Enhanced Antitumor Efficacy and Reduced Cardiotoxicity of Ultrasound-Mediated Doxorubicin Delivery by Microbubble-Liposome Complexes

OBJECTIVE: Doxorubicin (Dox) is standard of care for treatment of sarcomas, but cumulative dosing is often limited by cardiotoxicity. We hypothesized that ultrasound targeted microbubble (MB) cavitation (UTMC) of a liposomal doxorubicin (LDox) conjugated polymer microbubble complex (DoxLPX) would enhance tumor inhibition and limit Dox cardiotoxicity. METHODS: DoxLPX was intravenously injected in MCA205 sarcoma-bearing mice and concurrent ultrasound was delivered to the tumor site (DoxLPX + UTMC). Other mice received equivalent dosages of free Dox, LDox, or LDox + MB co-administration with UTMC (LDox + MB + UTMC). Tumor size and cardiac function were serially imaged with ultrasound. Postmortem cardiac tissue was analyzed for apoptosis. Biodistribution of Dox was performed with bioluminescence imaging postmortem where Cy5.5 was used as a fluorescent Dox analog. RESULTS: DoxLPX + UTMC showed increased drug concentration in the tumor, a significant slowdown in tumor growth and prolonged median survival time. LDox and DoxLPX formulations had reduced drug extravasation into the myocardium. LDox + MB + UTMC also demonstrated superior tumor growth inhibition compared to free Dox and LDox. Three weeks after treatment commenced, DoxLPX + UTMC group showed significantly better left ventricular function indices than the free Dox group, consistent with biodistribution findings. Concordantly, heart tissue showed normal architecture of cardiac myocytes and significantly less interstitial/perivascular fibrosis in the DoxLPX + UTMC group. CONCLUSIONS: DoxLPX formulation in conjunction with ultrasound provides a targeted drug delivery platform with superior anti-tumor efficacy and reduced cardiac toxicity compared with systemic administration of free Dox.