Convertible MRI contrast signaling delivery and release of anti-glioma nano-drug

可转换 MRI 对比信号传输和抗神经胶质瘤纳米药物的释放

• 批准号: 8876293
• 负责人: DAWEN ZHAO
• 金额: $ 6.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-08 至 2015-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876293
• 关键词: Antibodies; Arsenates; Arsenic; Arsenic Trioxide; Binding; Biodistribution; Brain; Cells; Clinical; Combined Modality Therapy; Complex; Data; Development; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Encapsulated; Endosomes; Endothelial Cells; Foundations; Glioblastoma; Glioma; Human; Image; Kinetics; Lead; Liposomes; Lysosomes; Magnetic Resonance Imaging; Malignant Intracranial Neoplasm; Malignant Neoplasms; Manganese; Membrane; Monitor; Mus; Neoplasms in Vascular Tissue; Normal tissue morphology; Organ; Pharmaceutical Preparations; Phosphatidylserines; Predisposition; Recurrence; Regulation; Relaxation; Reporting; Resistance; Signal Pathway; Signal Transduction; Solid Neoplasm; Surface; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor Tissue; Vascular Endothelial Cell; Weight; base; cancer imaging; cancer stem cell; cancer therapy; contrast imaging; cytotoxic; drug distribution; imaging agent; in vivo; in vivo imaging; interest; irradiation; mouse model; nano; nanocarrier; nanodrug; nanoformulation; nanoparticle; neoplastic cell; novel; novel strategies; public health relevance; response; standard of care; stem; success; targeted delivery; temozolomide; treatment response; tumor; uptake

 DESCRIPTION (provided by applicant): Incorporation of imaging agents into nano-drug delivery systems aims to achieve simultaneous cancer treatment and imaging. There has been considerable interest in developing switchable or activatable imaging contrast to sense the drug release, tissue distribution and pharmacokinetics. We have recently developed a phosphatidylserine (PS)-targeted nanoplatform for specific and sensitive in vivo imaging of glioblastoma (GBM). Our previous studies have shown significant PS exposure on the luminal surface of vascular endothelial cells (ECs) of GBM. In normal brain, PS is restricted to the inner membrane of ECs. Functionalizing the PEGylated liposomes with PS-targeting antibodies leads the liposome nanocarriers to bind specifically to PS-exposed tumor vascular ECs and tumor cells and subsequently become internalized into the cells. It is well known that GBM is highly resistant to multimodal therapies. Despite the improvement in GBM survival when adding temozolomide (TMZ) to the standard of care for GBM, recurrences are inevitable. Several recent studies have suggested the subpopulation of endogenous TMZ-resistant cells or cancer stem-like cells in GBM. Thus, it is imperative to seek an effective therapeutics against these cells. Promising data of arsenic trioxide (ATO) have shown that ATO is able to deplete such resistant GBM cells via inhibition key cancer stem cell signaling pathways. However, applications of ATO on solid tumors have been limited by its systemic toxicity. We have developed a novel strategy of utilizing manganese (Mn) to increase the encapsulation efficiency and stability of ATO while reducing its systemic toxicity. Moreover, formation of As-Mn precipitates in liposomes possesses a strong MR susceptibility effect (dark signal). Intriguingly, after the cell uptake, the As-Mn complex decomposes to release ionic Mn2+ and As3+ in response to low pH in endosome-lysosome system. The strong T1 contrast, Mn2+ gives a bright signal on T1- weighted images. Thus, monitoring of the conversion of MRI signal can be used as a surrogate of the delivery and release of As3+, the active form of ATO. Our preliminary data found that ATO is equally effective against the TMZ-sensitive or resistant GBM lines. Built on our PS-targeted nanoplatform, in this project, we propose to establish the GBM-targeted nanocarriers containing arsenic-manganese complex to enhance the delivery of ATO to treat glioma while minimizing systemic toxicity. We will test its therapeutic efficacy on various GBM tumors that are known to have differential response to TMZ. We further hypothesize that the delivery, release kinetics and biodistribution of liposomal ATO can be monitored spatially and temporally by MRI based on the convertible Mn contrast.

 描述（由申请人提供）：将显像剂纳入纳米药物递送系统旨在实现同时进行的癌症治疗和成像。人们对开发可切换或可激活的成像对比来感测药物释放、组织分布和药代动力学产生了相当大的兴趣。我们最近开发了一种针对磷脂酰丝氨酸（PS）的纳米平台，用于胶质母细胞瘤（GBM）的特异性和灵敏的体内成像。我们之前的研究表明，GBM 血管内皮细胞 (EC) 的管腔表面存在显着的 PS 暴露。在正常大脑中，PS 仅限于 EC 内膜。用 PS 靶向抗体功能化聚乙二醇化脂质体，导致脂质体纳米载体特异性结合暴露于 PS 的肿瘤血管 EC 和肿瘤细胞，随后内化到细胞中。众所周知，GBM 对多模式疗法具有高度抵抗力。尽管将替莫唑胺 (TMZ) 添加到 GBM 护理标准中可以改善 GBM 生存率，但复发是不可避免的。最近的几项研究表明 GBM 中存在内源性 TMZ 耐药细胞或癌症干细胞样细胞亚群。因此，迫切需要寻找针对这些细胞的有效疗法。三氧化二砷 (ATO) 的有希望的数据表明，ATO 能够通过抑制关键的癌症干细胞信号传导途径来耗尽此类耐药 GBM 细胞。然而，ATO在实体瘤上的应用因其全身毒性而受到限制。我们开发了一种利用锰 (Mn) 来提高 ATO 的封装效率和稳定性，同时降低其全身毒性的新策略。此外，脂质体中 As-Mn 沉淀的形成具有很强的 MR 磁化率效应（暗信号）。有趣的是，细胞摄取后，As-Mn 复合物响应内涵体-溶酶体系统中的低 pH 值而分解，释放离子 Mn2+ 和 As3+。强 T1 对比度，Mn2+ 在 T1 加权图像上给出明亮的信号。因此，对 MRI 信号转换的监测可以用作 As3+（ATO 的活性形式）递送和释放的替代指标。我们的初步数据发现，ATO 对 TMZ 敏感或耐药的 GBM 系同样有效。在我们的PS靶向纳米平台的基础上，在这个项目中，我们建议建立含有砷锰复合物的GBM靶向纳米载体，以增强ATO的输送来治疗神经胶质瘤，同时最大限度地减少全身毒性。我们将测试其对已知对 TMZ 有不同反应的各种 GBM 肿瘤的治疗效果。我们进一步假设脂质体 ATO 的递送、释放动力学和生物分布可以通过基于可转换 Mn 对比的 MRI 进行空间和时间监测。