Tumor targeted drug delivery nanoplatform to overcome therapy resistance glioblastoma

肿瘤靶向药物递送纳米平台克服胶质母细胞瘤治疗耐药性

• 批准号: 10558857
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 61.84万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558857
• 关键词: Address; Animal Model; Animals; Biodistribution; Brain Neoplasms; Cell Line; Cells; Chemoresistance; Chemotherapy and/or radiation; Clinical; Clinical Trials; Cytometry; Data; Delayed-Action Preparations; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Targeting; Drug resistance; Evaluation; Excision; Formulation; Future; Generations; Glioblastoma; Glioma; Growth; Human; Hydrogels; Immunocompetent; In Situ; In Vitro; Injections; Invaded; Laboratories; Lead; Liposomes; Local Therapy; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Mus; Nanotechnology; Neuropilin-1; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Pre-Clinical Model; Primary Neoplasm; Process; Prognosis; Radiation; Radiation Tolerance; Radiation therapy; Recurrence; Recurrent tumor; Regimen; Reporting; Research; Resistance; Role; SDZ RAD; Signal Pathway; Solubility; Surgically-Created Resection Cavity; System; Systemic Therapy; Techniques; Testing; Therapeutic; Toxic effect; Toxicology; United States National Institutes of Health; Validation; Vascular Endothelial Growth Factors; Water; Work; Xenograft procedure; blood-brain barrier crossing; cancer type; chemoradiation; clinically relevant; comparative; digital; drug release kinetics; effective therapy; efficacy evaluation; efficacy testing; improved; in vivo; in vivo Model; inhibitor; liposomal formulation; mTOR Inhibitor; mouse model; nanoformulation; nanotechnology platform; novel; preclinical evaluation; prevent; radiation resistance; radioresistant; refractory cancer; side effect; small molecule; standard care; stemness; targeted delivery; targeted treatment; temozolomide; therapeutically effective; therapy outcome; therapy resistant; translational potential; treatment strategy; tumor; tumor growth; tumor initiation; tumor-immune system interactions

Glioblastoma multiforme (GBM) is associated with poor prognosis due to its highly invasive and drug-resistant phenotype. Recurrence is a common phenomenon in GBM patients due to the presence of chemo- and radio- resistant Brain Tumor-Initiating Cells (BTICs). Consequently, current therapies including surgery followed by radiation or chemotherapy with Temozolomide (TMZ) failed to improve patient median overall survival emphasizing the necessity of novel treatment strategies for drug-resistant GBM. Interestingly, Neuroplin-1 (NRP1) has been shown to be implicated in the drug-resistance and stemness in multiple types of cancer. Recently, we showed that depletion of NRP1 improved survival compared to that of vascular endothelial growth factor (VEGF-A) depletion in mice bearing patient-derived GBM xenografts. NRP1 depletion also improved sensitivity to TMZ and enhanced the overall survival when combined with TMZ. Our preliminary data further showed that a proprietary tumor-targeted liposomal (TTL) formulation combining a first generation small- molecule NRP1 inhibitor (EG00229; G in short) with Everolimus (E) provided significant survival advantage in TMZ resistant glioma cells as compared to that of TMZ alone. However, EG00229 is poorly water soluble, and its liposomal formulation is not stable for long term storage. Hence, we developed a new generation of small- molecule NRP1 inhibitors (NRP1i, Ni in short) with better solubility in order to create a stable liposomal formulation. The central hypothesis of our proposal is that NRP1i combined with everolimus in a single payload using TTL, either as a systemic therapy or delivered locally in a hydrogel-based system, will reduce drug- resistance and stemness and augment radiation sensitivity in GBM, leading to better therapeutic outcomes. To validate our hypothesis, we propose three major aims. In Aim 1, we will combine the most effective NRP1i with everolimus as a single payload in TTL formulation (TTL-ENi) for evaluating in vitro efficacy in inhibiting stemness and drug-resistance signaling pathways and in vivo studies using multiple therapy resistance BTICs animal models including immune-competent mice models. Further, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi will be evaluated. We will also analyze the effect of our proposed therapy on the tumor immune microenvironment using two state-of-the-art techniques namely mass cytometry (CyTOF) and digital spatial profiling (DSP). In Aim 2, we will assess the efficacy of the local administration of TTL-ENi-hydrogel in a resection and recurrence model of GBM. Moreover, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi-hydrogel will be evaluated. Aim 3 will focus on the comparative pharmacokinetics, pharmacodynamics, and preliminary toxicity studies of the most potent formulation for future clinical trials. We expect that a successful execution of our proposed research will lead to clinical trial in near future for a better therapeutic strategy to override the drug-resistance in GBM patients as well as patients suffering from other drug-resistant cancers.

摘要多形性胶质母细胞瘤具有高度侵袭性和耐药性，预后不良。 表型。在GBM患者中，由于化疗和放疗的存在，复发是一种常见现象。 耐药脑肿瘤启动细胞(BTICs)。因此，目前的治疗方法包括手术，然后是 替莫唑胺(TMZ)的放疗或化疗未能提高患者的中位总生存率 强调对耐药的GBM采取新的治疗策略的必要性。有趣的是，Neuroplin-1 (Nrp1)已被证明与多种类型的癌症的耐药性和干性有关。 最近，我们发现，与血管内皮细胞生长相比，Nrp1的缺失可以提高存活率。 携带患者来源的GBM异种移植小鼠的因子(VEGF-A)耗竭。Nrp1的耗尽也有所改善 与TMZ联合应用时，患者对TMZ的敏感性增加，总体存活率提高。我们的初步数据进一步 显示了一种专有的肿瘤靶向脂质体(TTL)配方，它结合了第一代小分子- Nrp1分子抑制剂(EG00229；简称G)与埃博利莫斯(E)联合应用可显著提高患者的生存优势 耐TMZ的胶质瘤细胞与单独使用TMZ的胶质瘤细胞相比。然而，EG00229的水溶性很差，而且 其脂质体配方不稳定，不能长期储存。因此，我们开发了新一代小型- Nrp1分子抑制剂(简称NRP1i，Ni)具有更好的溶解性，以产生稳定的脂质体 配方。我们建议的中心假设是NRP1i与伊波利莫斯在单个有效载荷中结合 使用TTL，无论是作为一种全身疗法，还是以水凝胶为基础的系统局部传递，都将减少药物- GbM的耐受性和干性，以及增强辐射敏感性，导致更好的治疗结果。至 验证了我们的假设，我们提出了三个主要目标。在目标1中，我们将把最有效的NRP1i与 伊维洛莫司作为TTL制剂(TTL-ENI)中的单一有效载荷评价体外抑制茎的效果 多药耐药BTICs动物体内耐药信号转导途径研究 模型包括免疫能力强的小鼠模型。此外，放疗和化疗的相加作用 (例如，TMZ)与TTL-ENI相结合将被评估。我们还将分析我们提议的 应用两种先进技术--质量细胞术治疗肿瘤免疫微环境 (CyTOF)和数字空间剖面图(DSP)。在目标2中，我们将评估地方政府对 TTL-Eni-水凝胶在基底细胞瘤切除复发模型中的应用此外，放射治疗的附加效应 以及化疗(如TMZ)与TTL-ENI水凝胶的联合使用将得到评估。目标3将重点放在 最有效药物的比较药代动力学、药效学和初步毒性研究 用于未来临床试验的配方。我们希望成功地执行我们提议的研究将导致 近期将进行临床试验，寻找更好的治疗策略，以克服GBM患者的耐药性 以及患有其他耐药癌症的患者。