Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
J Control Release. 2012 Nov 10;163(3):361-7. doi: 10.1016/j.jconrel.2012.09.014. Epub 2012 Oct 4.
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 polymeric DEX-releasing systems. Furthermore, as the free dexamethasone circulating levels were similar when administered as DMSL2-PM or 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.
在当前的研究中，我们评估了载有三种不同 DEX 衍生物的核交联聚合物胶束（DEX-PMs）用于癌症治疗，并将其与另一种有效的纳米医学制剂（包载地塞米松的长循环脂质体，LCL-DEX）进行了比较。用放射性标记的地塞米松和聚合物进行的药代动力学研究表明，这些聚合物系统具有长循环半衰期，并且可能比脂质体更大量地积累在肿瘤部位。体外药物释放曲线和血液中的循环药物水平表明，通过含有砜酯键的连接物（DMSL2）共价包封地塞米松的 DEX-PM 与其他释放 DEX 的聚合物系统相比具有延长的循环时间和中等的药物释放动力学。此外，由于以 DMSL2-PM 或 LCL-DEX 给药时游离地塞米松的循环水平相似，因此同时评估了这些系统在 B16F10 黑色素瘤荷瘤小鼠中的抗肿瘤功效。靶向皮质类固醇的系统在抑制肿瘤生长方面达到了相似的程度，并且与游离药物相比都提高了存活率。最近，靶向制剂的抗肿瘤功效与全身效应相关：白细胞计数减少。在这项研究中，所有三种聚合物系统、脂质体以及游离药物对循环白细胞数量都有相似的影响，尽管接受游离药物的组中白细胞计数恢复得更快。总之，用聚合物系统或脂质体系统靶向皮质类固醇可产生相似的治疗效果。证明了 PM 具有很高的多功能性，可能优化和调整药物释放以适应治疗应用的要求，这清楚地表明了这些系统在治疗慢性炎症性疾病（包括癌症）方面的潜力。
