New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: In-vivo characterization
New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: In-vivo characterization
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DOI：
10.1016/j.jconrel.2010.09.004
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发表时间：
2010-12-20
影响因子：
10.8
通讯作者：
Bekeredjian, Raffi
中科院分区：
文献类型：
--
作者：
Tinkov, Steliyan;Coester, Conrad;Bekeredjian, Raffi
多柔比星（DOX）是一种有效的化疗药物，但通常受到严重不良反应（如心脏毒性和骨髓抑制）的限制。使用非侵入性技术的药物靶向将是期望的，旨在增加局部药物浓度和减少全身副作用。超声（US）靶向破坏载药微泡（MB）已发展成为一种有前途的战略，非侵入性局部基因和药物输送。最近开发的一种新型的DOX负载微泡（DOX-MB）制剂先前在体外进行了测试，具有最佳的DOX负载能力，理想的物理特性和保留的抗增殖功效。本研究的目的是评估的适用性和效力的DOX-加载MB在胰腺癌模型的大鼠。首先，立即毒性进行了测试，在大鼠排除体内MB凝聚/毛细血管粘连与随后的栓塞/闭塞的肺血管。在第二组实验中，将源自胰腺癌的肿瘤植入刘易斯大鼠的两侧腹。在建立肿瘤后，静脉内施用DOX-MB，同时将两个肿瘤中的一个暴露于US（1.3MHz;机械指数1.6）。实验后测量肿瘤和对照器官中的DOX组织浓度。最后，研究了肿瘤中DOX-MB的US靶向破坏的功效，观察两次治疗应用后的肿瘤生长。与对侧对照肿瘤相比，超声靶向破坏DOX-MB导致DOX的组织浓度高12倍，并且靶肿瘤中的肿瘤生长显著降低。总之，新型DOX负载的MB可以安全地施用于大鼠，导致局部药物浓度的相关增加和肿瘤生长的减少。(C)2010 Elsevier BV保留所有权利。
Doxorubicin(DOX) is a potent chemotherapy drug that is often limited by severe adverse effects such as cardiac toxicity and myelosupression. Drug targeting with non invasive techniques would be desirable, aiming at increased local drug concentration and reduced systemic side effects. Ultrasound (US) targeted destruction of drug loaded microbubbles (MBs) has evolved as a promising strategy for non invasive local gene and drug delivery. A recently developed novel DOX-loaded microbubble (DOX-MB) formulation was previously tested in-vitro, with optimal DOX loading capacity, ideal physical characteristics and preserved antiproliferative efficacy. The aim of this study was to evaluate applicability and efficacy of DOX-loaded MBs in a pancreas carcinoma model of the rat.First, immediate toxicity was tested in rats ruling out in-vivo MB agglomeration/capillary adhesion with subsequent embolisation/occlusion of the pulmonary vasculature. In a second set of experiments, tumors derived from pancreas carcinomas were implanted in both flanks of Lewis rats. After establishing the tumors, DOX-MBs were administered intravenously while one of the two tumors was exposed to US (1.3 MHz; mechanical index 1.6). DOX tissue concentration was measured in tumors and control organs after the experiment. Finally, efficacy of US targeted destruction of DOX-MBs in tumors was studied, looking at tumor growth after two therapeutic applications.All rats survived the DOX-MB administration without any sign of embolisation/occlusion of the pulmonary vasculature. US targeted destruction of DOX-MBs leads to a 12-fold higher tissue concentration of DOX and a significantly lower tumor growth in the target tumor compared to the contralateral control tumor.In conclusion, novel DOX-loaded MBs can be safely administered to rats, leading to a relevant increase in local drug concentration and reduction in tumor growth. (C) 2010 Elsevier B.V. All rights reserved.