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.

摘要 摘要多形性胶质母细胞瘤是最常见的脑部原发恶性肿瘤，占全脑的80%。 癌症患者。它通常与预后不良有关。GBM患者的护理标准包括 肿瘤大块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，但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，治疗方法是非常必要的。激活信号与转导蛋白3 (STAT3)转录因子已被证明是治疗恶性脑瘤的一个非常有吸引力的靶点， 因为它们的生长高度依赖于STAT3信号。我们团队的初步数据清楚地表明， 目前可用的小分子STAT3抑制剂在诱导GBM肿瘤消退方面非常有效 生长在外围。相反，这些小分子STAT3抑制剂在治疗中无效 基底膜肿瘤位于大脑内。我们证明，缺乏疗效是由于有限的血脑屏障转运。 其他已确定的化疗药物，特别是紫杉醇的输送也遇到了类似的困难。 (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 相对较低的疗效或需要侵入性的颅内递送，以使治疗药物能够通过 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传递 我们团队开发的携带者在全身给药后显著积累在颅内肿瘤中。在……里面 这项提议，我们的跨学科团队将开发和评估一种新颖的、可扩展的两室人类 基于血清白蛋白的载体系统，允许可控地包裹STAT3 siRNA的治疗比率 和PTX在同一白蛋白为基础的药物输送载体的不同隔室内，同时还包括 肿瘤穿透性多肽，此前已被证明可促进纳米颗粒渗透到基底膜中。 实验将检验所提出的双隔室(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，将显著改善医疗状况 脑内基底膜移植小鼠的存活。我们还假设STAT3 siRNA和PTX的共同释放， 当由适当设计的递送载体在空间和时间上协调时，将不会展示 对宿主的不良副作用，既不是大脑内部的，也不是全身的。这项工作可能会导致 GBM是一种肿瘤类型，目前还没有有效的治疗方法。关于以下方面的新信息 用药物接触脑瘤也会随之而来。我们的最终目标是将这种新颖的治疗方式 通过实施I期临床试验对GBM患者进行治疗。