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.
Utilizing the previously established glioma-targeted nanoplatform, we have developed a novel strategy of loading arsenate trioxide (ATO)-manganese (Mn) complex to increase the encapsulation efficiency and stability of ATO while reducing its systemic toxicity. Moreover, convertible MRI contrast of Mn in response to intracellular low pH (from dark to bright signal) can be used as a surrogate of the release of therapeutic arsenate. In this project, we will investigate the therapeutic efficacy of the glioma- targeted nano-ATO on various GBM tumors and the ability of the convertible Mn contrast to monitor the delivery and release and biodistribution of ATO by in vivo MRI.
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