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: 10584553
• 负责人: Maria G Castro
• 金额: $ 48.16万
• 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/10584553
• 关键词: Accounting; Adjuvant Chemotherapy; Albumins; Antibodies; Architecture; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Patient; Cell Death; Cells; Combined Modality Therapy; Data; Development; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Encapsulated; Excision; Exhibits; Formulation; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Human; Immune; Immunity; Immunologic Memory; In Vitro; Infiltration; Intracranial Neoplasms; Ionizing radiation; Knowledge; 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; blood-brain barrier permeabilization; cell type; chemotherapeutic agent; clinically relevant; curative treatments; design; docetaxel; drug action; 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.

抽象的 多形性胶质母细胞瘤（GBM）是常见的原发性恶性脑肿瘤，占所有脑肿瘤的80% 癌症患者。它通常与不良预后相关。 GBM 患者的护理标准包括 肿瘤块的整体手术切除结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，神经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，我们非常需要一些方法。激活信号和传感器3 (STAT3)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 STAT3 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 STAT3 抑制剂在引发 GBM 肿瘤消退方面非常有效 生长在外围。相比之下，这些相同的小分子 STAT3 抑制剂在治疗方面无效 GBM 肿瘤位于大脑内。我们证明缺乏功效是由于 BBB 运输有限。 其他已建立的化疗药物（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输送系统提供了潜在的解决方案，但目前的输送载体仍然 疗效相对较低或需要侵入性颅内输送，以实现治疗药物的跨部位运输 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 本课题组开发的载体在全身给药后在颅内肿瘤中显着富集。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且可扩展的双室人类 基于血清白蛋白的载体系统，可控制 STAT3 siRNA 治疗比例的封装 和 PTX 位于同一基于白蛋白的药物递送载体的不同隔室中，同时还包含 肿瘤穿透肽，之前已被证明可以促进纳米颗粒渗透到 GBM 中。 实验将检验所提出的双室 (bi-NP) STAT3i/PTX 递送的假设 携带者与标准护理相结合，即放射治疗 (IR) 和 TMZ，将显着改善内侧 颅内携带 GBM 的小鼠的存活率。我们还假设 STAT3 siRNA 和 PTX 的共同释放， 当由适当设计的交付载体在空间和时间上精心安排时，不会表现出 对宿主产生不良副作用，既不在大脑内，也不在全身。这项工作可能会导致 GBM（一种尚无有效治疗方法的肿瘤类型）的新治疗方式。新信息关于 用药物治疗脑肿瘤也将随之而来。我们的最终目标是转化这种新颖的治疗方式 通过实施 I 期临床试验来治疗 GBM 患者。