CellVue Maroon–labeled saposin C-dioleylphosphatidylserine nanovesicles

The CellVue Maroon (CVM)–labeled saposin C (SapC)-dioleylphosphatidylserine (DOPS) nanovesicle, abbreviated as CVM-SapC-DOPS, is an imaging agent developed by Qi et al. and Kaimal et al. for phospholipid (PS)-targeted optical imaging (1, 2). Saposins are a group of water-soluble lysosomal glycoproteins (SapA, SapB, SapC, and SapD) with molecular weights of 8–11 kDa (1-3). They are generated by the proteolytic processing of the common precursor prosaposin. Saposins localize primarily in the lysosomes and are required for the catabolism of glycosphingolipids (4, 5). The four saposins have a high degree of structural similarity and share lipid-binding and membrane-perturbing properties; however, they behave differently and exhibit different specificities (1, 3). SapC is the second saposin to be discovered, and it binds to membranes in a pH-controlled manner (6). SapC can directly activate enzymes and stimulate the hydrolysis of glycocerebroside and galactocerebroside (7). Deficiency of SapC leads to an abnormal juvenile form of Gaucher disease with accumulation of glucosylceramide in various organs, including the brain (5). SapC preferentially interacts with unsaturated, negatively charged PS such as DOPS at acidic pH (6, 8). PS is present in all cells and constitutes ~2%–10% of total cellular lipids. In normal tissues, PS is localized in the cell membrane leaflets that face the cytosol. However, in pathological conditions such as tumors, PS translocates to the outer leaflet of the plasma membrane, where it activates and participates in various cellular processes, including apoptosis and necrosis (5, 9). Phagocytes in healthy tissues rapidly and efficiently remove the PS-expressing cells and cell remnants, but these PS-expressing cells and cell remnants accumulate in diseased tissues as a result of the activation of the cell death process and the insufficient clearance of cells expressing PS externally (9). Because tumors express abundant PS on the cell surface and have a lower extracellular pH (pH ~6) than normal tissues (pH ~7), the SapC-PS interaction provides a valuable system for targeted tumor imaging and therapy (4, 9, 10). Qi et al. developed a SapC-DOPS nanovesicle system that induced apoptosis of tumor cells and inhibited growth of neuroblastomas and malignant peripheral nerve sheath tumors in animal models (1). Both fluorescently labeled SapC-DOPS (CVM-SapC-DOPS) and iron oxide particle–coupled SapC-DOPS (SapC-DOPS-IO) have been shown to preferentially accumulate in tumor xenografts (1, 2). These studies indicate that SapC-DOPS nanovesicles are promising as a new and robust theranostic agent for cancer-selective detection, visualization, and therapy. This chapter summarizes the data obtained with CVM-SapC-DOPS. The data obtained with SapC-DOPS-IO are summarized in another chapter in MICAD.