Poloxamer-linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high-risk neuroblastoma with primary and acquired chemoresistance.
Poloxamer-linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high-risk neuroblastoma with primary and acquired chemoresistance.
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DOI：
10.1096/fj.202101830rr
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Chorny M
中科院分区：
文献类型：
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作者：
Alferiev IS;Guerrero DT;Guan P;Nguyen F;Kolla V;Soberman D;Pressly BB;Fishbein I;Brodeur GM;Chorny M
由于多药耐药，高危实体瘤继续构成巨大的治疗挑战。在高风险原发性和复发性疾病中驱动化疗耐药的生物学机制是不同的：在新诊断的患者中，对治疗无反应通常与ABCG 2药物外排泵过表达引起的较高水平的肿瘤“干性”相关，而在非治愈性治疗后复发的肿瘤中，药物敏感性差最常见与肿瘤抑制蛋白p53功能障碍有关。在这项研究中，我们使用了侵袭性神经母细胞瘤的临床前模型，这些模型具有原发性和获得性耐药的特征机制，以实验评估结构增强的喜树碱类似物SN 22的大分子前药，抵抗ABCG 2介导的输出和葡萄糖醛酸化。通过与Pluronic F-108（PF 108）可逆偶联延长肿瘤暴露于治疗有效药物水平，这些特征转化为ABCG 2过表达和p53突变高危神经母细胞瘤模型中的快速肿瘤消退和长期生存，与临床使用的喜树碱衍生物伊立替康的边际效应形成对比。我们的研究结果表明，药效团增强，增加肿瘤摄取和最佳稳定的载体-药物结合整合到可水解活化的PF 108-[SN 22]2的设计中，有可能有效地对抗新诊断（化疗初治）和复发形式的侵袭性恶性肿瘤的多种化疗耐药机制。作为一种基于大分子载体的递送系统，对两种特别具有挑战性的高危神经母细胞瘤表现出显著的疗效，PF 108-[SN 22]2可以为目前缺乏有效治疗选择的多药耐药疾病患者迫切需要的稳健且临床可行的治疗策略铺平道路。
High‐risk solid tumors continue to pose a tremendous therapeutic challenge due to multidrug resistance. Biological mechanisms driving chemoresistance in high‐risk primary and recurrent disease are distinct: in newly diagnosed patients, non‐response to therapy is often associated with a higher level of tumor “stemness” paralleled by overexpression of the ABCG2 drug efflux pump, whereas in tumors relapsing after non‐curative therapy, poor drug sensitivity is most commonly linked to the dysfunction of the tumor suppressor protein, p53. In this study, we used preclinical models of aggressive neuroblastoma featuring these characteristic mechanisms of primary and acquired drug resistance to experimentally evaluate a macromolecular prodrug of a structurally enhanced camptothecin analog, SN22, resisting ABCG2‐mediated export, and glucuronidation. Together with extended tumor exposure to therapeutically effective drug levels via reversible conjugation to Pluronic F‐108 (PF108), these features translated into rapid tumor regression and long‐term survival in models of both ABCG2‐overexpressing and p53‐mutant high‐risk neuroblastomas, in contrast to a marginal effect of the clinically used camptothecin derivative, irinotecan. Our results demonstrate that pharmacophore enhancement, increased tumor uptake, and optimally stable carrier‐drug association integrated into the design of the hydrolytically activatable PF108‐[SN22]2 have the potential to effectively combat multiple mechanisms governing chemoresistance in newly diagnosed (chemo‐naïve) and recurrent forms of aggressive malignancies. As a macromolecular carrier‐based delivery system exhibiting remarkable efficacy against two particularly challenging forms of high‐risk neuroblastoma, PF108‐[SN22]2 can pave the way to a robust and clinically viable therapeutic strategy urgently needed for patients with multidrug‐resistant disease presently lacking effective treatment options.