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