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特性的新型有机材料，其形成由病毒颗粒成核。这些材料将用于开发新的免疫疗法或局部递送化疗药物。具体目标：（1）利用噬菌体展示来选择使肽水凝胶的形成成核的病毒颗粒（2）在小鼠模型中研究由水凝胶产生的全身运输和免疫应答（3）根据前两个目的的结果，探索基于病毒的水凝胶在免疫治疗或药物递送中的用途研究设计：我们将使用噬菌体展示来选择病毒颗粒，这些病毒颗粒成核形成新的有机材料。通过选择与已知的凝胶形成肽结合的噬菌体颗粒，我们将进化出一个经历可逆的热响应凝胶化的病毒样颗粒的小型文库。当冷却时，这些将是液体，但在生理温度下组装成凝胶。一旦选择了凝胶形成噬菌体，将研究它们在小鼠模型中引发免疫应答的能力。如果新材料具有免疫原性，则将寻求免疫途径。然而，如果凝胶基质减弱免疫应答，则将通过定向进化和/或小分子活化来开发局部药物递送系统。进化策略将通过将小分子封装在病毒颗粒内来实现，这些病毒颗粒已经进化成在与肿瘤相关的酸性环境中释放其内容物。后一种途径涉及引入一种小分子，该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亡原因，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导致严重的副作用，其严重程度可与疾病本身相媲美。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.