Dual cavity baskets as nano antidotes for overdose with fentanyl and its derivatives

项目摘要/摘要 非法使用合成阿片类药物的情况正在上升，按过量服药数量计算，俄亥俄州在全国排名第二 死亡。在这方面，芬太尼是一种容易获得和有效的止痛剂，自2000年以来一直在临床使用 20世纪60年代。由于易于生产和衍生化，这类药物一直是滥用的对象 它们与海洛因混合，导致服药过量。此外，卡芬太尼以气雾剂的形式用于 莫斯科恐怖袭击(2002年)，造成人员死亡。生产的各种芬太尼衍生物 秘密实验室(主要在中国)并分发给非法使用或可供恐怖分子使用的，有一个直接的 需要开发一种有效的、容易获得的解毒剂，并且(A)没有副作用或副作用最小，(B)容易 实施(注入)、(C)迅速启动行动和(D)更长时间的保护。事实上，纳洛酮作为一种 有效的拮抗剂能逆转过量用药的效果，但由于其清除速度快，只能提供短期的 保护。由于过量的亲脂性芬太尼分布在组织中，其缓慢释放到血液中导致 再矿化。为了解决这个问题以及副作用，我们在此建议调查对 芬太尼及其衍生物使用双腔篮子组装成纳米粒(即纳米解毒剂)。双人- 我们实验室开发的空心篮由两个相连的杯状框架组成，共享 同样的“底板”，每个杯子的末端有三个氨基酸或聚乙二醇酸。重要的是，多价篮子 三元络合物以正变构方式捕获两个抗癌蒽环类药物 组装成大约100纳米的纳米颗粒。这些有机纳米颗粒对HeLa细胞和 在生理pH的PBS中热力学稳定。篮子很容易拿到，而且容易快速 为了实现多样化，我们在此提出了一种策略，使它们具有生物相容基团(氨基酸， 多肽和聚乙二醇酸)，以便它们以纳米颗粒的形式捕获阳性芬太尼及其同系物 变构方式。通过形成稳定的纳米颗粒/药物组件，药物在体内的浓度 血流应该下降，导致浓度的负梯度，因此从中枢神经系统中清除 还有纸巾。通过化学修饰，纳米颗粒的循环时间将调整为24小时，以允许 建议的药代动力学作用模式。以确定篮子宿主具有强大的变构能力 复合芬太尼，我们将使用计算化学的工具来选择实验研究的候选者。 从SARS开始，我们将制定有效识别PBS、血清和血液中芬太尼的基本规则。 建立对芬太尼及其衍生物的有效识别的基础理解 竞争介质中的模块化非生物宿主将为研究合作纳米解毒剂及其 活体内行动。这两个团队在科学专长方面具有互补性(超分子化学和 生物医学)，位于同一座大楼内，有开发用于隔离/水解的分子的历史 神经毒剂。

PROJECT SUMMARY/ABSTRACT The illicit use of synthetic opioids is on the rise, with Ohio being second in the nation per number of overdose deaths. In this regard, fentanyl is an easily accessible and potent analgesic that has been used in the clinic since the 1960s. With facile production and derivatization, this class of drugs has been a subject of abuse in which they are mixed with heroin to lead to overdose. Moreover, carfentanil was in the form of aerosol used in the terrorist attack in Moscow (2002) resulting in fatalities. With a variety of fentanyl derivatives produced in clandestine labs (mostly in China) and distributed for illicit use or available to terrorists, there is an immediate need for developing effective an easily accessible antidote with (a) no or minimal side effects, (b) easy implementation (injection), (c) rapid onset of action and (d) longer protection. Indeed, naloxone acts as an effective antagonist to reverse the effect of overdose but due to its rapid clearance it only provides a short-term protection. As the excess of lipophilic fentanyl distributes in tissues, its slow release into the bloodstream causes renarcotization. To address the issue as well as side effects, we hereby propose investigating the recognition of fentanyl and its derivatives using dual-cavity baskets assembled into nanoparticles (i.e., nano-antidotes). Dual- cavity baskets were developed in our labs to consist of two conjoined and cup-shaped frameworks sharing the same “floor” with each cup having three amino acids or PEG acids at its terminus. Importantly, polyvalent baskets trapped two molecules of anticancer anthracyclines in the positive allosteric fashion with ternary complexes assembling into circa 100 nm nanoparticles. These organic nanoparticles were nontoxic to HeLa cells and thermodynamically stable in PBS at physiological pH. With baskets being easily accessible and prone to rapid diversification, we hereby propose a strategy to functionalize them with biocompatible groups (amino acids, peptides and PEG acids) so that they, in the form of nanoparticles, trap fentanyl and its congeners in the positive allosteric manner. By forming stable nanoparticle/drug assemblies, the concentration of the drug in the bloodstream should drop causing a negative gradient in the concentration and therefore its removal from CNS and tissues. The circulation time of nanoparticles will, via chemical modifications, be tuned to be >24 h to permit the proposed pharmacokinetic mode of action. To identify basket hosts capable of strongly and allosterically complexing fentanyl, we will use tools of computational chemistry for selecting candidates for experimental study. From SARs, we will develop basic rules pertaining the effective recognition of fentanyls in PBS, serum and blood. Developing a fundamental understanding of the effective recognition of fentanyl and its derivatives with a modular abiotic host in competitive media will set the stage for studying cooperative nano-antidotes and their action in vivo. The two teams are complementary in scientific expertise (supramolecular chemistry and biomedicine), located in the same building with a history of developing molecules for the sequestration/hydrolysis of nerve agents.