Molecular Evoluation of Virus based Hydrogels for Cancer Therapy

描述（由申请人提供）：本研究的目标是开发具有可定制性能的新型有机材料，其形成由病毒颗粒成核。这些材料将应用于开发新的免疫疗法或化疗药物的局部递送。具体目的：(1)利用噬菌体展示来选择形成肽水凝胶的病毒颗粒(2)研究水凝胶在小鼠模型中产生的全身运输和免疫反应(3)根据前两个目标的结果，探索基于病毒的水凝胶在免疫治疗或药物递送中的应用研究设计：我们将使用噬菌体展示来选择形成新型有机材料的病毒颗粒。通过选择与已知凝胶形成肽结合的噬菌体颗粒，我们将进化出一个小的病毒样颗粒库，这些颗粒可以进行可逆的热反应凝胶化。它们在冷却时是液体，但在生理温度下会聚集成凝胶。一旦凝胶形成噬菌体被选择，它们将被研究它们在小鼠模型中引发免疫反应的能力。如果新材料具有免疫原性，则将寻求免疫治疗途径。然而，如果凝胶基质减弱免疫反应，将通过定向进化和/或小分子激活来开发局部药物递送系统。这种进化策略将通过将小分子封装在病毒颗粒中来实现，这些病毒颗粒已经进化到在与肿瘤相关的酸性环境中释放其内容物。后一种途径是引入一种小分子，扰乱病毒衣壳的结构，从而导致药物释放。癌症是西方世界的第二大死因，在美国每年导致近60万人死亡。目前，大多数非侵入性癌症治疗都会产生严重的副作用，其凶猛程度堪比癌症本身。我们的目标是创造新的材料，将癌症治疗定位到肿瘤部位，从而提高癌症治疗的有效性，同时减少全身副作用。

DESCRIPTION (provided by applicant): The goal of this research is to develop novel organic materials with tailorable properties whose formation is nucleated by viral particles. These materials will be applied to the development of new immunotherapies or localized delivery of chemotherapeutics. Specific Aims: (1) Utilize phage display to select viral particles that nucleate the formation of peptide hydrogels (2) Study the systemic trafficking and immune response produced by the hydrogels in a mouse model (3) Depending on the results of the first two aims, explore the use of virus-based hydrogels in immunotherapy or drug delivery Study Design: We will use phage display to select for viral particles that nucleate the formation of novel organic materials. By selecting for phage particles that bind to known gel-forming peptides, we will evolve a small library of virus-like particles that undergo reversible thermo-responsive gelation. These will be liquids when cool, but assemble into gels at physiological temperatures. Once gel-forming phage are selected for, they will be studied for their ability to elicit an immune response in a mouse model. Should the new materials be immunogenic, an immunotherapeutic path will be pursued. However, should the gel matrix attenuate the immunological response, a localized drug delivery system will be developed through directed evolution and/or small molecule activation. The evolutionary strategy will be accomplished by encapsulation of small molecules within viral particles that have been evolved to release their contents in the acidic environment associated with tumors. The latter route involves the introduction of a small molecule that perturbs the structure of the viral capsid, thus leading to drug release. Cancer is the second leading cause of death in the western world, resulting in nearly 600,000 deaths annually in the United States. Currently, most non-invasive cancer treatments result in crippling side-effects that rival the disease itself in ferocity. We aim to create new materials that will localize cancer therapy to a tumor site, thus enhancing the effectiveness of cancer therapy while reducing the systemic side-effects.