The Use of Macrophages as Targeted Drug Delivery Vehicles
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Evans, Michael A.
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CitationEvans, Michael A. 2019. The Use of Macrophages as Targeted Drug Delivery Vehicles. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractDrug delivery research for cancer relies heavily on nanotechnology. However, nanotechnology has several problems, which have hindered its clinical translation. In an attempt to find solutions, scientists have begun to study the use of circulatory cells as carriers for drugs. In particular, macrophages have garnered much attention due to their ability to deliver large amounts of drugs deep into tumors. In this work, I utilize macrophages as delivery vehicles for hypoxia-activated prodrugs (HAPs). HAPs have tremendous clinical potential due to their selective toxicity towards poorly oxygenated tissues, which is a hallmark of solid tumors. However, despite their promising results in vitro, this class of drugs has failed to make a clinical impact. This is largely because tumor hypoxia is located far from blood vessels, making it difficult for these drugs to reach in therapeutically sufficient concentrations. Here, we report a generalized strategy to overcome this barrier by employing macrophages as drug carriers to enhance the penetration and accumulation of HAPs deep in solid tumors. Our system leverages nanoparticles that encapsulate a model HAP, tirapazamine (TPZ), and macrophages to phagocytose and transport those nanoparticles into hypoxic regions of solid tumors. We use a sequence of in vitro assays to refine the properties of the TPZ-containing nanoparticles and minimize carrier cell toxicity while maximizing their therapeutic efficacy. We demonstrate in vivo that our system improves drug accumulation in hypoxic areas of triple negative breast tumor models and slows their growth by itself and in combination with irinotecan. Our results provide early evidence that macrophages can significantly improve the transport and efficacy of hypoxic prodrugs by improving their tumor penetration, highlighting a potential strategy to advance other hypoxia selective drugs into the clinic.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42013072
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