Chemical Methods for Ferrous Iron Dependent Drug Delivery

二价铁依赖性药物递送的化学方法

• 批准号: 8843775
• 负责人: Adam R Renslo
• 金额: $ 39.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-29 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843775
• 关键词: Address; Animal Model; Animals; Antimalarials; Artemisinins; Biological; Blood; Catabolism; Cells; Cessation of life; Chemicals; Child; Combined Modality Therapy; Complex; Cysteine; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Effectiveness; Evaluation; Event; Exposure to; Generations; Goals; Health; Heme Iron; Hemoglobin; Histone Deacetylase Inhibitor; Homeostasis; Hour; In Situ; In Vitro; Infection; Iron; Life; Liver; Malaria; Metabolic; Methods; Morbidity - disease rate; Mus; Oral; Oxidation-Reduction; Parasites; Pathology; Pathway interactions; Patients; Peroxides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; Primaquine; Property; Reaction; Research; Resistance; Safety; Side; Staging; System; Technology; Therapeutic; Tissues; Work; analog; artemisinine; design; disease diagnosis; drug discovery; functional group; human disease; improved; in vitro activity; in vivo; inhibitor/antagonist; mortality; next generation; novel strategies; small molecule; standard of care; targeted delivery; therapeutic target

DESCRIPTION (provided by applicant): Hemoglobin-digesting parasites, including the malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free ferrous iron heme, which is formed as a result of hemoglobin catabolism by the parasite. These reactive forms of iron present an opportunity for iron(II)-targeted drug delivery, since free forms of ferrous iron are exceedingly rare in healthy tissue and cells. We have developed and validated in animals an iron(II)-targeted drug delivery technology for delivery of therapeutics to the malaria parasites, or more generally, to any biological compartment containing unbound ferrous iron. Drug delivery strategies have scarcely been investigated in anti-parasitic therapy but these approaches have the potential to target parasites selectively, protecting the patient from exposure to active drug species and possibly allowing the safe use of a broader range of therapeutics. Our delivery systems are comprised of a 1,2,4-trioxolane ring system as an iron(II)-sensing 'trigger' moiety and a 'traceless' linker to which the partner drug is attached an ultimately released via a ß-elimination reaction. The chemical design is such that drugs from a wide swath of chemical and therapeutic target space can in principle be delivered using the approach. In preliminary work, we synthesized prototypical delivery systems and demonstrated the iron(II)-dependent and parasite-selective delivery of a cysteine inhibitor to Plasmodium berghei parasites in infected mice. The goals of the proposed research are to evaluate in animals a new generation of more drug-like delivery systems, and to identify partner drug species that are optimally suited for this new approach to antimalarial therapy.

描述（由申请人提供）：血红蛋白消化寄生虫，包括疟疾寄生虫恶性疟原虫和间日疟原虫，产生显著浓度的游离亚铁血红素，其是由寄生虫催化血红蛋白形成的。这些铁的反应形式为铁（II）靶向药物递送提供了机会，因为游离的铁（II）是铁的主要来源。 在健康的组织和细胞中，亚铁的形式极其罕见。我们已经开发并在动物中验证了铁（II）靶向药物递送技术，用于将治疗剂递送至疟疾寄生虫，或更一般地，递送至含有未结合的亚铁的任何生物隔室。药物递送策略在抗寄生虫治疗中几乎没有被研究，但是这些方法具有选择性地靶向寄生虫的潜力，保护患者免于暴露于活性药物物种，并且可能允许安全使用更广泛的治疗剂。我们的递送系统由作为铁（II）敏感“触发”部分的1，2，4-三恶茂环系统和“无痕”接头组成，配偶体药物连接到该接头并最终通过α-消除反应释放。化学设计是这样的，原则上可以使用该方法递送来自广泛的化学和治疗靶向空间的药物。在初步工作中，我们合成了原型的传递系统，并证明了铁（II）依赖性和寄生虫选择性交付的半胱氨酸抑制剂的疟原虫伯氏寄生虫感染的小鼠。拟议研究的目标是在动物中评估新一代更像药物的递送系统，并确定最适合这种新的抗疟治疗方法的伙伴药物种类。