Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy
Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy
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顺铂负载的聚(L-谷氨酸)-g-甲氧基聚(乙二醇)复合纳米粒子用于肿瘤治疗的药代动力学、生物分布和体内疗效
DOI：
10.1016/j.jconrel.2014.12.022
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发表时间：
2015
影响因子：
10.8
通讯作者：
Chen Xuesi
中科院分区：
文献类型：
--
作者：
Yu Haiyang;Tang Zhaohui;Zhang Dawei;Song Wantong;Zhanga Ying;Yang Yan;Ahmad Zaheer;Chen Xuesi
铂基聚合物纳米药物，特别是顺铂聚合物纳米粒(CDDP-NPs)已被广泛用于实体肿瘤的治疗。然而，目前还不清楚聚合物载体材料的加工工艺和性质对CDDP-NPs的血药动力学、生物分布和体内药效的影响。本研究合成了一系列聚(L-谷氨酸)-g-甲氧基聚乙二醇酯(PLG-g-mEg)共聚物，用于制备顺铂PLG-g-mEg(CDDP/PLg-g-mEg)纳米粒。PLG相对分子质量、mPG/PLG质量比、mEg链长、超滤纯化和顺铂载药量等参数对CDDP/PLG-g-mPG纳米粒的血药动学均有显著影响。随着PLG相对分子质量、mPG/PLG质量比、mPEG链长和CDDP载量的增加，纳米粒的血液循环时间延长。超滤净化的使用也可以延长纳米粒的血液循环时间。药代动力学和生物分布实验表明，所选择的CDDP/PLG-g-mEg纳米粒NP10具有较长的血液循环时间，并能在Lewis肺癌(LLC)肿瘤中实现选择性和显著的蓄积。接受NP10的LLC荷瘤小鼠的铂血浆浓度仍然比接受等量游离CDDP的小鼠高出46倍。此外，NP10在48h内的血药浓度-时间曲线下面积(AUC)是游离CDDP的31倍，肿瘤组织中NP10与游离CDDP的铂浓度比高达9.4。NP10与CDDP的肿瘤AUC比为6。在小鼠C26肿瘤模型上，我们证明NP10与CDDP相比，在体内提高了安全性和耐受性，并有效地抑制了C26肿瘤的生长。此外，将NP10的剂量增加2倍或3倍游离CCDP可将其抗癌效果提高到相当或更高的水平。这些结果表明，CDDP/PLG-g-mpeg纳米粒在治疗实体瘤方面具有较大的临床应用潜力。
Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors. However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics, biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG-g-mPEG (CDDP/PLG-g-mPEG) nanoparticles. All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG-g-mPEG nanoparticles. The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG-g-mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48 h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG-g-mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application.