Background: Lipid and polymer microbubbles (MBs) are widely used as ultrasound contrast agents in clinical diagnosis, and possess great potential in ultrasound-mediated therapy due to their drug loading function. However, overcoming the limitations of stability and echo enhancement of MBs are still a considerable challenge.Methods: A series novel block, graft and block-graft copolymers was proposed and prepared in this work, and these copolymers were used as shells to encapsulate perfluoropentane as ultrasound contrast agents. First, block, graft and block-graft copolymers with different topological structures were prepared. Then, these copolymers were prepared into block copolymer phase-transition MBs, graft copolymer phase-transition MBs, and block-graft copolymer phase-transition MBs, respectively. Finally, the dexamethasone was used for drug-loaded phase-transition microbubbles model to explore the potential of theranostic microbubbles.Results: Finally, these three resulting copolymer MBs with average size of 4–5 μm exhibited well enhancement of ultrasound imaging under the influence of different frequencies and mechanical index, and they exhibited a longer contrast-enhanced ultrasound imaging time and higher resistance to mechanical index compared with SonoVue in vitro and in vivo. In vitro drug release results also showed that these copolymer MBs could encapsulate dexamethasone drugs, and the drug release could be enhanced by ultrasonic triggering. These copolymer MBs were therapeutic MBs for targeted triggering drug release.Conclusion: Therefore, the feasibility of block, graft, and block-graft copolymers as ultrasonic contrast agents was verified, and their ultrasonic enhancement performance in vitro and in vivo was compared. The ultrasound contrast agents developed in this work have excellent development potential in comprehensive diagnosis and treatment.
Background: Ultrasound-responsive nanodroplets (NDs) targeting tumors have shown great potential in ultrasound imaging and tumor therapy, but most of these studies are based NDs with lipid shells that cannot overcome the uptake by cells of the reticulo-endothelial system (RES). NDs with shells comprised of polyethylene glycol (PEG)-based polymers could effectively suppressed the uptake of RES, but the phase transition, contrast-enhanced imaging and drug release about these NDs have not been well illuminated. Methods: Folate receptor targeted NDs with shells of polymers and loaded with DOX (FA-NDs/DOX) were prepared. The particle size distribution and morphology of NDs was characterized with dynamic light scattering (DLS) and microscope. Phase transition and contrast-enhanced ultrasound imaging under different mechanical indices (MIs) was studied, and the intensity of contrast enhancement were quantitatively analyzed. The targeting property of FA-NDs/DOX to MDA-MB-231 cells and cellular uptake were observed using a fluorescence microscope. The anti-tumor effects of FA-NDs/DOX combined with low-intensity focused ultrasound (LIFU) was studied through cytotoxicity tests. Flow cytometry assays were used to detect cell apoptosis. Results: The average particle size of the FA-NDs/DOX was 448.0 ± 8.9 nm, and the zeta potential was 30.4 ± 0.3 mV. When exposed to ultrasound at 37 °C, ultrasound contrast enhancement of FA-NDs/DOX was observed when MI ≥0.19. A stronger acoustic signal was observed under higher MIs and concentrations. The results of quantitative analysis showed that the contrast enhancement intensity of FA-NDs/DOX (1.5 mg/mL) at MI of 0.19, 0.29 and 0.48 was 26.6 ± 0.9 dB, 97.0 ± 3.8 dB and 153.1 ± 5.7 dB, respectively. The contrast enhancement of the FA-NDs/DOX lasted for more than 30 minutes at an MI of 0.48. In targeting experiments, FA-NDs could be recognized by MDA-MB-231 cells, and significant cellular uptake was observed. The blank FA-NDs showed good biocompatibility, while the FA-NDs/DOX induced apoptosis of MDA-MB-231 and MCF-7 cells. By combining LIFU irradiation and FA-NDs/DOX treatment, the best cell-killing effect was achieved. Conclusions: The FA-NDs/DOX prepared in this study has excellent performance in contrast-enhanced ultrasound imaging, tumor targeting and enhanced chemotherapy. This FA-NDs/DOX with polymer shells provides a novel platform for ultrasound molecular imaging and tumor therapy.
危险品化学品经营许可证（带存储）