Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy.
Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy.
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DOI：
10.1016/j.biomaterials.2015.01.075
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发表时间：
2015-05
期刊：
影响因子：
14
通讯作者：
Chorny, Michael
中科院分区：
文献类型：
--
作者：
Alferiev, Ivan S.;Iyer, Radhika;Croucher, Jamie L.;Adamo, Richard F.;Zhang, Kehan;Mangino, Jennifer L.;Kolla, Venkatadri;Fishbein, Ilia;Brodeur, Garrett M.;Levy, Robert J.;Chorny, Michael
基于纳米医学的策略有可能改善各种抗癌药物的治疗性能。然而，纳米颗粒递送系统的成功实施需要开发适当尺寸的纳米载体，其以受保护的、可降解的形式将其治疗货物递送至靶标。目前的研究集中在SN-38的基于纳米载体的新型制剂策略上，SN-38是一种具有抗癌潜力的拓扑异构酶I抑制剂，其临床应用受到毒性、稳定性差和与常规递送载体不相容性的影响。SN-38以其与生育酚琥珀酸酯的可快速活化前药衍生物的形式包封在可生物降解的亚100 nm尺寸的纳米颗粒（NP）中，以剂量和暴露时间依赖性方式有效抑制神经母细胞瘤细胞的生长，表现出与游离SN-38不同的延迟反应模式。在神经母细胞瘤的异种移植模型中，前体药物负载的NP引起已建立的大肿瘤的快速消退，显著延迟治疗停止后的肿瘤再生长，并显著延长动物存活。通过药物分子的可逆化学修饰实现的NP制剂策略为SN-38递送提供了可行的手段，实现了持续的肿瘤内药物水平，并有助于抗肿瘤活性的效力和延长的持续时间，这两者都是有效治疗神经母细胞瘤和其他癌症的先决条件。
Nanomedicine-based strategies have the potential to improve therapeutic performance of a wide range of anticancer agents. However, the successful implementation of nanoparticulate delivery systems requires the development of adequately sized nanocarriers delivering their therapeutic cargo to the target in a protected, pharmacologically active form. The present studies focused on a novel nanocarrier-based formulation strategy for SN-38, a topoisomerase I inhibitor with proven anticancer potential, whose clinical application is compromised by toxicity, poor stability and incompatibility with conventional delivery vehicles. SN-38 encapsulated in biodegradable sub-100 nm sized nanoparticles (NP) in the form of its rapidly activatable prodrug derivative with tocopherol succinate potently inhibited the growth of neuroblastoma cells in a dose- and exposure time-dependent manner, exhibiting a delayed response pattern distinct from that of free SN-38. In a xenograft model of neuroblastoma, prodrug-loaded NP caused rapid regression of established large tumors, significantly delayed tumor regrowth after treatment cessation and markedly extended animal survival. The NP formulation strategy enabled by a reversible chemical modification of the drug molecule offers a viable means for SN-38 delivery achieving sustained intratumoral drug levels and contributing to the potency and extended duration of antitumor activity, both prerequisites for effective treatment of neuroblastoma and other cancers.
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