Doctor of Philosophy (PhD)
Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. In vitro studies showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes, and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells similar to HCQ. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the invasion of PC cells when compared with HCQ. No significant HCQ release from CQ-HES was observed, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Pharmacokinetic (PK) studies showed that CQ-HES preferentially distributed to the liver and kidney but had limited ability to alter distribution to tumors. Furthermore, levels observed in the eyes were 2-4 times higher when administering HCQ than CQ-HES. In an orthotopic syngeneic model of PC, the addition of CQ-HES to gemcitabine therapy reduced primary tumor growth and prolonged survival. Additionally, mice who received HCQ showed significantly higher levels of HCQ in the eyes compared to CQ-HES. Complete blood count and complete metabolic profiles did not identify any organ or tissue dysfunctions in mice receiving CQ-HES. Further pathohistological analysis confirmed the safety of CQ-HES as no microscopic indications of augmented tissue damage were observed. Lastly, pretreatment sensitization with CQ-HES improved survival in the setting of stereotactic body radiation therapy. Thus, CQ-HES appears to be safe, improves outcomes of radiation and chemotherapy, and reduces HCQ exposure to the eye, which may help prevent retinopathy.
Sleightholm, Richard, "Polymeric Chloroquine: Modifying an Old Drug to Make It a Little Sweeter" (2019). Theses & Dissertations. 346.
Available for download on Friday, April 16, 2021