances in the diagnosis or treatment of inflammatory disorders (e.g., cancer). This disconnect is rooted in the inefficient delivery of imaging and therapeutic agents to the inflamed site upon systemic delivery. A multitude of biological barriers pose insurmountable obstacles limiting the ability of the agent to effectively reach and accumulate at the target site. Nanoparticles (NP) surfaced as potential vectors to encapsulate and deliver biological agents. However, even after surface decoration, NP have failed to evade biological barriers (i.e., MPS) and to accumulate at the tumor site at therapeutic dosages, resulting in toxicity to healthy organs and other side effects.
The objective of these studies was to characterize multistage nanoporous silicon particles (NSP) for the loading and release of NP, degradation, and biocompatibility. Furthermore the development of novel solutions to redirect the biodistribution of NSP by using antibodies for vascular endothelial growth factor receptor 2 (VEGFR2) to enhance vascular targeting and relying on the natural tumor tropism of mesenchymal stem cells (MSC) to achieve dynamic targeting were investigated. Briefly, successful modulation of the release kinetics was achieved by adjusting the pore size of NSP regulated by the degree of penetration. In addition, by adjusting the pore size the degradation rates of NSP were significantly increased and removal of the nucleation layer triggered premature collapse of the pores resulting in a less stable NSP. NSP failed to alter advanced cellular functions (e.g., tube formation, multi-potent differentiation) and systemic administration did not any significant trigger immune response. Functionalization with α-VEGFR2 endowed NSP with a 5-fold increase in the specificity of targeting VEGFR2 allowing for enhanced docking and stable adhesion to tumor vasculature. Incorporation of NSP within MSC conserved their innate functions, including differentiation, interaction with inflamed endothelia, and homing towards cancer and inflammatory sites. In addition, NSP loaded with nanoparticles permitted MSC to be activated remotely and carry a toxic formulation while incorporation within MSC avoided sequestration by the MPS. These delivery strategy aims to direct therapy specifically to the tumor, thereby limiting harmful exposure to healthy tissues.
drug delivery, nanotechnology, stem cell, trojan horse, active targeting