Prevention of doxorubicin-induced cardiomyopathy using targeted MaFGF mediated by nanoparticles combined with ultrasound-targeted MB destruction

• Published in: International journal of nanomedicine Vol. 12; pp. 7103 - 7119
• Main Authors: Tian, Xin-Qiao, Ni, Xian-Wei, Xu, He-Lin, Zheng, Lei, ZhuGe, De-Li, Chen, Bin, Lu, Cui-Tao, Yuan, Jian-Jun, Zhao, Ying-Zheng
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2017; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Apoptosis; Cardiac function; Cardiomyopathy; Diabetes; Dosage and administration; Doxorubicin; Doxorubicin-induced cardiomyopathy; Fibroblast growth factors; Fibroblasts; Growth factors; Hospitals; Ischemia; Kinases; Laboratory animals; MaFGF; Morphology; Myocardial diseases; Nanoparticles; Original Research; Oxidative stress; Physiological aspects; Prevention; Proteins; Targeted therapy; Ultrasonic imaging; UTMD; China; UTMD; doxorubicin-induced cardiomyopathy; MaFGF; MaFGF-loaded
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S145799

The present study seeks to observe the preventive effects of doxorubicin-induced cardiomyopathy (DOX-CM) in rats using targeted non-mitogenic acidic fibroblast growth factor (MaFGF) mediated by nanoparticles (NP) combined with ultrasound-targeted MB destruction (UTMD). DOX-CM rats were induced by intraperitoneally injected doxorubicin. Six weeks after intervention, the indices from the transthoracic echocardiography and velocity vector imaging showed that the left ventricular function in the MaFGF-loaded NP (MaFGF-NP) + UTMD group was significantly improved compared with the DOX-CM group. The increased malondialdehyde and decreased superoxide dismutase were observed in the DOX-CM group, while a significant increase in superoxide dismutase and a decrease in malondialdehyde were detected in the groups treated with MaFGF-NP + UTMD. From the Masson staining, the MaFGF-NP + UTMD group showed a significant difference from the DOX-CM group. The cardiac collagen volume fraction and the ratio of the perivascular collagen area to the luminal area number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling positive cells in the MaFGF-NP + UTMD group decreased to 8.9%, 0.55-fold, compared with the DOX-CM group (26.5%, 1.7-fold). From terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling staining, the results showed the strongest inhibition of apoptosis progress in MaFGF-NP + UTMD group. The immunohistochemical staining of the TGF-β1 in MaFGF-NP + UTMD group reached 3.6%, which was much lower than that of the DOX-CM group (12.6%). These results confirmed that the abnormalities, including left ventricular dysfunction, myocardial fibrosis, cardiomyocytes apoptosis and oxidative stress, could be suppressed by twice weekly MaFGF treatments for 6 consecutive weeks (free MaFGF or MaFGF-NP+/UTMD), with the strongest improvements observed in the MaFGF-NP + UTMD group. Western blot analyses of the heart tissue further revealed the highest pAkt levels, highest anti-apoptosis protein (Bcl-2) levels and strongest reduction in proapoptosis protein (Bax) levels in the MaFGF-NP + UTMD group. This study confirmed the preventive effects of DOX-CM in the rats with MaFGF-NP and UTMD by retarding myocardial fibrosis, inhibiting oxidative stress, and decreasing cardiomyocyte apoptosis.