Synthetic Nanofiber Vaccines for Cocaine Addiction

用于治疗可卡因成瘾的合成纳米纤维疫苗

• 批准号: 8620446
• 负责人: Jai Rudra
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620446
• 关键词: Accident and Emergency department; Acute; Adjuvant; Affinity; Americas; Antibodies; Antibody Formation; Antibody Specificity; Antigens; Behavioral; Binding; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Brain; Buffers; Carrier Proteins; Chemicals; Chemistry; Chronic; Clinical; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Coupled; Coupling; Data; Development; Disease; Drug Formulations; Drug abuse; Drug usage; FDA approved; Fees; Goals; Haptens; Health; Human; Illicit Drugs; Immune; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Immunologic Adjuvants; Immunology; Injection of therapeutic agent; Lead; Length; Malaria Vaccines; Malignant Neoplasms; Methamphetamine; Morphine; Motor Activity; Mouse Strains; Mus; Nanotechnology; Nicotine; Opiates; Outcome; Overdose; Penetration; Peptides; Pharmaceutical Preparations; Physiological; Positioning Attribute; Public Health; Regimen; Relapse; Research; Route; Safety; Severities; Site; Specificity; Staging; Synthesis Chemistry; Tertiary Protein Structure; Testing; Vaccination; Vaccine Adjuvant; Vaccine Production; Vaccines; Visit; Work; addiction; aged; alternative treatment; analog; base; behavioral sensitization; carboxylate; cell motility; combat; design; drug of abuse; efficacy testing; immunogenic; immunogenicity; improved; insight; interest; mouse model; nanofiber; novel; pre-clinical; prevent; prophylactic; public health relevance; small molecule; social; success; therapeutic vaccine; treatment strategy; vaccine development

PROJECT SUMMARY Cocaine addiction is second only to opiates as the most problematic drug in the Americas with an enormous fee in human tragedy as well as in public health and safety. Currently there is no FDA approved pharmacological therapy for cocaine addiction, which has prompted the development of immuno-prophylactic alternatives. A therapeutic vaccine that elicits anti-cocaine antibodies will allow the rapid sequestration of the drug in circulation and reduce the amount and rate of its entry into the brain. A limiting factor to the success of small molecule drug vaccines is the low degree of immunity evoked by the addictive drug analog and lack of effective yet safe immune adjuvants. Also, clinical studies have unambiguously demonstrated that the design of proper haptens is critical for proper immune stimulation both in terms of amount of antibody elicited and antibody specificity. The goals of this proposal are to design and develop cocaine vaccines based on designed cocaine analogs in combination with a peptide nanofiber-based delivery platform for eliciting high titers of anti-cocaine antibodies and test their efficacy in a mouse motor activity assay. The work is divided into two aims: Aim 1) Design and synthesis of self-assembling peptide nanofiber-based cocaine vaccines. Aim 2) Test the efficacy of peptide nanofiber cocaine vaccine formulations in a mouse model. Our approach will be to design and chemically synthesize peptide nanofiber vaccines against cocaine. In aim 1, we will synthesize novel cocaine-based small molecule haptens modified at the P3 site with various chemical linkers and linker lengths. We will then conjugate the haptens to a self-assembling peptide domain using an orthogonal chemistry to produce peptide nanofibers that display the haptens in a multivalent fashion. In aim 2, we will investigate antibody responses against modified cocaine haptens coupled self-assembling peptides and the effect of linker chemistry and linker-length on the antibody titers. Mice will be immunized with synthetic cocaine nanofiber vaccines and the production of anti-cocaine antibodies will be investigated using a prime-boost regimen. Formulations that elicit high titers of anti-cocaine antibodies will be investigated for suppression of acute cocaine-induced motor activity and cocaine-induced behavioral sensitization. Success in these studies will provide us with insights into the development of small molecule drug analogs suitable for vaccination and the utility of self-assembling peptides as adjuvants for vaccines to treat addiction. Also, more broadly, completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and addiction to significantly impact human health.

项目概要 可卡因成瘾是仅次于阿片类药物的美洲最有问题的药物，影响巨大 为人类悲剧以及公共卫生和安全付出代价。目前尚无 FDA 批准 可卡因成瘾的药物治疗，促进了免疫预防药物的发展 替代方案。引发抗可卡因抗体的治疗性疫苗将能够快速隔离 药物循环并减少其进入大脑的数量和速率。成功的限制因素 小分子药物疫苗是由成瘾药物类似物引起的低度免疫，并且缺乏 有效且安全的免疫佐剂。此外，临床研究已明确证明该设计 适当的半抗原对于适当的免疫刺激至关重要，无论是在引发的抗体量还是在 抗体特异性。 该提案的目标是基于设计的可卡因类似物设计和开发可卡因疫苗 与基于肽纳米纤维的递送平台相结合，引发高滴度的抗可卡因抗体 并在小鼠运动活动测定中测试它们的功效。这项工作分为两个目标： 目标 1) 设计和 基于自组装肽纳米纤维的可卡因疫苗的合成。目的2）测试肽的功效 小鼠模型中的纳米纤维可卡因疫苗制剂。我们的方法是设计和化学 合成针对可卡因的肽纳米纤维疫苗。在目标 1 中，我们将合成新型可卡因小分子 在 P3 位点用各种化学接头和接头长度进行修饰的分子半抗原。我们随后将 使用正交化学将半抗原缀合至自组装肽结构域以产生肽 以多价方式显示半抗原的纳米纤维。在目标 2 中，我们将研究抗体反应 针对修饰的可卡因半抗原偶联的自组装肽以及连接化学的影响和 连接子长度对抗体滴度的影响。小鼠将接受合成可卡因纳米纤维疫苗的免疫接种 将使用初免-加强方案研究抗可卡因抗体的产生。引发的配方 将研究高滴度的抗可卡因抗体，以抑制可卡因引起的急性运动 活动和可卡因引起的行为过敏。 这些研究的成功将为我们提供小分子药物类似物开发的见解 适用于疫苗接种以及自组装肽作为治疗成瘾的疫苗佐剂的用途。 此外，更广泛地说，完成拟议的工作将整合合成化学领域， 纳米技术、免疫学和成瘾对人类健康产生重大影响。