Synthetic Nanofiber Vaccines for Cocaine Addiction

说明（由申请人提供）：可卡因成瘾是美洲仅次于阿片类药物的问题最严重的毒品，在人类悲剧以及公共健康和安全方面造成巨大损失。目前还没有FDA批准的药物治疗可卡因成瘾，这促使了免疫预防替代品的发展。一种能产生抗可卡因抗体的治疗性疫苗将使循环中的毒品迅速被隔离，并减少其进入大脑的数量和速度。小分子药物疫苗成功的一个限制因素是成瘾性药物类似物引起的免疫程度低，以及缺乏有效而安全的免疫佐剂。此外，临床研究已经明确表明，设计合适的半抗原对于适当的免疫刺激是至关重要的，无论是在抗体诱导量和抗体特异性方面。本提案的目标是设计和开发基于设计的可卡因类似物与基于肽纳米纤维的递送平台相结合的可卡因疫苗，以诱导高滴度的抗可卡因抗体，并在小鼠运动活性试验中测试其有效性。这项工作分为两个目标：目标1)设计和合成基于自组装肽纳米纤维的可卡因疫苗。目的2)在小鼠模型上测试肽纳米纤维可卡因疫苗制剂的有效性。我们的方法将是设计和化学合成抗可卡因的肽纳米纤维疫苗。在目标1中，我们将合成在P3位点修饰的新型基于可卡因的小分子半抗原，这些半抗原具有不同的化学连接体和连接体长度。然后，我们将使用正交化学将半抗原偶联到一个自组装的肽结构域，以生产肽纳米纤维，以多价方式显示半抗原。在目标2中，我们将研究针对修饰的可卡因半抗原偶联自组装肽的抗体反应，以及连接体化学和连接体长度对抗体滴度的影响。小鼠将被合成的可卡因纳米纤维疫苗免疫，抗可卡因抗体的产生将被研究使用一种初始增强方案。将研究引起高滴度抗可卡因抗体的配方，以抑制急性可卡因诱导的运动活动和可卡因诱导的行为致敏。这些研究的成功将为我们提供适合疫苗接种的小分子药物类似物的开发以及自组装肽作为治疗成瘾疫苗佐剂的效用的见解。此外，更广泛地说，完成拟议的工作将整合合成化学、纳米技术、免疫学和成瘾等领域，对人类健康产生重大影响。

DESCRIPTION (provided by applicant): 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 t 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 o 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.