Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment.
Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment.
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DOI：
10.1016/j.ijpharm.2013.06.046
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发表时间：
2013-09-15
影响因子：
5.8
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Larson, Nate;Yang, Jiyuan;Ray, Abhijit;Cheney, Darwin L.;Ghandehari, Hamidreza;Kopecek, Jindrich
本研究描述了多嵌段聚（N-2-羟丙基）甲基丙烯酰胺（HPMA）、吉西他滨（GEM）和紫杉醇（PTX）缀合物的组合递送的合成、表征和体外评价。研究了大分子量（Mw > 200 kDa）的多嵌段共聚物缀合物，并与传统的小分子量（Mw < 45 kDa）缀合物进行了比较。评价了偶联物在不同pH下的稳定性，并通过组合指数分析评价了它们组合对A2780人卵巢癌细胞的细胞毒性。探索了治疗持续时间（4和72小时）和添加顺序。此外，以类似的方式评价在侧链中具有GEM和PTX两者的HPMA共聚物缀合物，并与单独缀合物的物理混合物进行比较。通过RAFT聚合获得了具有窄分子量分布（Mw/Mn < 1.1）的缀合物，并且实现了5.5和9.2wt%之间的药物负载。偶联物表现出中等稳定性，在pH 7.4下24小时内释放小于65%，在溶酶体酶组织蛋白酶B存在下3小时内几乎完全释放药物。在组合中，缀合物的混合物的细胞毒性作用主要是累加的。当用多嵌段缀合物同时处理A2780人卵巢癌细胞4小时时，观察到协同效应（CI < 0.7）。当GEM和PTX两者均缀合至相同的共聚物主链时，观察到中度拮抗作用（CI 1.3-1.6）。这些结果表明，多嵌段HPMA共聚物-GEM和-PTX缀合物，当作为单独药剂的混合物递送时，有希望用于治疗卵巢癌。
The synthesis, characterization, and in vitro evaluation of a combination delivery of multiblock poly(N-2-hydroxypropyl)methacrylamide (HPMA), gemcitabine (GEM) and paclitaxel (PTX) conjugates is described in this study. Multiblock copolymer conjugates of a large molecular weight (Mw > 200 kDa) were studied and compared to traditional, small molecular weight (Mw < 45 kDa) conjugates. Stability of the conjugates in different pH was assessed, and their cytotoxicity in combination toward A2780 human ovarian cancer cells was evaluated by combination index analysis. Treatment duration (4 and 72 h) and sequence of addition were explored. In addition, an HPMA copolymer conjugate with both GEM and PTX in the side chains was evaluated in a similar manner and compared to a physical mixture of individual conjugates. Conjugates with narrow molecular weight distribution (Mw/Mn < 1.1) were obtained via RAFT polymerization, and drug loadings of between 5.5 and 9.2 wt% were achieved. Conjugates demonstrated moderate stability with less than 65% release over 24 h at pH 7.4, and near complete drug release in the presence of the lysosomal enzyme cathepsin B in 3 h. In combination, the cytotoxic effects of a mixture of the conjugates were primarily additive. Synergistic effects were observed when A2780 human ovarian cancer cells were treated simultaneously for 4 h with multiblock conjugates (CI < 0.7). When both GEM and PTX were conjugated to the same copolymer backbone, moderate antagonism (CI 1.3–1.6) was observed. These results demonstrate that multiblock HPMA copolymer–GEM and –PTX conjugates, when delivered as a mixture of individual agents, are promising for the treatment of ovarian cancer.
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影响因子：
5.5
作者：
Luo K;Yang J;Kopečková P;Kopeček J
通讯作者：
Kopeček J
影响因子：
16.1
作者：
Kopecek, Jindrich
通讯作者：
Kopecek, Jindrich
影响因子：
8.6
作者：
Larson, Nate;Ghandehari, Hamidreza
通讯作者：
Ghandehari, Hamidreza
影响因子：
50.5
作者：
Bookman, M. A.
通讯作者：
Bookman, M. A.
DOI：
10.1186/1756-9966-31-14
发表时间：
2012-02-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Kim A;Ueda Y;Naka T;Enomoto T
通讯作者：
Enomoto T