Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.
Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.
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DOI：
10.1111/cas.12592
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发表时间：
2015-03
期刊：
影响因子：
5.7
通讯作者：
Maeda H
中科院分区：
文献类型：
--
作者：
Tsukigawa K;Liao L;Nakamura H;Fang J;Greish K;Otagiri M;Maeda H
在此之前，我们以苯乙烯-马来酸共聚物（SMA）为药物载体，制备了一种以非共价键形式包裹活性THP的胶束药物。我们现在已经开发了共价缀合的SMA-THP（SMA-THP缀合物）用于进一步的临床开发研究，因为已知共价连接的聚合物-药物缀合物在循环中比药物包封的胶束更稳定。SMA-THP偶联物在水溶液中也能形成胶束并显示出与白蛋白的结合能力，这表明该偶联物在血液循环中表现为大分子。因此，SMA-THP偶联物与游离THP相比显示出显著延长的循环时间和通过增强的渗透性和保留（EPR）效应的高肿瘤靶向效率。结果表明，对小鼠两种肿瘤均具有显著的抗肿瘤作用，且无明显不良反应。值得注意的是，转移性肺肿瘤也显示EPR效应，并且该缀合物在30 mg/kg静脉注射一次（小于最大耐受剂量的五分之一）时几乎完全减少了肺中的转移性肿瘤。虽然SMA-THP偶联物本身在体外几乎没有细胞毒性，（游离药物THP的1/100），通过EPR效应的肿瘤靶向积累确保肿瘤中足够的药物浓度以产生抗肿瘤作用，而对正常组织的毒性要小得多。这些发现表明SMA-THP缀合物作为具有良好稳定性和体内肿瘤靶向性的抗癌纳米药物的高度有利的候选者的潜力。
Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene–maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer–drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor-targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.
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影响因子：
5.8
作者：
Hasan, A. Sheikh;Socha, M.;Ubrich, N.
通讯作者：
Ubrich, N.
DOI：
10.1016/j.jconrel.2013.06.039
发表时间：
2013-11-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Hollis CP;Weiss HL;Leggas M;Evers BM;Gemeinhart RA;Li T
通讯作者：
Li T
影响因子：
1.7
作者：
Daruwalla, Jurstine;Greish, Khaled;Christophi, Chris
通讯作者：
Christophi, Chris
影响因子：
10.8
作者：
Malugin, A.;Kopeckova, P.;Kopecek, J.
通讯作者：
Kopecek, J.
影响因子：
3.2
作者：
Fang, Jun;Seki, Takahiro;Maeda, Hiroshi
通讯作者：
Maeda, Hiroshi