Structural Optimization and Enhanced Prodrug-Mediated Delivery Overcomes Camptothecin Resistance in High-Risk Solid Tumors.
Structural Optimization and Enhanced Prodrug-Mediated Delivery Overcomes Camptothecin Resistance in High-Risk Solid Tumors.
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DOI：
10.1158/0008-5472.can-20-1344
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发表时间：
2020-10-01
期刊：
影响因子：
11.2
通讯作者：
Brodeur GM
中科院分区：
文献类型：
--
作者：
Nguyen F;Guan P;Guerrero DT;Kolla V;Naraparaju K;Perry LM;Soberman D;Pressly BB;Alferiev IS;Chorny M;Brodeur GM
喜树碱是用于治疗高危儿科实体瘤的有效拓扑异构酶I抑制剂，但由于内在或获得性耐药性，它们通常显示出较差的疗效。在这里，我们开发了一种结构优化的喜树碱（SN 22）的多价，基于聚合物的前药，旨在克服关键的耐药性机制。测试了SN 22与SN 38（伊立替康/CPT-11的活性形式）克服外排泵驱动的耐药性的能力。测定了与SN 38相比，作为基于聚合物的前药（PEG-[SN 22]4）的SN 22的肿瘤摄取和生物分布。比较PEG-[SN 22]4与CPT-11在以下中的治疗功效：a）转基因TH-MYCN小鼠中的自发性神经母细胞瘤（NB）; B）耐药NB系SK-N-BE（2）C（突变的TP 53）的原位异种移植物; c）耐药NB-PDX的侧腹异种移植物;以及d）尤文肉瘤和横纹肌肉瘤的异种移植物。与SN 38不同，SN 22抑制NB细胞生长而不管ABCG 2表达水平。SN 22前药递送导致持续的肿瘤内药物浓度，在所有时间点显著高于SN 38的那些。CPT-11/SN 38处理对转基因小鼠的肿瘤仅具有边际效应，但PEG-[SN 22]4处理导致持续6个月以上的完全肿瘤消退（尸检时无肿瘤）。PEG-[SN 22]4还显著延长了具有耐药性原位NB的小鼠的存活期，并且在80-100%的NB和肉瘤异种移植物中引起长期（6个月以上）缓解。与CPT-11相比，作为多价聚合物前药施用的SN 22导致增加和延长的肿瘤药物暴露，导致内在或获得性耐药性的NB模型和高风险肉瘤模型的长期“治愈”，从而使其进一步开发用于临床试验。
Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but they often show poor efficacy due to intrinsic or acquired chemoresistance. Here we developed a multivalent, polymer-based prodrug of a structurally optimized camptothecin (SN22) designed to overcome key chemoresistance mechanisms. The ability of SN22 vs. SN38 (the active form of irinotecan/CPT-11) to overcome efflux pump-driven drug resistance was tested. Tumor uptake and biodistribution of SN22 as a polymer-based prodrug (PEG-[SN22]4) compared to SN38 was determined. The therapeutic efficacy of PEG-[SN22]4 to CPT-11 was compared in: a) spontaneous neuroblastomas (NB) in transgenic TH-MYCN mice; b) orthotopic xenografts of a drug-resistant NB line SK-N-BE(2)C (mutated TP53); c) flank xenografts of a drug-resistant NB-PDX; and d) xenografts of Ewing sarcoma and rhabdomyosarcoma. Unlike SN38, SN22 inhibited NB cell growth regardless of ABCG2 expression levels. SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points. CPT-11/SN38 treatment had only marginal effects on tumors in transgenic mice, but PEG-[SN22]4 treatment caused complete tumor regression lasting over 6 months (tumor-free at necropsy). PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ month) remissions in 80-100% of NB and sarcoma xenografts. SN22 administered as a multivalent polymeric prodrug resulted in increased and protracted tumor drug exposure compared to CPT-11, leading to long-term “cures” in NB models of intrinsic or acquired drug resistance, and models of high-risk sarcomas, warranting its further development for clinical trials.