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

基本信息

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
项目类别：
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

项目摘要

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，俄亥俄州每用药过量排名第二死亡人数。在这方面，芬太尼是一种易于接近且潜在的镇痛药，因为 1960年代。随着轻松的生产和衍生化，这类药物一直是虐待的主题它们与海洛因混合在一起，导致服药过量。此外，carfentanil是在使用中使用的气溶胶的形式莫斯科的恐怖袭击（2002）导致死亡。与多种芬太尼衍生物产生的秘密实验室（主要在中国），并分发供恐怖分子使用或可用于恐怖分子需要开发有效的易于访问的解毒剂，没有（a）没有或最小的副作用，（b）实施（注射），（c）行动快速发作和（d）更长的保护。确实，纳洛酮充当有效的拮抗剂可以扭转过量的效果，但由于其快速清除，它仅提供短期保护。随着组织中的亲脂性芬太尼分布过多，其缓慢释放到血液中。肾脏化。为了解决该问题以及副作用，我们在此提议调查认可芬太尼及其衍生物使用组装成纳米颗粒的双腔篮（即纳米 - 抗物体）。在我们的实验室中开发了腔篮，由两个共享和杯形框架组成，共享相同的“地板”，每个杯子在其末端都有三个氨基酸或钉酸。重要的是，多价篮子以阳性变构形式将两个分子与三元络合物捕获组装成大约100 nm纳米颗粒。这些有机纳米颗粒对HeLa细胞无毒，并且在物理pH下的PBS中热力学稳定。篮子很容易进入，容易快速多元化，我们在此提出了一种使它们与生物相容性基团（氨基酸，，，肽和钉酸），以便它们以纳米颗粒的形式诱捕芬太尼及其同源物在阳性中变构的方式。通过形成稳定的纳米颗粒/药物组件，药物的浓度血液应下降，从而导致浓度为负梯度，从而从CNS中移除和组织。通过化学修饰，纳米颗粒的循环时间将> 24 h调节以允许提出的药代动力学作用方式。识别能够强烈和变构的篮子宿主易芬太尼复合，我们将使用计算化学工具为实验研究选择候选物。从SARS来看，我们将制定基本规则，以有效识别PBS，血清和血液中的芬太尼。对芬太尼及其衍生物有效认识的基本了解竞争媒体中的模块化非生物宿主将为研究合作纳米抗体及其在体内行动。这两个团队在科学专业知识上是完整的（超分子化学和生物医学），位于同一建筑物中，有隔离/水解分子的史神经毒剂。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.