Disease morbidity and progression are made more burdensome by the lack of a suitable dosage form for oral administration, primarily because of inadequate solubility and permeability properties of the drug. This is especially true for cancer chemotherapy. As a result, injectable dosage forms are administered which has greater risks of toxicity, discomfort to the patient, complexity of use and associated health care costs. Transporter-targeting strategies for oral drug delivery are especially important in the pharmaceutical industry since the chemical space of recent drug discovery efforts is trending toward more hydrophilic new chemical entities, primarily because of the toxicity and CYP-mediated drug-drug interactions observed with lipophilic drugs. Thus, prodrug strategies have been utilized to overcome undesirable physical-chemical properties of the drug, and to improve oral bioavailability. In particular, many studies have addressed the use of amino acid ester prodrugs for the improved delivery of anti-viral and anti-cancer agents. However, little attention has focused on the activation process and, in particular, the use of activity-based protein profiling as a tool for identifying the serine hydrolases (SHs) responsible for hydrolyzing amide, ester and thioester bonds in small molecule substrates. It is clear that new paradigms are needed to improve the intestinal absorption and bioavailability of polar (i.e., BCS Class III) therapeutic agents, and to translate these findings in a relevant animal model prior to testing in humans. Thus, the long-term objectives of this grant application are to develop orally administered prodrugs that are effective in treating cancer patients. Our working hypothesis is that the PEPT1-targeted approach in humanized mice, coupled to the chemoproteomic strategy for prodrug activation, will be effective in generating novel prodrugs for oral administration of te anti-cancer compound gemcitabine. To test this hypothesis, the following specific aims are proposed:
Aim 1. To characterize the intestinal permeability and oral absorption of the prodrug valacyclovir in a mouse model humanized for PEPT1 and determine if a species difference exists between the human and mouse PEPT1 orthologs, Aim 2. To determine the prodrug binding protein expression of serine hydrolases in the intestine and liver using advanced activity based protein profiling (ABPP) mass spectrometry-based proteomics, and Aim 3. To determine the transport and activation pathways of gemcitabine prodrugs for the development of orally administrable cancer compounds. By combining molecular, genetic, activity-based protein profiling, and whole animal studies in humanized (and transgenic) mice, the proposed studies will greatly advance our understanding of hPEPT1- targeted uptake and activation of ester prodrugs and the development of new orally available compounds to treat cancer.
This project will develop orally available prodrugs for the treatment of cancer by utilizing novel protein targets for intestinal absorption followed by enzymatic activation to the active drug species.
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