Nanodelivery of FP polymers to improve treatment of metastatic colorectal cancer

项目总结 转移性结直肠癌(MCRC)尽管几十年来一直在优化5-氟尿嘧啶(5-FU)- 以治疗为中心的联合化疗方案。治疗失败的原因 基于5-FU的方案包括对主要活性代谢物FdUMP的代谢减少，以及 FdUMP的分子靶标胸苷酸合酶(TS)的过度表达。为了改善结果和 克服阻力我们开发了一种纳米级的FP聚合物CF10，它由FdUMP单体组成 连接在单链DNA骨架上，只需一步就能释放FdUMP。CF10显示明显 与5-FU相比，抗肿瘤活性增强，全身毒性低，是临床翻译的候选药物。 我们假设CF10的纳米制剂可以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)的配方已被证明是一种健壮的 多核酸药物的给药策略，并与AIM的纳米血管治疗技术(NTX)合作 1我们将测试两种CF10：LNP配方，旨在针对肝脏和更广泛的靶点进行不同的CF10靶向 同时保护CF10在血浆中不被降解。在目标2中，我们将研究聚乙二醇化 CF10与靶向肿瘤组织的环状RGD多肽偶联活性靶向 整合素V3在恶性组织中特异表达。我们将测试我们的新型纳米材料是否具有更好的抗腐蚀性 转移活性使用：(I)一种新的基因工程小鼠模型，IKAP，它在 转移到肝脏和肺的结肠；和(Ii)已建立的结直肠癌肝的大鼠模型 转移瘤(CRLM)。药代动力学图谱(PK)将使用LC/MS/MS进行评估。在Aim 3中，我们将 开发包括5-乙炔基-2‘-脱氧尿苷(EDU)的第三代FP聚合物，EDU是一种胸苷类似物 通过与FDU互补的机制发挥细胞毒作用。我们将使用最佳的LNP配方和聚乙二醇化 目标1和目标2中确定的CF10战略，以开发具有特殊潜力的高度新颖的纳米材料 以改善对多发性结直肠癌的治疗。

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.