Multidomain Peptide Hydrogels as a Therapeutic Delivery Platform for Cancer Treatment

多域肽水凝胶作为癌症治疗的治疗传递平台

• 批准号: 10743144
• 负责人: Brett Pogostin
• 金额: $ 4.92万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10743144
• 关键词: Acids; Address; Adjuvant; Adult; Adverse effects; Affinity; Aftercare; Amino Acids; Antibodies; Antineoplastic Agents; Award; Behavior; Binding; Biocompatible Materials; Biological; Biological Immunotherapy; Biological Products; Boronic Acids; Bortezomib; Breast Cancer Model; Carcinoma; Catechols; Cause of Death; Cell Death; Cells; Combination immunotherapy; Development; Diagnosis; Diffusion; Dose; Drug Controls; Drug Delivery Systems; Epithelium; FDA approved; Face; Flow Cytometry; Glycols; Goals; Half-Life; Head and Neck Squamous Cell Carcinoma; Healthcare; Histology; Hydrogels; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Injections; Investigation; Kinetics; Malignant Neoplasms; Multiple Myeloma; Mus; Natural Killer Cells; Needles; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Property; Quality of life; Recurrent Malignant Neoplasm; Safety; Solid Neoplasm; System; T-Lymphocyte; Tertiary Protein Structure; Testing; Therapeutic; Thinness; Tissues; Toxic effect; Treatment Efficacy; Tumor Immunity; United States; anti-CTLA4 antibodies; anti-PD-1; anti-cancer; antibody inhibitor; biomaterial compatibility; cancer cell; cancer immunotherapy; cancer recurrence; cancer therapy; chemotherapy; controlled release; covalent bond; delivery vehicle; design; efficacy evaluation; healing; immune checkpoint blockade; immunogenic; immunogenic cell death; improved; in vivo; innovation; interest; intravenous administration; local drug delivery; malignant breast neoplasm; melanoma; minimally invasive; mouse model; self assembly; side effect; small molecule; synergism; systemic toxicity; treatment strategy; tumor; water solubility

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.

抽象的 在美国，癌症是死亡的第二大原因，预计我们所有人中有39.5％ 成人一生中将被诊断出患有癌症。癌最多占美国癌症病例的90％。 化学治疗剂和抗体免疫检查点抑制剂（ICI）是对这些的有希望的治疗方法 癌症但在所有情况下都不有效，并且由于脱离目标而对患者的生活质量造成了很大的影响 毒性。该建议的目的是为当地开发基于肽的水凝胶治疗平台 递送化学治疗剂和ICI，以最大化治疗功效并减轻全身毒性。 含硼酸的小分子药物（BACSMS）是一类增长的化学治疗药 癌症的治疗。硼替佐米是FDA批准的BACM，用于治疗多发性骨髓瘤和 引起免疫原性癌细胞死亡，以帮助人体发展抗癌免疫反应。有 兴趣将硼替佐米的使用扩展到实体瘤，但是由于无法 在没有全身毒性的情况下，保持肿瘤中的局部浓度较高。多域肽（MDP）水凝胶 是已研究的癌症免疫疗法和药物递送的自我辅助材料。这 通过使用MDP水凝胶作为局部药物输送平台可以改善硼替佐米的局限性 允许局部肿瘤内药物递送，以最大化治疗功效，同时最大程度地减少脱靶毒性。 已知硼酸与二醇，儿茶酚和水杨羟醛酸形成动态共价键 （SHA），我计划用来控制水凝胶的抗癌BACSM。在F99阶段 该提议，我旨在开发用于局部硼替佐米的Catechol-和SHA功能化的MDP水凝胶 提高这种化学治疗的功效，安全性和可及性。我假设MDP 佐剂将与硼替佐米诱导的免疫原性死亡协同作用，以产生保护性抗癌药 头颈部鳞状细胞癌（HNSCC）的鼠模型中的免疫力。这些硼酸结合 MDP可用于控制任何具有硼酸部分的有效载荷的释放。因此，在K00中 该提案的阶段，我旨在用非规范的硼酸基序修改ICI抗体以微调其 从设计的MDP释放。我将使用此平台将肿瘤内共同寄托硼替佐米与免疫 检查点抑制剂，以促进HNSCC，黑色素瘤，黑色素瘤鼠模型中的抗癌免疫反应 和乳腺癌以证明该平台的广泛效用。这些材料可以帮助治疗患者 患有恶性肿瘤，并在缓解副作用的同时保护它们免受癌症的复发 与化学疗法和ICIS相关。