# Advanced Microbubbles as a Multifunctional Platform Combining Imaging and Therapy
## 2 Advanced Microbubbles for Imaging and Therapy
### Drug/Gene Delivery  
The technology of ultrasound-targeted microbubble destruction (UTMD) has become one of the most promising strategies for the targeted delivery of drugs/genes, which can protect the drugs/genes from capture or destruction by the external environment, and achieve US-triggered targeted drug/gene delivery to the lesions. Studies show that the efficiency of UTMD is mainly determined by the pressure, duration of US exposure and MB concentration [87]. [PERSON] et al. used the heparinized MBs carrying acidic fibroblast growth factor (aFGF) in combination with UTMD to study rat models with myocardial infarction, and found that the technique of UTMD could effectively facilitate aFGF delivery to the myocardium and therefore improve cardiac function recovery [88]. [PERSON] injected stem cell factor (SCF) and stromal cell-derived factor (SDF-1\(\alpha\)) into rats with myocardial infarction with the assistance of UTMD. The results showed that the delivery of SCF and SDF-1\(\alpha\) to the infarcted myocardium recruited progenitor cells after treatments, and led to increased vascular density and enhanced tissue repair [89]. [PERSON] et al. disclosed US-MB-mediated diclofenac delivery to treat adjuvant-induced rheumatoid arthritis (RA) in rats. By combining US and MBs, the skin permeability could be increased which thereby enhanced the delivery of diclofenac sodium gel and also inhibited inflammation of the tissues surrounding the arthritic ankle. Color Doppler-mode US imaging revealed that US-MB combinatory treatments induced a rapid reduction in synovial neoangiogenesis in the arthritic area [90]. [PERSON] et al. further optimized the UTMD technique by improving the in vivo transfection efficiency of the enhanced green fluorescent protein (EGFP) plasmid in the synovial pannus in an antigen-induced arthritis rabbit model. The EGFP expression in the synovial pannus of the US + MBs + plasmid group was significantly higher than that of the other four groups. This validated that UTMD has become a safe and effective non-viral gene transfection procedure for arthritis therapy [91]. [PERSON]'s group developed simvastatin (Sim)-loaded polymeric MBs for targeting inflamed vascular endothelium to serve the diagnosis and treatment of atherosclerosis. This gas-filled MBs for drug delivery demonstrated promises to provide a stable acoustic enhancement and effectively identify atherosclerotic areas of plaque within the ventral aorta of rabbits [92]. [PERSON] modified the surface of DNA nanocarriers with heparin to inhibit passive gene transfer in both the target and the off-target tissues, and selectively activated heparin-inhibited gene to transfer at the target site by using UTMD [93]. They observed that the engraftment reduced off-target gene expression in the liver by more than 700-fold compared to the non-heparinized PEGylated liposomes; tumor-directed UTMD increased gene transfer with heparin-modified nanoplexes by more than 10-fold (Figure 5). Not only can UTMD increase the delivery of drugs/genes, but the ultrasound itself can also improve the efficiency of delivery. In a study, [PERSON] designed a novel \({}^{68}\)Ga-labeled integrin \(\alpha\)2B1-targeted PET tracer \({}^{68}\)Ga-NOTA-PEG4-cyclo (GDGEAyK) (\({}^{68}\)Ga-A2B1) and uptake was higher in subcutaneous U87 MG tumor-bearing athymic mice [94]. Then they found that with or without tracer integration of microbubbles, \({}^{68}\)Ga-A2B1 tumor uptake could be improved in combination with focus ultrasound (Figure 6). The UTMD technology does not only increase the localized drug concentration at the targeted organs or tissues, but it also reduces the side effects of systemic drugs. This has been proved by [PERSON] et al. who prepared hydrogen sulfide-loaded MBs (hs-MBs) with different H2S/C3F8 ratios, and US-targeted hs-MB destruction was applied in a rodent model of myocardial ischemia-reperfusion injury. The optimal ratio of H2S/C3F8 was found to be 2/2 with the highest H2S-loading capacity.