Use of nanoparticulate drug-carriers, dosing alteration, pharmacokinetic and pharmacodynamic modeling to optimize therapy
Aljuffali, Ibrahim Abdulrahman
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The overall goals of this dissertation were to exploit differences in tumor microenvironment, develop dosing schedules to facilitate optimization of nanoparticulate drug-carriers, and use pharmacokinetic/pharmacodynamic modeling to improve therapy. Cancer represents the second leading cause of death in the US. Developing therapeutic strategies for metastatic disease can improve clinical outcomes and survival. Low-dose chemotherapeutic exposure can increase anticancer activity, but the mechanisms underlying this effect are not understood fully. Metronomic dosing is hypothesized to suppress tumor angiogenesis, however, we hypothesized that metronomic schedules could also mediate direct effects on the tumor parenchyma, further improving antitumor activity. Using in vitro and in vivo studies we demonstrated that topotecan dosed metronomically increased it’s antitumor activity. Molecular studies suggest mechanisms distinct from the established mechanism for conventional therapy. Spatial differences in tumor microenvironment can impact treatment efficacy. We found that tumor oxygenation and pH had significant effects on the anticancer activity of topotecan. Exploiting the acidic tumor microenvironment, a novel topotecan nanoparticulate drug targeting strategy was developed to improve it’s anticancer activity and reduce toxicity. A goal of drug therapy is to achieve optimal target-site exposure in vivo and reduce non-target tissue toxicity. Controlling the rate and extent of drug release from drug-carriers is one approach that can be used, but is difficult to quantify in vivo. We prepared and characterized prototype liposomes encapsulating gadolinium-DTPA, a magnetic resonance imaging probe, to determine carrier release kinetics in vivo and optimize target-site drug exposure. These studies suggest that tumor microenvironment and metronomic schedules can be exploited to improve cancer chemotherapy. Furthermore, we have developed a novel approach to quantify drug-carrier release kinetics non-invasively. Pharmacokinetic/pharmacodynamic modeling offers a computational method to describe data and develop testable hypothesis that can lead to novel treatment strategies. We determined the pharmacokinetics of ketanserin, a 5HT2-antagonist, and developed a pharmacokinetic/pharmacodynamic model to optimize its dosing in horses. The model accurately captured the plasma concentration time data and was used to predict alternate dosing schedules that could be used to treat equine laminitis. Similar approaches can be used to facilitate development of drug-carriers and optimization of dosing schedules for cancer chemotherapies.