Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice
Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice
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DOI：
10.1016/j.ejpb.2014.10.007
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发表时间：
2015-02-01
影响因子：
4.9
通讯作者：
Maeda, Hiroshi
中科院分区：
文献类型：
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作者：
Nakamura, Hideaki;Koziolova, Eva;Maeda, Hiroshi
先前我们表明，线性聚（N-（2-羟丙基）甲基丙烯酰胺）共轭吡拉齐（THP），LP-THP，MW约39 kDa，表现出更好的肿瘤积累和治疗效果比亲本游离THP。为了进一步改善LP-THP的药代动力学，合成了高分子量的聚酰胺-胺（PAMAM）树枝状大分子与半遥爪HPMA共聚物（PHPMA）的缀合物[星星聚合物（SP）; 400 kDa]，并通过含腙键的间隔基与THP缀合（5P-THP）。THP与SP通过酸可裂解的腙键结合形成SP-THP，其响应于肿瘤组织的酸性环境。因此，它会释放游离THP，通过积极的治疗原则。SP-THP在水溶液中的流体动力学直径（25.9 nm）比LP-THP（8.2 nm）大。由于肿瘤体积较大，SP-THP的AUC_（5h）~（72）h是LP-THP的3.3倍。更重要的是，释放的游离THP选择性地保留在肿瘤组织中至少长达72小时后，SP-THP的管理。我们发现SP-THP对S-180荷瘤小鼠和AOM/DS5化学诱导的结肠癌荷瘤小鼠的体内抗肿瘤作用优于LP-THP，这很可能是由于它们的分子大小不同。在我们对SP-THP和LP-THP的体内外行为的比较研究中，我们得出结论，SP-THP不仅对移植性肿瘤而且对原位自发性肿瘤都表现出增强的治疗效果，尽管其毒性比LP-THP高。基于这些发现，将很快进行使用各种肿瘤（包括转基因和转移性肿瘤）的进一步研究。(C)2014爱思唯尔有限公司版权所有。
Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (5P-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h_72h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DS5-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopicfspontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon. (C) 2014 Elsevier B.V. All rights reserved.