Nanodelivery of FP polymers to improve treatment of metastatic colorectal cancer

FP 聚合物的纳米递送可改善转移性结直肠癌的治疗

• 批准号: 10734188
• 负责人: William H Gmeiner
• 金额: $ 59.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734188
• 关键词: Adjuvant; Bile fluid; Biodistribution; Cancer Model; Chemistry; Chemotherapy-Oncologic Procedure; Collaborations; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Combination Drug Therapy; DNA; Deoxyuridine; Dose; Drug Kinetics; Extrahepatic; Fluorouracil; Formulation; Generations; Genetically Engineered Mouse; Goals; Half-Life; Hepatic; Immune response; In Vitro; Injections; Integrins; Link; Liver; Lung; Malignant - descriptor; Metabolism; Metastatic Neoplasm to the Liver; Methodology; Methods; Modeling; Molecular Target; Mus; Nanodelivery; Nucleic Acids; Peptides; Periodicity; Pharmaceutical Preparations; Phase; Plasma; Plasma Enhancement; Polyethylene Glycols; Polymers; Prevention; Property; RGD (sequence); Rattus; Recurrence; Recurrent disease; Regimen; Relapse; Resistance; Ribonucleotides; Risk; Risk Reduction; Single-Stranded DNA; Specificity; System; Testing; Therapeutic; Thymidine; Thymidylate Synthase; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Treatment Failure; Tumor Tissue; Vertebral column; analog; anticancer activity; cancer cell; clinical candidate; clinical development; clinical translation; colon cancer patients; copolymer; cytotoxic; cytotoxicity; design; fluoropyrimidine; improved; improved outcome; in vivo evaluation; lipid nanoparticle; liquid chromatography mass spectrometry; metastatic colorectal; monomer; mouse model; nanoformulation; nanomaterials; nanopolymer; nanoscale; novel; novel strategies; nucleotide analog; overexpression; pharmacologic; potency testing; pre-clinical; preclinical study; pyrimidine metabolism; scaffold; standard of care; systemic toxicity; tumor; tumor specificity

PROJECT SUMMARY Metastatic colorectal cancer (mCRC) remains highly lethal despite decades of optimizing 5-fluorouracil (5-FU)- based combination chemotherapy regimens that are central to treatment. The causes of treatment failure with 5-FU-based regimens include decreased metabolism to FdUMP, the primary active metabolite, and overexpression of thymidylate synthase (TS), the molecular target of FdUMP. To improve outcomes and overcome resistance we have developed a nanoscale FP polymer, CF10, that is comprised of FdUMP monomers linked in a single-stranded DNA backbone that releases FdUMP in a single step. CF10 displays markedly improved anti-tumor activity with low systemic toxicity relative to 5-FU and is a candidate for clinical translation. We hypothesize that nanoformulation of CF10 to increase plasma retention and actively target malignant tissue will improve anti-tumor activity and specificity. Lipid nanoparticle (LNP) formulation has proven to be a robust delivery strategy for multiple nucleic acid drugs, and in collaboration with NanoVation Therapeutics (NTx) in Aim 1 we will test two CF10:LNP formulations designed to differentially target CF10 to liver and more broadly to target metastatic tissue while protecting CF10 from degradation in plasma. In Aim 2, we will investigate PEGylation of CF10 together with active targeting to tumor tissue through conjugation with a cyclic RGD peptide that targets integrin V3 expressed specifically in malignant tissue. We will test our novel nanomaterials for improved anti- metastatic activity using: (i) a novel genetically engineered mouse model, iKAP, that forms tumors specifically in the colon with metastatic progression to the liver and lung; and (ii) a rat model of established colorectal liver metastases (CRLMs). Pharmacokinetic profiling (PK) will be evaluated using LC/MS/MS. In Aim 3, we will develop a 3rd generation FP polymer that includes 5-ethynyl-2’-deoxyuridine (EdU), a thymidine analog that is cytotoxic through complementary mechanisms to FdU. We will use the optimal LNP formulation and PEGylation strategies determined for CF10 in Aims 1 and 2 to develop a highly novel nanomaterial with exceptional potential for improved treatment of mCRC.

项目摘要 尽管经过数十年的优化，转移性结直肠癌（mCRC）仍然具有高致死性。 基于联合化疗方案，这是治疗的核心。治疗失败的原因 基于5-FU的治疗方案包括降低主要活性代谢产物FdUMP的代谢， FdUMP的分子靶点胸苷酸合成酶（TS）的过表达。改善结果， 克服阻力，我们开发了一种纳米级FP聚合物CF 10，它由FdUMP单体组成 连接在单链DNA骨架中，在一个步骤中释放FdUMP。CF 10显著显示 与5-FU相比，具有改善的抗肿瘤活性和低的全身毒性，是临床转化的候选药物。 我们假设纳米制剂CF 10增加血浆滞留并主动靶向恶性组织， 将提高抗肿瘤活性和特异性。脂质纳米颗粒（LNP）制剂已被证明是一种稳健的 多种核酸药物的递送策略，并与Aim的NanoVation Therapeutics（NTx）合作 1我们将测试两种CF 10：LNP制剂，其被设计为将CF 10差异性地靶向肝脏和更广泛地靶向 转移组织，同时保护CF 10免于在血浆中降解。在目标2中，我们将研究聚乙二醇化的 CF 10连同通过与靶向肿瘤组织的环状RGD肽缀合而主动靶向肿瘤组织 整合素α V β 3在恶性肿瘤组织中特异性表达。我们将测试我们的新型纳米材料， 转移活性，其使用：（i）新的基因工程小鼠模型iKAP，其特异性地在 结肠转移进展至肝和肺;和（ii）建立结肠直肠肝的大鼠模型 转移（CRLM）。将使用LC/MS/MS评价药代动力学特征（PK）。在目标3中，我们将 开发第三代FP聚合物，包括5-乙炔基-2 '-脱氧尿苷（EdU），一种胸苷类似物， 通过与FdU互补的机制产生细胞毒性。我们将使用最佳的LNP配方和PEG化 在目标1和2中确定了CF 10的战略，以开发具有特殊潜力的高度新颖的纳米材料 用于改善mCRC的治疗。