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

双腔篮作为芬太尼及其衍生物过量服用的纳米解毒剂

• 批准号: 10369058
• 负责人: Jovica Badjic
• 金额: $ 19.41万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369058
• 关键词: Acids; Acute; Address; Aerosols; Amino Acids; Analgesics; Anesthetics; Anthracycline; Antidotes; Antineoplastic Agents; Basic Science; Binding; Biochemistry; Blood; Blood Circulation; Buffers; Caliber; Carbon; Characteristics; Chemicals; Chemistry; China; Clinic; Complex; Computing Methodologies; Detection; Doxorubicin; Drops; Drug Kinetics; Excision; Fentanyl; Floor; Goals; Hela Cells; Heroin; Hydrolysis; Injectable; Injections; Laboratories; Lead; Liver; Metabolic Clearance Rate; Modification; Molecular; Moscow; Naloxone; Ohio; Opioid; Overdose; Oxides; Peptides; Pharmaceutical Preparations; Physiological; Poisoning; Preparation; Production; Recording of previous events; Role; Serum; Structure; Terrorism; Therapeutic; Thermodynamics; Time; Tissues; Universities; Work; Xenobiotics; antagonist; anti-cancer; base; biological systems; biomaterial compatibility; carfentanil; cavitand; computational chemistry; computer studies; computerized tools; cooperative study; cytotoxicity; design; experimental study; fentanyl overdose; improved; in vivo; lipophilicity; molecular recognition; nano; nanocarrier; nanoparticle; nanoparticle drug; nanoparticulate; nerve agent; novel; opioid epidemic; organ injury; overdose death; prevent; programs; side effect; synergism; synthetic opioid; zeta potential

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.

项目摘要/摘要 合成阿片类药物的非法使用正在上升，俄亥俄州在全国过量使用人数中排名第二 死亡在这方面，芬太尼是一种容易获得的强效镇痛药，自年以来一直用于临床。 上世纪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，其中 与海洛英混在一起，导致过量吸食。此外，卡芬太尼以气雾剂的形式用于 莫斯科恐怖袭击（2002年），造成人员伤亡。生产的各种芬太尼衍生物 秘密实验室（主要在中国）和分发非法使用或提供给恐怖分子，有一个立即 需要开发一种有效的容易获得的解毒剂，其（a）没有副作用或副作用最小，（B）容易 执行（注射），（c）迅速起效和（d）更长时间的保护。事实上，纳洛酮作为一种 有效的拮抗剂，以扭转过量的影响，但由于其快速清除，它只提供了短期的 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， 再麻醉化为了解决这个问题以及副作用，我们在此建议调查对 使用组装成纳米颗粒的双腔篮的芬太尼及其衍生物（即，纳米解毒剂）。双- 在我们的实验室中开发了腔篮，由两个连接的杯形框架组成， 相同的“地板”，每个杯在其末端具有三个氨基酸或PEG酸。重要的是，多价篮 用三元配合物以正变构方式捕获两个抗癌蒽环类药物分子 组装成大约100纳米的纳米颗粒。这些有机纳米颗粒对HeLa细胞无毒， 在生理pH值的PBS中具有生物学稳定性。 多样化，我们在此提出了用生物相容性基团（氨基酸， 肽和PEG酸），使得它们以纳米颗粒的形式将芬太尼及其同系物捕获在正向环境中。 变构方式通过形成稳定的纳米颗粒/药物组装体，药物在纳米颗粒/药物组装体中的浓度可以降低。 血流应该下降，导致浓度的负梯度，因此从CNS中清除 和纸巾。纳米颗粒的循环时间将通过化学改性调整为>24小时，以允许 拟定的药代动力学作用模式。鉴定能够强烈和变构地 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SAR，我们将制定有关有效识别PBS，血清和血液中芬太尼的基本规则。 发展对芬太尼及其衍生物的有效识别的基本理解， 竞争性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 体内作用。这两个团队在科学专业知识（超分子化学和 生物医学），位于同一建筑物内，具有开发用于螯合/水解的分子的历史 神经毒剂。

项目成果

Rapid Access to Chiral and Tripodal Cavitands from β-Pinene.

• DOI: 10.1002/chem.202202416
• 发表时间: 2022-12-27
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Wang, Xiuze;Pavlovic, Radoslav Z.;Finnegan, Tyler J.;Karmakar, Pratik;Moore, Curtis E.;Badjic, Jovica D.
• 通讯作者: Badjic, Jovica D.

Molecular Recognition of Nerve Agents and Their Organophosphorus Surrogates: Toward Supramolecular Scavengers and Catalysts.

• DOI: 10.1002/chem.202101532
• 发表时间: 2021-09-20
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Finnegan TJ;Gunawardana VWL;Badjić JD
• 通讯作者: Badjić JD