A New Class of Magnetic Nanoparticles for Glioma Targeted Drug Delivery

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。目前胶质母细胞瘤治疗的标准治疗包括最大限度的手术切除 随后进行化疗和放疗。不幸的是，它很难对肿瘤产生长期控制 进展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 在脑肿瘤治疗中，大多数是令人失望的，通常是由于化疗剂的不良递送 来源于它们的低水溶性和/或不能穿过血脑屏障（BBB）或血液肿瘤 屏障（BTB）。尽管基于纳米材料的药物递送系统已经显示出通过增强药物递送的优点， 递送效率和改善治疗剂相对于常规化疗的安全性 尽管这些制剂在治疗许多癌症中的应用，但它们在脑肿瘤治疗中的开发和应用在很大程度上受到限制。 这是有限的，因为在当前尺寸为10-200 nm的纳米递送系统中存在递送挑战。支持 前提是：1）ferumoxytol（Feraheme®），FDA批准的用于治疗铁的氧化铁纳米颗粒， 缺铁性贫血，可用于脑肿瘤患者的磁共振成像（MRI）， 2）我们的亚5 nm超细氧化铁纳米颗粒（uIONP）可以到达颅内胶质瘤中的脑肿瘤 小鼠模型，以增强肿瘤在MRI与T1对比，这个STTR第一阶段项目的目的是开发一种新的 一类携带药物并靶向胶质母细胞瘤的IONP，用于递送高效但不溶于水的 化疗剂SN 38，化疗剂伊立替康（CPT-11）的活性和更有效的形式 在肿瘤临床上用于治疗许多其他癌症，用于治疗颅内肿瘤。我们将合并 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， uIONP包封疏水性SN 38，由于其不良的生物相容性，其尚未用于治疗脑肿瘤。 颅内递送。选择具有良好记录的功能和安全性特征的三肽RGD作为 用于功能化uIONP以靶向胶质母细胞瘤中过表达的αvβ3整联蛋白的配体。拟议 项目，我们将制备和优化具有SN 38负载的RGD缀合的uIONP（RGD-uIONP/SN 38）， 一致的理化和生物学特性，包括SN 38装载效率、表面电荷、密度 缀合的靶向配体、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，我们将使用颅内小鼠模型来研究血液半衰期、生物分布， 开发的RGD-uIONP/SN 38的清除率、肿瘤摄取和肿瘤内分布以及 目的2中该平台在血液和器官中的稳定性，然后确定RGD-1的功效。 基于体内MRI和组织病理学分析，证实了uIONP/SN 38抑制肿瘤生长的作用。结果 将导致该系统在第二阶段项目中向临床转化的进一步发展。

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.