A New Class of Magnetic Nanoparticles for Glioma Targeted Drug Delivery

用于神经胶质瘤靶向药物输送的新型磁性纳米颗粒

• 批准号: 10258239
• 负责人: Yuancheng Li
• 金额: $ 40万
• 依托单位: 5M BIOMED, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258239
• 关键词: Biodistribution; Biological; Blood; Blood Circulation; Brain Neoplasms; Cell Death; Cells; Charge; Chemistry; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Management; Clinical Oncology; Combination Drug Therapy; Cyclic Peptides; Development; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Encapsulated; Excision; FDA approved; Formulation; Glioblastoma; Glioma; Goals; Half-Life; Hydrophobicity; In Vitro; Integrin alphaVbeta3; Integrins; Intracranial Neoplasms; Investigation; Iron deficiency anemia; Lead; Legal patent; Ligands; Liposomes; Magnetic Resonance Imaging; Magnetic nanoparticles; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Morphology; Mus; Nano delivery; Nature; Oncology; Operative Surgical Procedures; Organ; Outcome; Patients; Pharmaceutical Preparations; Phase; Play; Polymers; Preparation; Prognosis; Property; RGD (sequence); Radiation therapy; Reporting; Reproducibility; Role; Safety; Small Business Technology Transfer Research; Surface; System; Systems Development; Technology; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Ultrafine; Universities; Water; amphiphilicity; analytical method; base; biomaterial compatibility; blood-brain barrier crossing; blood-brain tumor barrier; brain tumor imaging; cancer cell; chemical property; chemotherapeutic agent; chemotherapy; clinical translation; contrast enhanced; contrast imaging; cytotoxicity; density; efficacy evaluation; ethylene glycol; ferumoxytol; glycidyl ethers; imaging modality; improved; in vivo; in vivo imaging; irinotecan; iron oxide nanoparticle; mouse model; nanocarrier; nanomaterials; nanomedicine; nanoparticle; nanoparticle delivery; novel drug class; overexpression; pharmacokinetics and pharmacodynamics; physical property; prevent; side effect; standard care; stem; subcutaneous; success; targeted biomarker; targeted delivery; theranostics; therapeutically effective; tumor; tumor growth; tumor progression; uptake; water solubility

Project Summary Glioblastoma is the most common and aggressive malignant brain tumor with extremely poor prognosis. Current standard care for glioblastoma treatment consists of maximal surgical resection followed by chemotherapy and radiation therapy. Unfortunately, it hardly produces long-term control on tumor progression. Due to the highly heterogeneous, infiltrating and recurring natures of glioblastomas, chemotherapy plays a crucial role in clinical management of glioblastomas. However, existing chemotherapies in brain tumor treatment are mostly disappointing, often due to poor delivery of chemotherapy agents stemming from their low water solubility and/or inability of crossing the blood brain barrier (BBB) or blood tumor barrier (BTB). Although nanomaterial-based drug delivery systems have shown advantages by enhancing the delivery efficiency and improving the safety profile of therapeutics over conventional chemotherapy formulations in treating many cancers, their development and applications in brain tumor treatment are largely limited, because of delivery challenges in current nano-delivery systems with sizes of 10-200 nm. Supported by the premises that: 1) ferumoxytol (Feraheme®), an FDA approved iron oxide nanoparticle for treating iron deficiency anemia, can be used for imaging brain tumor with magnetic resonance imaging (MRI) in patients, and 2) our sub-5 nm ultrafine iron oxide nanoparticle (uIONP) can reach brain tumors in the intracranial glioma mouse model to enhance tumors in MRI with T1 contrast, this STTR Phase I project aims to develop a new class of drug-carrying and glioblastoma targeted IONP for delivering highly potent yet water-insoluble chemotherapy agent SN38, the active and much more potent form of chemotherapy agent Irinotecan (CPT-11) used in treating many other cancers in oncology clinic, for treating intracranial brain tumors. We will incorporate our patented amphiphilic poly(ethylene glycol)-block-(allyl glycidyl ether) (PEG-b-AGE) coating polymer for uIONPs to encapsulate hydrophobic SN38, which has not been used for treating brain tumors due to poor intracranial delivery. Tri-peptide RGD with well-documented functions and safety profile is selected as the ligand for functionalizing uIONPs to target αvβ3 integrin overexpressed in glioblastomas. In the proposed project, we will prepare and optimize the RGD-conjugated uIONP with SN38 loading (RGD-uIONP/SN38) with consistent physiochemical and biological properties, including SN38 loading efficiency, surface charge, density of conjugated the targeting ligand, glioblastoma cell targeting, intracellular drug release and cytotoxicity, and stability (Aim 1). We will then use an intracranial mouse model to investigate the blood half-life, biodistribution, clearance, and tumor uptake and intra-tumoral distribution of developed RGD-uIONP/SN38 as well as the stability of this platform in blood and organs in Aim 2, followed by determining the efficacy of RGD- uIONP/SN38 in inhibiting the tumor growth based on MRI in vivo and histopathological analysis. The results will lead to the further development of this system towards clinical translation in the Phase II project.

胶质母细胞瘤是最常见和最具侵袭性的恶性脑肿瘤。 预后不良。目前治疗胶质母细胞瘤的标准护理包括最大限度的手术切除 随后是化疗和放射治疗。不幸的是，它很难产生对肿瘤的长期控制。 进步。由于胶质母细胞瘤的高度异质性、浸润性和复发性， 化疗在胶质母细胞瘤的临床治疗中起着至关重要的作用。然而，现有的化疗方法 在脑肿瘤的治疗中大多令人失望，往往是由于化疗药物输送不力 由于它们的低水溶性和/或无法通过血脑屏障(BBB)或血液肿瘤 屏障(BTB)。虽然基于纳米材料的药物传递系统通过增强 与常规化疗相比，治疗药物的给药效率和安全性改善 治疗多种癌症的制剂及其在脑肿瘤治疗中的开发和应用在很大程度上 有限，因为目前尺寸为10-200纳米的纳米递送系统中的递送挑战。支持： 前提是：1)阿魏酸(Feraheme®)，FDA批准的用于处理铁的氧化铁纳米颗粒 缺乏性贫血，可用于对患者脑肿瘤进行磁共振成像(MRI)， 2)我们的亚5 nm超细氧化铁纳米颗粒(Uionp)可以到达脑胶质瘤中的脑肿瘤。 用小鼠模型增强肿瘤在MRI中的T1对比度，这一STTRI期项目旨在开发一种新的 一类以IONP为靶点的载药和胶质母细胞瘤，可提供高效但不溶于水的药物 化疗药物SN38，活性更强的化疗药物伊立替康(CPT-11) 用于治疗肿瘤临床中的许多其他癌症，用于治疗颅内脑肿瘤。我们将把 我们的专利两亲性聚乙二醇嵌段(烯丙基缩水甘油醚)(PEG-b-AGE)涂层聚合物，用于 UIONPs包裹疏水SN38，因质量差尚未用于脑肿瘤治疗 颅内分娩。选用具有良好功能和安全性的三肽RGD作为 针对αvβ3整合素的uIONPs功能化配体在胶质母细胞瘤中过表达。在建议的 项目中，我们将制备和优化SN38负载的RGD共轭uIONP(RGD-uIONP/SN38) 一致的物理化学和生物特性，包括SN38负载效率、表面电荷、密度 结合的靶向配体，胶质母细胞瘤细胞靶向，细胞内药物释放和细胞毒性，以及 稳定性(目标1)。然后我们将使用一个颅内小鼠模型来研究血液的半衰期，生物分布， RGD-uIONP/SN38的清除、肿瘤摄取和肿瘤内分布以及 目标2中该平台在血液和器官中的稳定性，随后测定RGD-2的疗效 体内MRI和组织病理学观察uIONP/SN38对肿瘤生长的抑制作用。结果是 将导致该系统在第二阶段项目中向临床翻译的进一步发展。

项目成果

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

• DOI: 10.1002/adhm.202102816
• 发表时间: 2022-07
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Li, Yuancheng;Xie, Manman;Jones, Joshua B.;Zhang, Zhaobin;Wang, Zi;Dang, Tu;Wang, Xinyu;Lipowska, Malgorzata;Mao, Hui
• 通讯作者: Mao, Hui