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

基本信息

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
项目类别：
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

项目摘要

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.

多形性胶质母细胞瘤（GBM）因其高度侵袭性和耐药性而与不良预后相关表型。由于化疗和放射治疗的存在，复发是 GBM 患者的常见现象。抗性脑肿瘤起始细胞（BTIC）。因此，目前的治疗方法包括手术后替莫唑胺 (TMZ) 放疗或化疗未能改善患者中位总生存期强调耐药 GBM 新型治疗策略的必要性。有趣的是，Neuroplin-1 (NRP1) 已被证明与多种癌症的耐药性和干性有关。最近，我们发现，与血管内皮生长相比，NRP1 的消耗可以提高存活率携带患者来源的 GBM 异种移植物的小鼠中的因子 (VEGF-A) 耗竭。 NRP1 消耗也有所改善与 TMZ 联合使用时，可提高对 TMZ 的敏感性并提高总体生存率。我们的初步数据进一步表明，一种专有的肿瘤靶向脂质体（TTL）配方结合了第一代小分子 NRP1 抑制剂（EG00229；简称 G）与依维莫司 (E) 一起提供了显着的生存优势 TMZ 耐药性神经胶质瘤细胞与单独 TMZ 的细胞相比。然而，EG00229 的水溶性较差，并且其脂质体制剂长期储存不稳定。因此，我们开发了新一代小型分子NRP1抑制剂（NRP1i，简称Ni）具有更好的溶解度，以形成稳定的脂质体配方。我们提案的中心假设是 NRP1i 与依维莫司在单一有效负载中结合使用 TTL，无论是作为全身疗法还是在基于水凝胶的系统中局部给药，都将减少药物抵抗力和干性并增强 GBM 的放射敏感性，从而带来更好的治疗结果。到为了验证我们的假设，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 与依维莫司作为 TTL 制剂 (TTL-ENi) 中的单一有效负载，用于评估抑制干性的体外功效和耐药信号通路以及使用多种治疗耐药性 BTIC 动物的体内研究模型包括免疫活性小鼠模型。此外，放疗和化疗的叠加效应（例如 TMZ）与 TTL-ENi 的结合将被评估。我们还将分析我们提议的效果使用两种最先进的技术（即质谱流式细胞术）对肿瘤免疫微环境进行治疗 (CyTOF) 和数字空间分析 (DSP)。在目标 2 中，我们将评估当地政府的有效性 GBM 切除和复发模型中的 TTL-ENi-水凝胶。此外，放射治疗的累加效应将评估化疗（例如 TMZ）与 TTL-ENi-水凝胶的组合。目标3将重点关注最有效的药物的比较药代动力学、药效学和初步毒性研究为未来的临床试验制定配方。我们期望我们提议的研究的成功执行将导致在不久的将来进行临床试验，寻找更好的治疗策略来克服 GBM 患者的耐药性以及患有其他耐药癌症的患者。