Multidomain Peptide Hydrogels as a Therapeutic Delivery Platform for Cancer Treatment

摘要 在美国，癌症是第二大死因，据预测，全美39.5%的人 成年人一生中都会被诊断出患有癌症。癌症占美国所有癌症病例的90%。 化疗药物和抗体免疫检查点抑制剂(ICIS)是治疗这些疾病的有希望的治疗方法。 癌症，但并不是在所有情况下都有效，并且由于偏离目标而对患者的生活质量造成很大影响 毒性。该方案的目标是开发一种基于多肽的水凝胶治疗平台，用于局部 提供化疗药物和ICIS，以最大限度地提高治疗效果并减轻全身毒性。 含硼酸小分子药物(BACSM)是近年来发展起来的一类治疗肿瘤的化疗药物。 癌症的治疗。Bortezomib是FDA批准的BACSM，用于治疗多发性骨髓瘤和 导致免疫原性癌细胞死亡，帮助身体产生抗癌免疫反应。的确有 有兴趣将Bortezomib扩大到实体肿瘤，但由于无法 在肿瘤中保持较高的局部浓度，而不会产生全身毒性。多结构域肽(MDP)水凝胶 是一种自我调节材料，已被研究用于癌症免疫治疗和药物输送。这个 通过使用MDPS水凝胶作为局部给药平台，可以改善Bortezomib的局限性 允许局部肿瘤内给药，以最大限度地提高治疗效果，同时将非靶标毒性降至最低。 已知的是，硼酸与二醇、儿茶酚和水杨基异羟肟酸形成动态共价键。 (沙斯)，我计划用它来控制水凝胶中抗癌BACSM的输送。在F99阶段 这项提议，我的目标是开发邻苯二酚和SHA功能化的MDP水凝胶，用于当地的Bortezomib递送 以提高这种化疗治疗的有效性、安全性和可及性。我假设MDP 佐剂将与Bortezomib诱导的免疫原性细胞死亡协同产生保护性抗癌 头颈部鳞状细胞癌(HNSCC)小鼠模型的免疫功能。这些与硼酸结合的物质 MDPS可用于控制任何含有硼酸部分的有效载荷的释放。因此，在K00 在这个提议的阶段，我的目标是用非规范的硼酸基序修饰ICI抗体，以微调它们的 从设计的MDP中释放。我将利用这个平台在肿瘤内联合注射博替佐米和免疫 检查点抑制剂促进HNSCC，黑色素瘤小鼠模型的抗癌免疫反应 和乳腺癌，展示了这个平台的广泛用途。这些材料可以帮助治疗病人 在减轻副作用的同时，防止癌症在治疗后复发 与化疗和ICIS有关。

ABSTRACT In the United States, cancer is the second leading cause of death, and it is projected that 39.5% of all US adults will be diagnosed with cancer in their lifetimes. Carcinomas comprise up to 90% of all US cancer cases. Chemotherapeutics and antibody immune checkpoint inhibitors (ICIs) are promising treatments for these cancers but are not effective in all cases and exact a large toll on the quality of life of patients due to off-target toxicity. The goal of this proposal is to develop a peptide-based hydrogel therapeutic platform for the local delivery of chemotherapeutics and ICIs to maximize treatment efficacy and mitigate systemic toxicity. Boronic acid-containing small molecule drugs (BACSMs) are a growing class of chemotherapeutics for the treatment of cancer. Bortezomib is an FDA-approved BACSM for the treatment of multiple myeloma and causes immunogenic cancer cell death to help the body develop an anti-cancer immune response. There is interest to expand the use of bortezomib to solid tumors but these efforts face challenges due to the inability to maintain high local concentrations in the tumor without systemic toxicity. Multidomain peptide (MDP) hydrogels are self-adjuvanting materials that have been investigated for cancer immunotherapy and drug delivery. The limitations of bortezomib may be ameliorated by using MDPs hydrogels as a local drug delivery platform by allowing for local intratumoral drug delivery to maximize treatment efficacy while minimizing off-target toxicity. Boronic acids are known to form dynamic covalent bonds with diols, catechols, and salicylhydroxamic acids (SHAs), which I plan to use to control the delivery of anti-cancer BACSMs from hydrogels. In the F99 phase of this proposal, I aim to develop catechol- and SHA-functionalized MDP hydrogels for local bortezomib delivery to improve the efficacy, safety, and accessibility of this chemotherapeutic treatment. I hypothesize that MDP adjuvancy will synergize with bortezomib-induced immunogenic cell death to generate protective anti-cancer immunity in a murine model of head and neck squamous cell carcinoma (HNSCC). These boronic acid-binding MDPs can be used to control the release of any payload that has a boronic acid moiety. Thus, in the K00 phase of this proposal, I aim to modify ICI antibodies with noncanonical boronic acid motifs to fine-tune their release from the designed MDPs. I will use this platform to intratumorally co-deliver bortezomib with immune checkpoint inhibitors to facilitate an anti-cancer immune response in murine models of HNSCC, melanoma, and breast cancer to demonstrate the broad utility of this platform. These materials could help treat patients with malignant tumors and protect them from cancer recurrence after treatment while mitigating side effects associated with chemotherapy and ICIs.