Glycol chitosan/heparin-immobilized gold-deposited iron oxide (IO) nanoparticles (NPs), abbreviated as composite NPs, are a NP-based contrast agent developed by Yuk et al. for tumor stroma-targeted magnetic resonance imaging (MRI) (1).
Tumor tissue is different from normal tissue in the content and function of its stroma. At the initial stage of tumor development, tumor cells secrete growth factors, including vascular permeability factor that renders the local microvasculature hyperpermeable to fibrinogen and other plasma proteins. Extravasated fibrinogen crosslinks with fibrin and other proteins, forming a meshwork in the tumor stroma (2, 3). This sequence also occurs in the process of wound-healing and in the progression of many other diseases, but the tumor stroma contains increased amounts of fibrinogen, collagen, fibronectin, fibrinogen-derived products, and other proteins (2, 4). These proteins either come from the leaky blood vessels or are inappropriately synthesized by the tumor cells. Functionally, normal stroma generates an antiproliferative environment, whereas tumor stroma promotes tumor cell proliferation, migration, and lymphovascular invasion by providing adhesion proteins, proteases, and growth factors (5).
Abnormal formation of clotted plasma protein meshwork in the tumor stroma and on the tumor blood vessel walls has prompted investigators to generate tumor stroma-targeted imaging and therapeutic agents. Pilch et al. screened a phage library on plasma clots and obtained two cyclic decapeptides (CLT; CLT1 and CLT2) (3). The fluorescence-labeled CLT peptides specifically accumulated in the fibrillar meshwork that existed in tumor stroma, but they were not detectable in other tissues in animal models of human tumors. Ye et al. conjugated the CLT1 peptide with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), and the generated agent