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和低效的过程。许多从初步筛选中确定的有希望的命中经常被排除在进一步的调查之外 这是由于它们的水溶性差和/或生物利用度低。在药物发现过程的早期阶段积累药物制剂专业知识是促进对水溶性差的有希望的候选药物进行临床前和临床评价的重要策略。JP 4 -039和XJB 5 - 131是稳定的氮氧（4-氨基-TEMPO）抗氧化剂，其与短杆菌肽S衍生的肽片段缀合以促进它们在线粒体中的富集。这些新化合物在大鼠失血性休克模型和各种小鼠辐射模型中的治疗作用已被广泛证实。这些化合物进入临床应用的主要障碍之一是它们的水溶性差。过去必须使用有机溶剂（如乙醇、DMSO、Cremophor EL/乙醇）评估其体内活性。我们最初开发了一种基于乳剂的制剂，其可用于全身性（i. p.和i. v.）或局部（皮肤）施用。然而，负载JP 4 -039的乳液制剂相对不稳定。随着时间的推移，药物慢慢地从颗粒中分离出来。低载药量和制剂不稳定性是配制中等疏水性的试剂的常见问题，主要是由于疏水性不足的试剂与表面活性剂和乳剂油核中高度亲脂的脂族链混合不充分。最初与油芯混合的药物倾向于缓慢移动到乳剂颗粒的界面，并最终与颗粒分离。我们假设，通过使用一种新型表面活性剂，即在亲水性PEG和亲脂性锚之间具有内置药物相互作用域的表面活性剂，可以将水溶性差且中等疏水性的药物有效地掺入乳剂或胶束制剂中。JP 4 -039将用作模型药物以检验假设。该项目将追求三个目标。在目标1中，我们将合成和表征具有各种相互作用结构域的许多PEG-脂肽，以确定JP 4 -039胶束制剂的最佳结构。在目的2中，我们将检查负载JP 4 -039的胶束的体内药代动力学和生物分布。在目的3中，我们将研究载JP 4 -039的胶束在放射和失血性休克小鼠模型中的治疗功效。该研究的成功完成将导致新策略的开发，该新策略将不仅促进JP 4 -039的体内应用，而且还促进水溶性差且难以用现有的药物系统配制的许多其它治疗剂的体内应用

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