Novel Transport and Activation Strategy to Improve the Bioavailability of Targeted Prodrugs

提高靶向前药生物利用度的新型转运和激活策略

基本信息

批准号：
9273586
负责人：
GORDON L AMIDON
金额：
$ 42.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273586
关键词：
Address Affinity Amides Amino Acids Animal Model Animals Antineoplastic Agents Applications Grants Attention Binding Proteins Biological Availability Cancer Patient Chemicals Chemotherapy-Oncologic Procedure Coupled Development Diet Dipeptides Disease Dosage Forms Dose Drug Delivery Systems Drug Industry Drug Interactions Enzymes Esters Exhibits Health Care Costs Human In Situ Injectable Intestinal Absorption Intestines Knockout Mice Laboratories Liver Malignant Neoplasms Mass Spectrum Analysis Mediating Molecular Genetics Morbidity - disease rate Mus Oral Oral Administration Orthologous Gene Pathway interactions Patients Peptides Perfusion Permeability Pharmaceutical Preparations Process Prodrugs Property Proteins Proteomics Regulation Risk Role Serine Hydrolase Solubility Testing Therapeutic Agents Time Tissues Toxic effect Translating Viral absorption activity-based protein profiling base cancer therapy chemical property chemoproteomics drug discovery functional restoration gemcitabine humanized mouse hydrophilicity improved in vivo intestinal peptide-proton cotransporter lipophilicity member mouse model novel protein expression public health relevance small molecule species difference thioester tool trend uptake valacyclovir

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：由于缺乏适合口服给药的剂型，疾病的发病和进展变得更加繁重，这主要是因为药物的溶解度和渗透性特性不足，这对于癌症化疗尤其如此。由于最近药物发现的化学领域，注射剂型的给药具有更大的毒性风险、患者不适、使用复杂性和相关的医疗保健成本，因此口服药物递送的转运蛋白靶向策略在制药工业中尤其重要。努力正趋向于更加亲水的新化学实体，主要是因为亲脂性药物的毒性和 CYP 介导的药物间相互作用，因此，前药策略已被用来克服药物的不良物理化学性质，并提高口服生物利用度。特别是，许多研究已经解决了使用氨基酸酯前药来改善抗病毒和抗癌药物的递送，但是很少有人关注其激活过程，特别是其使用。基于活性的蛋白质分析作为识别负责水解小分子底物中酰胺、酯和硫酯键的丝氨酸水解酶（SH）的工具，显然需要新的范例来改善极性（即， BCS III 类）治疗剂，并在人体测试之前将这些发现转化为相关动物模型。因此，本次拨款申请的长期目标是开发口服给药的前药。我们的工作假设是，人源化小鼠中的 PEPT1 靶向方法与前药激活的化学蛋白质组学策略相结合，将有效产生用于口服抗癌化合物吉西他滨的新型前药。根据这一假设，提出以下具体目标：目标 1. 表征 PEPT1 人源化小鼠模型中前药伐昔洛韦的肠道通透性和口服吸收，并确定是否存在物种差异人类和小鼠 PEPT1 直向同源物之间的比较，目标 2. 使用先进的“基于活性的蛋白质分析”（ABPP）基于质谱的蛋白质组学来确定肠和肝脏中丝氨酸水解酶的前药结合蛋白表达，目标 3. 确定通过结合分子、遗传、基于活性的蛋白质分析和整体动物，研究吉西他滨前药的转运和激活途径，用于开发口服给药的癌症化合物。在人源化（和转基因）小鼠中进行的研究，拟议的研究将极大地增进我们对 hPEPT1 靶向摄取和酯前药激活的理解，以及开发新的口服化合物来治疗癌症。