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Combination nanomedicine targeting cancer stem cells and bulk tumor cells for treatment of prostate cancer.

机译：靶向癌症干细胞和大块肿瘤细胞的纳米药物联合治疗前列腺癌。

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摘要

Prostate cancer is the most common malignancy and second leading cause of cancer-related deaths in men in the United States. Despite improved management of patients with early stage prostate cancer, the mortality rate is still high due to frequent relapse, progression and metastasis following current antiprostate cancer therapies. Recently, research evidences support the presence of a subpopulation of cancer stem cells (CSCs) with infinite self-renewal and differentiation abilities. These drug-resistant CSCs, surviving following traditional anticancer therapies, contribute to cancer recurrence and metastasis. Therefore, to overcome the failure of current therapies and improve prostate cancer patient outcomes, it is necessary to not only shrink the tumor mass, but also inhibit CSC growth and maintenance. To this end, we designed the combination macromolecular therapeutics containing two types of HPMA copolymer-drug conjugates: one effectively killing non-CSC bulk tumor cells, the other preferentially killing prostate CSCs.;Docetaxel, a first line chemotherapeutic agent for advanced prostate cancer, is employed in the bulk tumor cell-killing HPMA copolymer-drug conjugate. Cyclopamine (a hedgehog pathway inhibitor) or GDC-0980 (a PI3K/mTOR dual inhibitor), with antiprostate CSC activity, is incorporated in the CSC-killing conjugate. The two types of HPMA copolymer-drug conjugates were synthesized by RAFT (reverse addition-fragmentation chain-transfer) copolymerization, with well controlled molecular weight and narrow molecular weight distribution. The anti-CSC and antibulk tumor effects of individual and combination of the two HPMA copolymer-drug conjugates were evaluated in vitro and in vivo. The in vitro evaluations show that the CSC-killing conjugate decreased the relative amount of CD133+ prostate CSC enriched population and impaired prostasphere forming ability. On the other hand, HPMA copolymer-docetaxel conjugate failed to decrease the relative amount of CD133+ cancer cells. The combination treatment led to the strongest tumor growth inhibition in long-term. For the in vivo evaluations, single and combination treatment all inhibited tumor growth immediately in PC-3 prostate tumor bearing mice. However, only the combination therapy led to sustained tumor growth inhibition in long-term. The characterizations of residual tumor cells suggest a decreased proportion of CD133+ cells following combination therapy.
机译：在美国，前列腺癌是最常见的恶性肿瘤，是与癌症相关的死亡的第二大诱因。尽管改善了对早期前列腺癌患者的治疗，但是由于当前抗前列腺癌疗法后的频繁复发，进展和转移，死亡率仍然很高。最近，研究证据支持了具有无限自我更新和分化能力的癌症干细胞（CSC）亚群的存在。这些抗药性的CSC在传统的抗癌治疗后仍然存在，有助于癌症的复发和转移。因此，为了克服当前疗法的失败并改善前列腺癌患者的结局，不仅需要缩小肿瘤块，而且还必须抑制CSC的生长和维持。为此，我们设计了包含两种类型的HPMA共聚物-药物共轭物的大分子组合疗法：一种有效杀死非CSC块状肿瘤细胞，另一种优先杀死前列腺CSC。多西他赛是晚期前列腺癌的一线化疗剂，在大量的杀死肿瘤细胞的HPMA共聚物-药物缀合物中使用“苯丙氨酸”。具有抗前列腺CSC活性的环丙胺（一种刺猬蛋白途径抑制剂）或GDC-0980（一种PI3K / mTOR双重抑制剂）被掺入CSC杀灭结合物中。通过RAFT（反向加成-断裂链转移）共聚反应合成了两种类型的HPMA共聚物-药物共轭物，分子量控制得很好，分子量分布窄。在体外和体内评估了两种HPMA共聚物-药物偶联物的个体及其组合的抗CSC和抗大块肿瘤效应。体外评估表明，杀死CSC的结合物降低了CD133 +前列腺CSC富集人群的相对数量，并削弱了前列腺素的形成能力。另一方面，HPMA共聚物-多西他赛缀合物不能降低CD133 +癌细胞的相对量。从长期来看，联合治疗导致最强的肿瘤生长抑制作用。为了进行体内评估，单一和联合治疗均立即抑制了PC-3前列腺癌荷瘤小鼠的肿瘤生长。但是，只有联合治疗才能长期持续抑制肿瘤生长。残留肿瘤细胞的特征表明联合治疗后CD133 +细胞比例降低。

著录项

  • 作者

    Zhou, Yan.;

  • 作者单位

    The University of Utah.;

  • 授予单位 The University of Utah.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 179 p.
  • 总页数 179
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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