Page 80 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 4
tMB). The tMB have a ligand added in their coating by which the tMB can adhere to disease-specific cell membrane biomarkers [31, 32].
It was previously shown that 45–60 nm SPIO (Resovist) could be delivered in vivo into the swine brain using SonoVue lipid-coated non-tMB and ultrasound (28-kHz ultrasound with 100-ms burst length and repetition rate of 1 Hz at 0.6 – 1 MPa (mechanical index (MI) 4.8 – 6.0) applied for 5 min; MRI performed 3 h after treatment) [33]). Brain tumor delivery of SPIO (mean diameter 6 – 10 nm [34] or 35.7 ± 9.2 nm [35]) loaded in the lipid-coating of in-house produced non-tMB was shown in vivo in rats using ultrasound (0.4 MHz with 1,000 cycles and repetition rate of 1 Hz at 325 kPa (MI 0.5) applied for 90 s; MRI performed 40 min after treatment [34] or 1 MHz with 5,000 cycles and repetition rate of 1 Hz at 300 kPa (MI 0.3) applied for 4 min; MRI performed 1 and 3 h after treatment [35]). Delivery of 120 – 180 nm SPIO (Feridex) was also shown in the aortic arch by SonoVue and ultrasound treatment (8.5 MHz ultrasound at an MI of 1.2 applied for 20 min; MRI performed 1 h after treatment) [36]. These studies demonstrate the possibility of SPIO-loaded MB or co-administrated SPIO with MB for labeling extravascular tissues and subsequent MRI imaging of the SPIO, but do not cover cell labeling. Successful SPIO (Revovist) mesenchymal stem cell labeling using SonoVue and ultrasound (1 MHz, 50% duty cycle, 1.0 W/cm2 acoustic power applied for 60 s) has been reported in vitro [37]. SPIO (12 nm mean diameter) loaded in the polymer coating of in-house produced non-tMB were used to successfully label tumor cells in vitro using ultrasound (1 MHz, 20 cycles per burst, repetition rate of 10 kHz, 0.1 – 0.75 W/cm2 acoustic power applied for 40 s) [38]. However, MB are blood pool agents. Endothelial cells, which form the inner lining of vessels, are therefore the main target of intravascular administered MB [39, 40]. Exceptions are tumors that invade into the vasculature, as reported for hepatocellular cancer (i.e. a primary liver tumor) [41] and colorectal cancer [42]. On the other hand, tMB were shown to target ovarian cancer cells preclinically by an alternative administration route, namely intraperitoneal injection [43]. Additionally, tMB are preferable instead of non-tMB since they can be specifically targeted to the cells of interest and upon binding are close to the endothelium, which is a perquisite for the MB-mediated drug delivery effectiveness [26]. The in vivo study by Gao et al. demonstrated arterial wall uptake of SPIO particles using non-tMB and ultrasound [36], but only under one acoustic setting (8.5 MHz ultrasound at
78