Chemical Methods for Ferrous Iron Dependent Drug Delivery

描述(申请人提供)：消化血红蛋白的寄生虫，包括疟疾寄生虫恶性疟原虫和间日疟原虫，会产生大量的游离亚铁血红素，这是由于寄生虫分解血红蛋白而形成的。这些铁的活性形式为铁(II)靶向药物输送提供了机会，因为它是免费的 亚铁的形态在健康的组织和细胞中极为罕见。我们已经开发并在动物身上验证了一种铁(II)靶向药物输送技术，用于将治疗药物输送到疟疾寄生虫，或者更一般地，输送到任何含有游离亚铁的生物舱。药物递送策略在抗寄生虫治疗中很少被研究，但这些方法有可能选择性地针对寄生虫，保护患者免受活性药物种类的影响，并可能允许更广泛的治疗药物的安全使用。我们的给药系统由一个1，2，4-三氧杂环己烷环系统组成，作为铁(II)敏感的“触发器”部分和一个“无痕迹”连接物，伙伴药物连接到该连接物上，并通过？消除反应最终释放。化学设计是这样的，原则上可以使用该方法从大范围的化学和治疗靶区输送药物。在前期工作中，我们合成了原型递送系统，并在感染的小鼠中展示了半胱氨酸抑制剂对伯氏疟原虫铁(II)依赖性和寄生虫选择性的递送。这项拟议研究的目标是在动物身上评估新一代更类似药物的给药系统，并确定最适合这种新的抗疟疾治疗方法的伙伴药物种类。

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.