Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models.
Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models.
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DOI：
10.3390/ijms23031752
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发表时间：
2022-02-03
影响因子：
5.6
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;Soberman D;Guan P;Nguyen F;Kolla V;Fishbein I;Pressly BB;Brodeur GM;Chorny M
尽管采用了强化多模式治疗，但大多数高危神经母细胞瘤（NB）患者不能存活。如果在给药策略上没有显著的改进，作为高危肿瘤一线治疗的抗癌药物往往不能在弥散性、复发性或难治性疾病的情况下提供有临床意义的结果。喜树碱家族拓扑异构酶I抑制剂的纳米载体介导递送，通过增强药理学选择性、有利地改变生物分布、增强肿瘤细胞杀伤能力和克服耐药性，有可能显著提高治疗效果并减少副作用。在这项研究中，一种结构增强的喜树碱类似物SN22与氧化还原沉默的工具衍生物（生育酚酰草酸酯）可逆偶联，使其在聚乙二醇化的亚100 nm纳米颗粒（NP）上具有最佳稳定的包封和控释，表现出强大的NB细胞生长抑制活性，转化为原位mycn扩增的NB肿瘤的快速消退和持久抑制再生。在重现高风险疾病不同阶段（诊断时与多药化疗后获得性p53功能丧失的复发时）的临床前模型中取得的强大抗肿瘤效果和显著延长的生存期表明，SN22以可水解切割的超疏水前药的形式递送，包裹在可生物降解的纳米载体中，作为治疗高风险癌症难治性实体瘤的实验策略病人。
Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.
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