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.

摘要 在美国，癌症是第二大死亡原因，据预测，39.5%的美国人 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（ICI）是有希望的治疗方法， 但并非在所有情况下都有效，并且由于脱靶而对患者的生活质量造成很大影响 毒性该提案的目标是开发一种基于肽的水凝胶治疗平台， 递送化疗剂和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（BACSM）是一类不断增长的用于癌症的化疗药物。 癌症的治疗。硼替佐米是FDA批准的用于治疗多发性骨髓瘤的BACSM， 导致免疫原性癌细胞死亡，以帮助身体产生抗癌免疫反应。有 但这些努力面临挑战，因为不能 在肿瘤中保持高的局部浓度而没有全身毒性。多结构域肽（MDP）水凝胶 是自佐剂材料，已被研究用于癌症免疫治疗和药物输送。的 硼替佐米的局限性可以通过使用MDP水凝胶作为局部药物递送平台来改善， 允许局部肿瘤内药物递送以最大化治疗功效同时最小化脱靶毒性。 已知硼酸与二醇、儿茶酚和水杨基异羟肟酸形成动态共价键 （SHAs），我计划用它来控制水凝胶中抗癌BACSM的释放。在F99阶段， 在这个建议中，我的目标是开发儿茶酚和SHA功能化的MDP水凝胶，用于局部硼替佐米递送 以提高该化疗治疗的有效性、安全性和可及性。我假设MDP 免疫抑制将与硼替佐米诱导的免疫原性细胞死亡协同作用，产生保护性抗癌作用。 在头颈部鳞状细胞癌（HNSCC）的鼠模型中的免疫。这些结合硼酸的 MDP可用于控制具有硼酸部分的任何有效负载的释放。因此，在K00中 在这个建议的第一阶段，我的目标是用非规范的硼酸基序修饰ICI抗体，以微调它们的功能。 从设计的MDP中释放。我将使用这个平台在肿瘤内联合递送硼替佐米和免疫抑制剂， 在HNSCC，黑素瘤， 和乳腺癌来证明这个平台的广泛用途。这些材料可以帮助治疗病人 与恶性肿瘤，并保护他们从癌症复发治疗后，同时减轻副作用 与化疗和ICI相关。