Mingyu He, Xucai Chen, Francois Yu, Bin Qin, Huizhu Wang, Linda Lavery, Flordeliza S Villanueva
{"title":"超声介导的微泡脂质体给药阿霉素增强抗肿瘤疗效和降低心脏毒性。","authors":"Mingyu He, Xucai Chen, Francois Yu, Bin Qin, Huizhu Wang, Linda Lavery, Flordeliza S Villanueva","doi":"10.1016/j.ultrasmedbio.2025.04.010","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":49399,"journal":{"name":"Ultrasound in Medicine and Biology","volume":" ","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Enhanced Antitumor Efficacy and Reduced Cardiotoxicity of Ultrasound-Mediated Doxorubicin Delivery by Microbubble-Liposome Complexes.\",\"authors\":\"Mingyu He, Xucai Chen, Francois Yu, Bin Qin, Huizhu Wang, Linda Lavery, Flordeliza S Villanueva\",\"doi\":\"10.1016/j.ultrasmedbio.2025.04.010\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. 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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.
期刊介绍:
Ultrasound in Medicine and Biology is the official journal of the World Federation for Ultrasound in Medicine and Biology. The journal publishes original contributions that demonstrate a novel application of an existing ultrasound technology in clinical diagnostic, interventional and therapeutic applications, new and improved clinical techniques, the physics, engineering and technology of ultrasound in medicine and biology, and the interactions between ultrasound and biological systems, including bioeffects. Papers that simply utilize standard diagnostic ultrasound as a measuring tool will be considered out of scope. Extended critical reviews of subjects of contemporary interest in the field are also published, in addition to occasional editorial articles, clinical and technical notes, book reviews, letters to the editor and a calendar of forthcoming meetings. It is the aim of the journal fully to meet the information and publication requirements of the clinicians, scientists, engineers and other professionals who constitute the biomedical ultrasonic community.