Systemic Delivery of Targeted Bi-Compartmental Nanoparticles for Glioblastoma Therapeutics

用于胶质母细胞瘤治疗的靶向双室纳米颗粒的系统递送

• 批准号: 10462033
• 负责人: Maria G Castro
• 金额: $ 48.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462033
• 关键词: Accounting; Adjuvant Chemotherapy; Albumins; Antibodies; Architecture; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Patient; Cell Death; Cells; Characteristics; Combined Modality Therapy; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Excision; Exhibits; Formulation; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Human; Immune; Immunity; Immunologic Memory; In Vitro; Intracranial Neoplasms; Ionizing radiation; Knowledge; Leucocytic infiltrate; Malignant - descriptor; Malignant neoplasm of brain; Medial; Medical; Mission; Modality; Modeling; Molecular; Mus; Operative Surgical Procedures; Organ; Paclitaxel; Patients; Pattern; Penetration; Peptides; Phagocytes; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Polymers; Prognosis; Proteins; RNA; Radiation therapy; Reporting; Serum Albumin; Signal Transduction; Signaling Molecule; Small Interfering RNA; Survival Rate; System; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Toxic effect; Transcription Factor 3; Transducers; Translating; Translations; Treatment Efficacy; United States National Institutes of Health; Validation; Work; base; blood-brain barrier permeabilization; cell type; chemotherapeutic agent; clinically relevant; curative treatments; design; docetaxel; effective therapy; efficacy evaluation; experimental study; immunogenic cell death; improved; inhibitor; innovation; innovative technologies; nanoparticle; nanoparticle delivery; novel; novel strategies; novel therapeutics; pre-clinical; response; side effect; small molecule; small molecule inhibitor; standard of care; synthetic protein; targeted delivery; temozolomide; therapeutic target; tumor; tumor microenvironment; uptake

Abstract Glioblastoma multiforme (GBM) is the prevalent primary malignant brain tumor accounting for 80% of all brain cancer patients. It is typically associated with poor prognosis. The standard of care for GBM patients consists of bulk surgical resection of the tumor mass in combination with focal radiotherapy and adjuvant chemotherapy, using temozolomide (TMZ). Despite intense efforts, the prognosis of glioma patients remains dismal. Novel approaches are greatly needed for this devastating form of brain cancer. Signal and Transducer of Activation 3 (STAT3) transcription factor has been proven to be a very attractive therapeutic target for malignant brain tumors, as their growth is highly dependent of STAT3 signaling. Preliminary data from our team clearly suggest that currently available small molecule STAT3 inhibitors are highly effective at eliciting regression of GBM tumors growing in the periphery. In contrast, these same small molecule STAT3 inhibitors were ineffective in treating GBM tumors located within the brain. We demonstrated that the lack of efficacy is due to limited BBB transport. Similar difficulties are encountered for the delivery of other established chemotherapeutics, specifically paclitaxel (PTX). Nanoparticle-based drug delivery systems offer potential solutions, but current delivery carriers have still relatively low efficacy or require invasive intracranial delivery, to enable transport of therapeutics across the blood-brain-barrier. In our preliminary studies, we were able to demonstrate that albumin-based drug delivery carriers developed by our group significantly accumulate in intracranial tumors after systemic administration. In this proposal, our interdisciplinary team will develop and evaluate a novel and scalable bi-compartmental human serum albumin-based carrier system that allows controlled encapsulation of therapeutic ratios of STAT3 siRNA and PTX within distinct compartments of the same albumin-based drug delivery carrier, while also incorporating tumor-penetrating peptides, which have been previously shown to promote nanoparticle penetration into GBMs. The experiments will test the hypothesis that the proposed bi-compartmental (bi-NP) STAT3i/PTX delivery carriers in combination with standard of care, i.e., radiation therapy (IR) and TMZ, will significantly improve medial survival of intracranial GBM bearing mice. We also hypothesize that the co-release of STAT3 siRNA and PTX, when spatially and temporally orchestrated by an appropriately designed delivery carrier, will not exhibit untoward adverse side effects in the host, neither within the brain, nor systemically. This work may result in a new treatment modality for GBM, a tumor type, for which no effective treatments exist. New information on accessing brain tumors with drugs will also ensue. Our ultimate goal is to translate this novel therapeutic modality to patients with GBM by implementing Phase I clinical trials.

摘要 多形性胶质母细胞瘤（GBM）是最常见的原发性脑恶性肿瘤，占脑肿瘤的80% 癌症患者。它通常与预后不良有关。GBM患者的标准治疗包括 肿瘤块的大块手术切除联合局部放疗和辅助化疗， 使用替莫唑胺（TMZ）。尽管付出了巨大的努力，胶质瘤患者的预后仍然令人沮丧。小说 对于这种毁灭性的脑癌形式，非常需要方法。激活3的信号和传感器 STAT 3转录因子已被证明是恶性脑肿瘤非常有吸引力的治疗靶点， 因为它们的生长高度依赖于STAT 3信号传导。我们团队的初步数据清楚地表明， 目前可用的小分子STAT 3抑制剂在引起GBM肿瘤消退方面是高度有效的 生长在外围。相比之下，这些相同的小分子STAT 3抑制剂在治疗中无效。 GBM肿瘤位于脑内。我们证明，缺乏疗效是由于有限的血脑屏障运输。 对于其它已建立的化学治疗剂，特别是紫杉醇的递送，也遇到类似的困难 （PTX）。基于纳米颗粒的药物递送系统提供了潜在的解决方案，但是目前的递送载体仍然具有局限性。 相对较低的功效或需要侵入性颅内递送，以使治疗剂能够穿过 血脑屏障在我们的初步研究中，我们能够证明基于白蛋白的药物递送 我们小组开发的载体在全身给药后在颅内肿瘤中显著积累。在 根据这项提议，我们的跨学科团队将开发和评估一种新颖的、可扩展的双房室人体模型。 基于血清白蛋白的载体系统，其允许STAT 3 siRNA的治疗比例的受控包封 和PTX在相同的基于白蛋白的药物递送载体的不同隔室内，同时还掺入 肿瘤穿透肽，其先前已显示出促进纳米颗粒穿透GBM。 实验将检验所提出的双隔室（bi-NP）STAT 3 i/PTX递送 载体与标准护理的组合，即，放射治疗（IR）和TMZ，将显着改善中 颅内GBM荷瘤小鼠的存活率。我们还假设STAT 3 siRNA和PTX的共释放， 当由适当设计的递送载体在空间和时间上协调时， 在宿主中的不良副作用，既不在脑内，也不在全身。这项工作可能会导致 GBM是一种没有有效治疗方法的肿瘤类型。的新信息 用药物进入脑肿瘤也将随之而来。我们的最终目标是将这种新的治疗方式 对GBM患者进行I期临床试验