| Exosomes are small endogenous lipid vehicles, 30-100 nm in diameter, derived in the endocytotic pathway, and exocytosed into the extracellular space. Exosomes are believed to facilitate extracellular communication as there is increasing evidence that exosomes can deliver functional cargo in the form of proteins, mRNA, and miRNA, to recipient cells. The primary goal of this thesis was to explore the use of tumor-derived exosomes as a drug delivery vehicle. Tumor-derived exosomes have a distinct protein and lipid composition resembling that of the cells from which they are derived, suggesting that exosomes may be uniquely suited to interact with their parent cell line as opposed to cells of various origins. To test this hypothesis we incubated tumor-derived exosomes with their parent cells and with cells derived from tissues of varying origin. While there was limited, if any, specificity of exosomes to their parent cell line, we found that exosomes associate with their cellular targets to a significantly greater extent than liposomes of a similar size. This suggests that the protein and lipid composition of exosomes facilitates exosome adherence and internalization but does not actively target the cells from which they were derived. Our second study aimed to examine the biodistribution profile of intravenously-injected tumor derived exosomes in comparison to specific liposomal formulations of similar size. Tumor-derived exosomes, PC:Chol liposomes, and liposomes made from the lipid extract of exosomes, are all rapidly removed from circulation by the liver and spleen. Analysis of the biodistribution results suggest that exosomes' unique composition does not promote extended circulation times nor accumulation in tumor tissue. Further, the rapid clearance of exosomes is likely mediated by cells of the innate immune system. The rapid clearance and limited tumor accumulation of intravenously-injected tumor-derived exosomes makes them unsuitable for tumor specific drug delivery; however, when injected intratumorally, exosomes remain associated with tumor tissue to a significantly greater extent than PC:Chol liposomes. The final chapter of this thesis was focused on developing a method by which the surface of exosomes could be chemically modified. We report a novel technique, using click chemistry, to functionalize the surface of exosomes. |
