Negative preclinical results with stealth® nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model
Negative preclinical results with stealth® nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model
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DOI：
10.1016/j.jconrel.2004.07.019
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发表时间：
2004-11-05
影响因子：
10.8
通讯作者：
Vassal, G
中科院分区：
文献类型：
--
作者：
Brigger, I;Morizet, J;Vassal, G
先前的研究结果表明，peg包被聚（十六烷基氰基丙烯酸酯）（PEG-PHDCA）纳米球在大鼠静脉注射后，在原位9L胶质肉瘤模型中显示出显著的积累。因此，本研究的目的是在相同的模型中评估该载体在装载多柔比星时的临床前疗效，多柔比星是一种在中枢神经系统中分布不良的抗癌药物。游离和纳米球封装阿霉素给予多剂量治疗。分别在健康大鼠和颅内产9l大鼠中测定了它们的最大耐受剂量（MTD）和延长寿命。在荷瘤组中还进行了负载阿霉素和未负载PEG-PHDCA纳米球的比较生物分布研究。结果表明，纳米粒阿霉素的累积MTD是游离阿霉素的1.5倍。然而，包封的阿霉素在9L胶质瘤中不能引起更好的治疗反应。生物分布研究显示，携带阿霉素的纳米球在9L肿瘤中的累积程度是未携带纳米球的2.5倍，并且它们主要局限于肺和脾脏。这种典型的轮廓表明，由于这些负载粒子的表面带正电荷，它们与血浆蛋白聚集；药物包封引起的离子相互作用是导致9L治疗失败的主要原因。(C) 2004年Elsevier B.V.出版
Previous results have shown that PEG-coated poly(hexadecylcyanoacrylate) (PEG-PHDCA) nanospheres displayed a significant accumulation within an orthotopic 9L gliosarcoma model, after i.v. administration to rats. Hence, the aim of the present study was to evaluate in the same model the pre-clinical efficacy of this carrier when loaded with Doxorubicin, an anticancer drug which poorly distributes in the CNS. Free and nanospheres-encapsulated Doxorubicin were administered with a multiple dose treatment. Their maximum tolerated dose (MTD) and increase in life span were respectively assessed in healthy and intracranially 9L-bearing rats. A comparative biodistribution study of Doxorubicin-loaded and unloaded PEG-PHDCA nanospheres was also performed in the tumor-bearing group. The results showed that the cumulative MTD of nanoparticulate doxorubicin was 1.5 times higher than this of free Doxorubicin. Nevertheless, encapsulated Doxorubicin was unable to elicit a better therapeutic response in the 9L gliosarcoma. Biodistribution study revealed that the Doxorubicin-loaded nanospheres accumulated to a 2.5-fold lesser extent in the 9L tumor as compared to the unloaded nanospheres and that they were mainly localized in the lungs and the spleen. Such a typical profile indicated aggregation with plasma proteins as a consequence of the positive surface charge of these loaded particles; this ionic interaction resulting from drug encapsulation was mainly responsible for 9L treatment failure. (C) 2004 Published by Elsevier B.V.