Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells.
Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells.
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DOI：
10.1016/j.biomaterials.2011.11.029
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发表时间：
2012-02
期刊：
影响因子：
14
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Zhou, Yan;Yang, Jiyuan;Kopecek, Jindrich
改善前列腺癌的治疗方法非常需要克服致命的复发和转移。靶向具有自我更新和分化能力的致瘤性癌症干细胞（CSCs）似乎是一种很有前途的策略。环巴胺阻断参与干细胞自我更新的重要通路hedgehog （Hh）信号通路，导致前列腺癌长期消退而不复发，强烈提示Hh通路与前列腺CSCs之间的联系。在这里，我们设计了一种基于HPMA （N-（2-羟丙基）甲基丙烯酰胺）的环巴胺递送系统，作为csc选择性的大分子治疗药物，具有提高药物溶解度和降低全身毒性的作用。为此，采用RAFT（可逆加成-断裂链转移）工艺，将HPMA与n-甲基丙烯酰甘酰基苯基丙烯酰酰酰甘酰基噻唑烷-2-硫酮共聚，然后进行环巴胺的聚合物模拟附着。在具有端粒酶逆转录酶转导的人前列腺癌上皮细胞RC-92a/hTERT细胞上评价了该偶联物对CSCs的选择性。通过干细胞标记物表达和前列腺球培养验证了RC-92a/hTERT细胞作为体外CSC模型的可行性。环巴胺与聚合物偶联后仍保持生物活性。此外，HPMA聚合物偶联环巴胺对RC-92a/hTERT细胞具有抗CSC作用，通过降低干细胞标志物表达和CSC活力来评估。
Improved treatments for prostate cancer are in great need to overcome lethal recurrence and metastasis. Targeting the tumorigenic cancer stem cells (CSCs) with self-renewal and differentiation capacity appears to be a promising strategy. Blockade of the hedgehog (Hh) signaling pathway, an important pathway involved in stem cell self-renewal, by cyclopamine leads to long-term prostate cancer regression without recurrence, strongly suggesting the connection between Hh pathway and prostate CSCs. Here we designed a HPMA (N-(2-hydroxypropyl)methacrylamide)-based cyclopamine delivery system as a CSC-selective macromolecular therapeutics with improved drug solubility and decreased systemic toxicity. To this end, HPMA and N-methacryloylglycylphenylalanylleucylglycyl thiazolidine-2-thione were copolymerized using the RAFT (reversible addition-fragmentation chain transfer) process, followed by polymer-analogous attachment of cyclopamine. The selectivity of the conjugate toward CSCs was evaluated on RC-92a/hTERT cells, the human prostate cancer epithelial cells with human telomerase reverse transcriptase transduction. The use of RC-92a/hTERT cells as an in vitro CSC model was validated by stem cell marker expression and prostasphere culture. The bioactivity of cyclopamine was retained after conjugation to the polymer. Furthermore, HPMA polymer-conjugated cyclopamine showed anti-CSC efficacy on RC-92a/hTERT cells as evaluated by decreased stem cell marker expression and CSC viability.
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DOI：
10.1126/science.1171837
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rosen JM;Jordan CT
通讯作者：
Jordan CT
影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
影响因子：
10.8
作者：
Dvorák, M;Kopecková, P;Kopecek, J
通讯作者：
Kopecek, J
影响因子：
11.2
作者：
Miki, Jun;Furusato, Bungo;Rhim, Johng S.
通讯作者：
Rhim, Johng S.
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ