Müller Fiedler Augusto, Medeiros Michelle, Fiedler Haidi Dalinda
Department of Neurological Surgery, University of Miami/Jackson Memorial Hospital, Miami, FL, United States.
National Institute of Science and Technology for Catalysis, Department of Chemistry, Federal University of Santa Catarina, Florianópolis, Brazil.
JMIR Res Protoc. 2023 Aug 11;12:e49417. doi: 10.2196/49417.
Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options due to the blood-brain barrier's (BBB's) impedance and inherent resistance to chemotherapy. Gold nanoparticles (AuNPs) functionalized with transferrin-like peptides show promise in overcoming these challenges, enhancing drug delivery to the brain, and reducing chemotherapy resistance.
The primary goal of this study is to establish a detailed protocol for synthesizing and stabilizing AuNPs, functionalizing them with de novo-engineered transferrin-like peptides, and conjugating them with the chemotherapeutic agent temozolomide. This strategy aims to improve drug delivery across the BBB and circumvent chemotherapy resistance. The secondary objective includes an assessment of the safety and potential for in vivo use of the synthesized nanoparticle complex.
The proposal involves multiple steps with rigorous quality control of AuNP synthesis, stabilization with surfactants, and polyethylene glycol coating. The engineered transferrin-like peptides will be synthesized and attached to the AuNPs' surface, followed by the attachment of temozolomide and O6-methylguanine-DNA methyltransferase inhibitors. The resulting complex will undergo in vitro testing to assess BBB penetration, efficacy against GBM cells, and potential toxicity.
Initial preliminary experiments and simulations suggest successful synthesis and stabilization of AuNPs and effective attachment of transferrin-like peptides. We propose peptide attachment verification using Fourier transform infrared spectroscopy and surface plasmon resonance. Additionally, we will conduct pH stability tests to ensure our functionalized AuNPs retain their properties in acidic brain tumor microenvironments.
The proposed functionalization of AuNPs with de novo-engineered transferrin-like peptides represents a novel approach to GBM treatment. Our strategy opens new avenues for drug delivery across the BBB and chemotherapy resistance reduction. While we primarily focus on in vitro studies and computational modeling at this stage, successful completion will lead to further development, including in vivo studies and nanoparticle design optimization. This proposal anticipates inspiring future research and funding in neuro-oncology, presenting a potentially innovative and effective treatment option for GBM.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/49417.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，由于血脑屏障（BBB）的阻碍以及其对化疗的固有抗性，治疗选择有限。用类转铁蛋白肽功能化的金纳米颗粒（AuNPs）在克服这些挑战、增强药物向脑部递送以及降低化疗抗性方面显示出前景。
本研究的主要目标是建立一个详细方案，用于合成和稳定AuNPs，用从头设计的类转铁蛋白肽对其进行功能化，并将其与化疗药物替莫唑胺偶联。该策略旨在改善药物穿过血脑屏障的递送并规避化疗抗性。次要目标包括评估合成的纳米颗粒复合物的体内安全性和应用潜力。
该方案涉及多个步骤，对AuNP合成进行严格质量控制，用表面活性剂稳定并进行聚乙二醇包被。将合成工程化的类转铁蛋白肽并连接到AuNPs表面，随后连接替莫唑胺和O6-甲基鸟嘌呤-DNA甲基转移酶抑制剂。所得复合物将进行体外测试，以评估血脑屏障穿透性、对GBM细胞的疗效以及潜在毒性。
初步的初步实验和模拟表明成功合成并稳定了AuNPs，且类转铁蛋白肽有效连接。我们建议使用傅里叶变换红外光谱和表面等离子体共振来验证肽的连接。此外，我们将进行pH稳定性测试，以确保功能化的AuNPs在酸性脑肿瘤微环境中保持其性质。
用从头设计的类转铁蛋白肽对AuNPs进行功能化的提议代表了一种治疗GBM的新方法。我们的策略为跨血脑屏障的药物递送和降低化疗抗性开辟了新途径。虽然我们现阶段主要专注于体外研究和计算建模，但成功完成将导致进一步发展，包括体内研究和纳米颗粒设计优化。本提议预期会激发神经肿瘤学领域未来的研究和资金投入，为GBM提供一种潜在的创新且有效的治疗选择。
国际注册报告识别码（IRRID）：RR1-10.2196/49417。
