HPMA copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects.
HPMA copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects.
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DOI：
10.1016/j.jconrel.2013.09.005
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发表时间：
2013-12-28
期刊：
影响因子：
--
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Zhou Y;Yang J;Rhim JS;Kopeček J
目前对前列腺癌的治疗仍然不令人满意，经常导致肿瘤再生长和转移。抗前列腺癌治疗无效的主要原因之一是未能耗尽癌症干细胞样细胞（CSC）-具有增强的致瘤能力的癌细胞亚群。因此，针对CSC和大块肿瘤细胞的药剂的组合可以提供更好的治疗益处。具有抗癌干/祖细胞活性的几种分子已处于临床前评价中。然而，它们的低溶解度和非特异性毒性限制了它们的临床转化。在此，我们设计了包含两种药物缀合物的组合大分子疗法：HPMA共聚物-环巴胺缀合物（P-MTX）优先对癌症干/祖细胞有毒，以及HPMA共聚物-多西他赛缀合物（P-DTX）有效地减瘤。两种缀合物都是使用RAFT（可逆加成-断裂链转移）聚合合成的，导致窄分子量分布。在体外和体内评价两种缀合物对肿瘤细胞和CSCs的杀伤作用。在PC-3或RC-92 a/hTERT前列腺癌细胞中，P-DTX优先杀死并损害CD 133+前列腺癌干/祖细胞的功能; P-DTX能够杀死大量肿瘤细胞而不是CSC。在PC-3小鼠移植瘤模型中，P-DTX和P-MTX的组合显示出最有效和持久的肿瘤生长抑制作用。此外，在联合或P-gp治疗后，残留肿瘤含有较少的CD 133+癌细胞，表明具有干细胞/祖细胞特性的癌细胞的选择性杀伤。
Current treatments for prostate cancer are still not satisfactory, often resulting in tumor regrowth and metastasis. One of the main reasons for the ineffective anti-prostate cancer treatments is the failure to deplete cancer stem-like cells (CSCs) - a subset of cancer cells with enhanced tumorigenic capacity. Thus, combination of agents against both CSCs and bulk tumor cells may offer better therapeutic benefits. Several molecules with anti-cancer stem/progenitor cell activities have been under preclinical evaluations. However, their low solubility and nonspecific toxicity limit their clinical translation. Herein, we designed a combination macromolecular therapy containing two drug conjugates: HPMA copolymer-cyclopamine conjugate (P-CYP) preferentially toxic to cancer stem/progenitor cells, and HPMA copolymer-docetaxel conjugate (P-DTX) effective in debulking the tumor mass. Both conjugates were synthesized using RAFT (reversible addition-fragmentation chain transfer) polymerization resulting in narrow molecular weight distribution. The killing effect of the two conjugates against bulk tumor cells and CSCs were evaluated in vitro and in vivo. In PC-3 or RC-92a/hTERT prostate cancer cells, P-CYP preferentially kills and impairs the function of CD133+ prostate cancer stem/progenitor cells; P-DTX was able to kill bulk tumor cells instead of CSCs. In PC-3 xenograft mice model, combination of P-DTX and P-CYP showed the most effective and persistent tumor growth inhibitory effect. In addition, residual tumors contained less CD133+ cancer cells following combination or P-CYP treatments, indicating selective killing of cancer cells with stem/progenitor cell properties.
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影响因子：
11.5
作者：
Dubrovska, Anna;Elliott, Jimmy;Schultz, Peter G.
通讯作者：
Schultz, Peter G.
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：
17.1
作者：
Atkinson RL;Zhang M;Diagaradjane P;Peddibhotla S;Contreras A;Hilsenbeck SG;Woodward WA;Krishnan S;Chang JC;Rosen JM
通讯作者：
Rosen JM
影响因子：
3.8
作者：
Lipinski, Robert J.;Hutson, Paul R.;Bushman, Wade
通讯作者：
Bushman, Wade
影响因子：
11.2
作者：
Miki, Jun;Furusato, Bungo;Rhim, Johng S.
通讯作者：
Rhim, Johng S.