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

 描述(申请人提供)：将显像剂引入纳米药物输送系统，旨在实现癌症治疗和成像的同时。人们对开发可切换或可激活的成像对比剂以感知药物释放、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以磷脂酰丝氨酸(PS)为靶点的纳米平台，用于胶质母细胞瘤(GBM)的特异和灵敏的体内成像。我们以前的研究表明，在GBM的血管内皮细胞(ECs)的管腔表面有显著的PS暴露。在正常脑中，PS仅局限于内皮细胞的内膜。将聚乙二醇化的脂质体与PS靶向抗体功能化，导致脂质体纳米载体与PS暴露的肿瘤血管内皮细胞和肿瘤细胞特异性结合，随后内化到细胞内。众所周知，GBM对多模式治疗具有高度抵抗力。尽管加入替莫唑胺(TMZ)治疗基底膜的标准可提高基底膜的存活率，但复发是不可避免的。最近的几项研究表明，在GBM中存在内源性TMZ耐药细胞或肿瘤干细胞亚群。因此，寻求针对这些细胞的有效治疗方法势在必行。关于三氧化二砷(ATO)的研究显示，ATO能够通过抑制关键的癌症干细胞信号通路来耗尽这种耐药的GBM细胞。然而，ATO的全身毒性限制了其在实体瘤中的应用。我们开发了一种新的策略，利用锰(Mn)来提高ATO的包封率和稳定性，同时降低其全身毒性。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，在细胞摄取后，内酶体-溶酶体系统中的As-Mn复合体在低pH值下分解释放出离子Mn2+和As3+。强T1对比度下，Mn2+在T1加权图像上显示出明亮的信号。因此，监测MRI信号的转换可以作为ATO的活性形式As3+传递和释放的替代。我们的初步数据发现，ATO对TMZ敏感或抗性的GBM株系同样有效。在我们的PS靶向纳米平台的基础上，在这个项目中，我们建议建立包含砷锰络合物的GBM靶向纳米载体，以增强ATO的传递，以治疗胶质瘤，同时将全身毒性降至最低。我们将测试它对各种已知对TMZ有不同反应的GBM肿瘤的治疗效果。我们进一步假设，基于可转换的MN对比度，MRI可以在空间和时间上监测脂质体ATO的传递、释放动力学和生物分布。

 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.