Antitumor efficacy of dexamethasone-loaded core-crosslinked polymeric micelles
Antitumor efficacy of dexamethasone-loaded core-crosslinked polymeric micelles
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DOI：
10.1016/j.jconrel.2012.09.014
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发表时间：
2012-11-10
影响因子：
10.8
通讯作者：
Schiffelers, R. M.
中科院分区：
文献类型：
--
作者：
Coimbra, M.;Rijcken, C. J. F.;Schiffelers, R. M.
在目前的研究中，核心交联聚合物胶束（DEX- pms）装载了三种不同的DEX衍生物，以显示不同的药物释放动力学，评估了癌症治疗的效果，并与另一种有效的纳米药物制剂（长循环脂质体包裹地塞米松，LCL-DEX）进行了比较。放射性标记地塞米松和聚合物的药代动力学研究表明，这些聚合物系统具有较长的循环半衰期，并且可能比脂质体在肿瘤部位积聚的程度更高。体外药物释放谱和血流中循环药物水平表明，与其他聚合物dex释放系统相比，通过含砜酯连接物（DMSL2）共价包裹地塞米松的dex - pm具有较长的循环时间和中间药物释放动力学。此外，由于DMSL2-PMor LCL-DEX给药时游离地塞米松循环水平相似，因此同时评估了这些系统在B16F10黑色素瘤小鼠中的抗肿瘤功效。与游离药物相比，皮质类固醇靶向系统抑制肿瘤生长的程度相似，两者都提高了生存率。最近，靶向制剂的抗肿瘤功效与一种全身效应相关：白细胞计数的减少。在这项研究中，所有三种聚合物系统、脂质体和游离药物对循环白细胞的数量有相似的影响，尽管接受游离药物组的白细胞计数恢复得更快。总之，皮质类固醇靶向与聚合物系统或脂质体系统翻译相似的治疗效果。经证实，PM具有高通用性，可以根据治疗应用的需要对药物释放进行优化和调整，清楚地表明这些系统在治疗包括癌症在内的慢性炎症性疾病方面的潜力。(C) 2012 Elsevier B.V.版权所有
In the current study, core-crosslinked polymeric micelles (DEX-PMs) loaded with three different DEX derivatives designed to display different drug release kinetics, were evaluated for cancer therapy and compared to another effective nanomedicine formulation (long-circulating liposomes encapsulating dexamethasone, LCL-DEX). Pharmacokinetic studies with both radiolabeled dexamethasone and polymer showed that these polymeric systems have long circulating half-lives and may accumulate at the tumor site to a higher extent than liposomes. The in vitro drug release profiles and circulating drug levels in the blood stream show that DEX-PMs with dexamethasone covalently entrapped via a sulfone ester-containing linker (DMSL2) have prolonged circulation time and intermediate drug release kinetics compared to the other polymericDEX-releasing systems. Furthermore, as the free dexamethasone circulating levels were similar when administered as DMSL2-PMor LCL-DEX, these systems were evaluated simultaneously for antitumor efficacy in B16F10 melanoma bearing mice. The corticosteroid-targeted systems inhibited tumor growth to a similar extent and both increased survival compared to free drug. Recently antitumor efficacy of targeted formulations has been correlated with a systemic effect: a decrease of white blood cell count. In this study all three polymeric systems, liposomes as well as free drug had similar effects on the number of circulating white blood cells, although white blood cell counts recovered faster in the group receiving free drug. In conclusion, corticosteroid-targeting with a polymeric system or a liposomal system translates in similar therapeutic effects. The proven high versatility of the PM with possible optimization and adjustment of the drug release to that required by the therapeutic application, clearly demonstrates the potential of these systems for the treatment of chronic inflammatory diseases including cancer. (C) 2012 Elsevier B.V. All rights reserved.