Rational Design of Lipidic Vectors for Mitochondria-Targeted Antioxidants

描述(由申请人提供)：药物发现是一个昂贵且低效的过程。许多从初步筛查中发现的有希望的命中结果往往被排除在进一步调查之外 由于其较差的水溶性和/或较低的生物利用度。在药物发现过程中早期纳入药物配方专业知识是促进对水溶性较差的有前途的候选药物进行临床前和临床评估的重要战略。JP4-039和XJB5-131是一种稳定的氮氧化物(4-氨基-TEMPO)抗氧化剂，与革兰菌素S衍生的多肽片段结合，以促进它们在线粒体中的富集性。这些新化合物的治疗作用已在大鼠失血性休克模型和小鼠各种辐射模型中得到广泛验证。这些化合物进入临床应用的主要障碍之一是它们较差的水溶性。过去，为了评估它们的体内活性，必须使用有机溶剂，如乙醇、DMSO、Cremphor EL/乙醇。我们最初开发了一种基于乳剂的配方，可用于以下两种系统(I.P.和静脉注射)或局部(皮肤)应用。然而，JP4-039乳剂配方相对不稳定。随着时间的推移，药物会慢慢从颗粒中解离。药物载药量低和配方不稳定是配制中等疏水性药剂的常见问题，主要是由于疏水性不足的药剂与表面活性剂和乳剂油芯中的高亲油脂肪链混合不充分所致。最初与油核混合的药物倾向于慢慢移动到乳化液颗粒的界面，最终与颗粒分离。我们假设，通过使用一种新型表面活性剂，在亲水性聚乙二醇酯和亲脂性锚点之间具有内置的药物相互作用结构域，可以有效地将难于溶于水和适度疏水的药物并入乳剂或胶束配方中。JP4-039将被用作模型药物来检验这一假说。这个项目将追求三个目标。在目标1中，我们将合成和表征一些具有不同相互作用结构域的聚乙二醇脂多肽，以确定JP4-039胶束形成的最佳结构。在目标2中，我们将研究JP4-039胶束的体内药代动力学和生物分布。目的3研究JP4-039胶束对小鼠放射性休克和失血性休克的治疗作用。这项研究的成功完成将导致开发一种新的策略，不仅将促进JP4-039的体内应用，还将促进许多其他难于溶于水且难以用现有脂质体系配制的疗法的应用

DESCRIPTION (provided by applicant): Drug discovery is a costly and inefficient process. Many promising hits identified from initial screening are often excluded from further investigation due to their poor water solubility and/or low bioavailability. Incorporating drug formulation expertise early in the drug discovery process represents an important strategy to facilitate preclinical and clinical evaluations of promising candidates that are poorly water soluble. JP4-039 and XJB5- 131 are stable nitroxide (4-amino-TEMPO) antioxidants conjugated to a peptide fragment derived from gramicidin S to facilitate their enrichment in mitochondria. Therapeutic effects of these novel compounds have been extensively demonstrated in rat hemorrhagic shock model and various radiation models in mice. One of the major hurdles for these compounds to advance into clinical applications is their poor water solubility. Organic solvents such as ethanol, DMSO, Cremophor EL/ethanol had to be used in the past for the assessment of their in vivo activity. We initially developed an emulsion-based formulation that could be used for either systemic (i.p. and i.v.) or topical (skin) application. However JP4-039-loaded emulsion formulation is relatively unstable. The drug is slowly disassociated from the particles over time. Low drug loading capacity and formulation instability are common problems in formulating agents that are moderately hydrophobic, mostly due to inadequate mixing of the insufficiently hydrophobic agents with the highly lipophilic aliphatic chains in surfactants and oil core of emulsions. Drugs that are initially mixed with oil core tend to slowly move to the interface of emulsion particles and eventually are disassociated from the particles. We hypothesize that drugs that are poorly water soluble and moderately hydrophobic can be effectively incorporated into emulsion or micellar formulations via the use of a novel surfactant that has a built-in drug-interactive domain between the hydrophilic PEG and the lipophilic anchor. JP4-039 will be used as a model drug to test the hypothesis. Three aims will be pursued in this project. In Aim 1, we will synthesize and characterize a number of PEG-lipopeptides with various interactive domains to identify the optimal structure for micellar formulation of JP4-039. In Aim 2, we will examine the in vivo pharmacokinetics and biodistribution of JP4-039- loaded micelles. In Aim 3, we will investigate the therapeutic efficacy of JP4-039-loaded micelles in mouse models of irradiation and hemorrhagic shock. Successful completion of this study will lead to the development of a new strategy that will facilitate the in vivo application of not only JP4-039 but also many other therapeutics that are poorly water soluble and difficult to formulate with existing lipidic systems