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）：将成像剂并入纳米药物递送系统旨在实现同时的癌症治疗和成像。人们对开发可切换或可激活的成像对比度以感测药物释放、组织分布和药代动力学有相当大的兴趣。我们最近开发了一种磷脂酰丝氨酸（PS）靶向的纳米平台，用于胶质母细胞瘤（GBM）的特异性和敏感性体内成像。我们之前的研究表明，GBM血管内皮细胞（EC）的腔表面存在显着的PS暴露。在正常脑中，PS仅限于EC的内膜。用PS靶向抗体官能化PEG化脂质体导致脂质体纳米载体特异性结合PS暴露的肿瘤血管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抗性。尽管在GBM的标准治疗中加入替莫唑胺（TMZ）可改善GBM的生存率，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耐药细胞或癌干细胞样细胞亚群。因此，必须寻求针对这些细胞的有效治疗方法。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消耗这种耐药的GBM细胞。然而，ATO的全身毒性限制了其在实体瘤中的应用。我们已经开发了一种新的策略，利用锰（Mn），以增加ATO的包封效率和稳定性，同时降低其全身毒性。此外，脂质体中As-Mn沉淀物的形成具有强的MR敏感性效应（暗信号）。有趣的是，在细胞摄入后，As-Mn复合物会响应内体-溶酶体系统中的低pH而分解释放离子型Mn 2+和As 3+。T1对比度强，Mn 2+在T1加权图像上显示明亮信号。因此，监测MRI信号的转换可以用作ATO的活性形式As 3+的递送和释放的替代。我们的初步数据发现ATO对TMZ敏感或抗性GBM系同样有效。基于我们的PS靶向纳米平台，在本项目中，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治疗胶质瘤的递送，同时最大限度地减少全身毒性。我们将测试其对已知对TMZ具有差异反应的各种GBM肿瘤的治疗功效。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基于可转换的Mn对比度通过MRI在空间和时间上监测。