# Advanced Microbubbles as a Multifunctional Platform Combining Imaging and Therapy
## 2 Advanced Microbubbles for Imaging and Therapy
### Inflammation  
The pathophysiology of inflammation is a series of molecular signals generated by the inflammatory responses that turn the leukocytes into the inflamed tissues. Leukocytes firmly adhere to the vascular endothelial cell wall before they transmigrate from the blood circulation into inflamed tissues. P-selectin expresses rapidly on activated endothelial cells upon inflammation occurs. The endothelial cells also overexpress E-selectin, and leucocytes can overexpress L-selectin, intercellular adhesion molecule1 (ICAM-1) and vascular cell adhesion molecule1 (VCAM-1) which can mediate the adhesion of leucocytes and endothelial cells at the inflammatory lesions. Therefore, P-, E- and L-selectin, ICAM-1 and VCAM-1 can be used as specific biomarkers of inflammation to evaluate their occurrence at an early stage. Molecular US imaging has been successfully applied to inflammations including inflammatory bowel diseases, myocardial ischemia, arthosclerosis, and rejection in cardiac transplantation. [PERSON] developed P-selectin glycoprotein-functionalized MBs (MBrPSGL-Ig) [60]. The adhesion efficiency of \begin{table}
\begin{tabular}{c c c c} \hline
**Target** & **Ligand** & **Tumor Model** & **Reference** \\ \hline VEGFR2/KDR & Heterodimeric peptide (BR55) & Colon carcinoma & [45] \\ \hline VEGFR2 & Heterodimeric peptide (BR55) & \begin{tabular}{c} Mammary carcinoma, Breast cancer, \\ Prostate adenocarcinoma, \\ Renal cell carcinoma \\ \end{tabular} & [46; 47; 48] \\ \hline VEGFR2 & Antibody & \
\begin{tabular}{c} Breast cancer, Pancreatic cancer, \\ Squamous cell carcinoma, \\ Angiogenesis sarcoma (SVR), Glioma (C6) \\ \end{tabular} & [49; 50; 51] \\ \hline \(\alpha\)v\(\beta\)3 & Cyclic RGD peptide & Breast cancer & [33] \\ \hline \(\alpha\)v\(\beta\)3 & RGD & Squamous cell carcinoma & [52] \\ \hline \(\alpha\)v\(\beta\)3 & Echistatin & Glioma & [53] \\ \hline \(\alpha\)v\(\beta\)3 & Knottin & Ovarian cancer & [54] \\ \hline Endoglin (CD105) & Antibody & Pancreatic cancer & [50] \\ \hline SFRP2 & Antibody & Angiosarcoma (SVR) & [39] \\ \hline VEGFR2, \(\alpha\)v\(\beta\)3, Endoglin &
\begin{tabular}{c} Subtaneous cancers (breast, \\ ovarian, pancreatic cancer) \\ \end{tabular} & [55] \\ \hline VEGFR2, \(\alpha\)v\(\beta\)3, P-selectin & Antibody & Breast cancer & [37] \\ \hline \(\alpha\)v\(\beta\)3, ICAM-1 & Antibody & Prostate cancer & [56] \\ \hline VEGFR2 + \(\alpha\)v\(\beta\)3 & Antibody & Ovarian cancer & [57] \\ \hline VEGFR2 + \(\alpha\)v\(\beta\)3 + ICAM1 & Antibody & Human MDA-MB-231 breast cancer & [58] \\ \hline CRPPR, ATWLPPR & Antibody & Breast cancer & [59] \\ \hline \end{tabular}
\end{table} 
Table 2: Assessment tumor angiogenesis with different targeted microbubbles (MBs). Figure 3: Comparison of before and after i.v (intravenously) injection of (**A**) AlgNC; and (**B**) CaCO\({}_{3}\)-AlgNC in vivo ultrasound imaging of tumors showed in the red outline; (**C**) Significant differences between contrast-enhanced ratio of CaCO\({}_{3}\)-AlgNC and AlgNC post-injection. *, \(p\) < 0.05, and _#, p_ > 0.05. **Note:** Copyright 2016, American Chemical Society. Abbreviation: NC: nanocarrier. MBrPSGL-Ig constructs under static or flow conditions and molecular imaging studies were performed in the rat inflammatory model by intravenous injection of MBs with monitoring the accumulation of targeted MBs in the muscle. It proved that they could interact specifically and efficiently with E- and P-selectin at the surface of inflamed endothelial cells. The echo signals measured with MBrPSGL-Ig in the inflamed muscles was 20-fold higher compared with control MBs. The in vivo adhesion of MBrPSGL-Ig was 2- and 7-fold higher compared with P-selectin or E-selectin-specific MBs, respectively. [PERSON] developed dual-targeted MBs (MBSelectin) for P- and E-selectin-specific inflammation in a murine acute colitis model [61]. Small animal imaging experiments showed that MB-selectin had strong attachment to both human and mouse P- and E-selectin and significantly increased US signals in mice.