在播散性神经母细胞瘤小鼠模型中，经血管注射肿瘤靶向神经祖细胞可实现干扰素-β的靶向递送并限制肿瘤生长。

Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma.

作者信息

Dickson Paxton V, Hamner John B, Burger Rebecca A, Garcia Elizabeth, Ouma Annastasia A, Kim Seung U, Ng Catherine Y C, Gray John T, Aboody Karen S, Danks Mary K, Davidoff Andrew M

机构信息

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

出版信息

J Pediatr Surg. 2007 Jan;42(1):48-53. doi: 10.1016/j.jpedsurg.2006.09.050.

DOI:10.1016/j.jpedsurg.2006.09.050

PMID:17208540

Abstract

BACKGROUND

Interferon-beta (IFN-beta) has potent antitumor activity; however, systemic toxicity has limited its clinical use. We investigated the potential of targeted delivery using tumor-tropic neural progenitor cells (NPCs) transduced to express human IFN-beta (hIFN-beta).

METHODS

Disseminated neuroblastoma was established in SCID mice by tail vein injection of tumor cells. Fourteen days after tumor cell inoculation, systemic disease was confirmed with bioluminescence imaging (BLI). Mice were then treated by intravenous injection of human F3.C1 NPCs that had been transduced with a replication deficient adenovirus to overexpress hIFN-beta (F3-IFN-beta). Two injections were given: the first at 14 days and the second at 28 days following tumor cell injection. Control mice received NPCs transduced with empty vector adenovirus at the same time points. Progression of disease was monitored using BLI. At sacrifice, organ weights and histology further evaluated tumor burden.

RESULTS

After initiation of therapy, BLI demonstrated a significant decrease in the rate of disease progression in mice receiving F3-IFN-beta. At necropsy, control mice had bulky tumor replacing the liver and kidneys, as well as extensive retroperitoneal and mediastinal adenopathy. Impressively, these sites within mice receiving F3-IFN-beta therapy appeared grossly normal with the exception of small nodules within the kidneys of some of the F3-IFN-beta-treated mice. The accumulation of F3.C1 cells within sites of tumor growth was confirmed by fluorescence imaging. Importantly, systemic levels of hIFN-beta in the treated mice remained below detectable levels.

CONCLUSIONS

These data indicate that in this model of disseminated neuroblastoma, the tumor-tropic property of F3.C1 NPCs was exploited to target delivery of IFN-beta to disseminated tissue foci, resulting in significant tumor growth delay. The described novel approach for effective IFN-beta therapy may circumvent limitations associated with the systemic toxicity of IFN-beta.

摘要

背景

β-干扰素（IFN-β）具有强大的抗肿瘤活性；然而，全身毒性限制了其临床应用。我们研究了利用转导以表达人IFN-β（hIFN-β）的肿瘤嗜性神经祖细胞（NPCs）进行靶向递送的潜力。

方法

通过尾静脉注射肿瘤细胞在SCID小鼠中建立播散性神经母细胞瘤。肿瘤细胞接种14天后，通过生物发光成像（BLI）确认全身性疾病。然后通过静脉注射用复制缺陷型腺病毒转导以过表达hIFN-β的人F3.C1 NPCs（F3-IFN-β）对小鼠进行治疗。给予两次注射：第一次在肿瘤细胞注射后14天，第二次在28天。对照小鼠在相同时间点接受用空载体腺病毒转导的NPCs。使用BLI监测疾病进展。处死时，通过器官重量和组织学进一步评估肿瘤负荷。

结果

开始治疗后，BLI显示接受F3-IFN-β的小鼠疾病进展速率显著降低。尸检时，对照小鼠有巨大肿瘤取代肝脏和肾脏，以及广泛的腹膜后和纵隔淋巴结病。令人印象深刻的是，接受F3-IFN-β治疗的小鼠体内这些部位除了一些接受F3-IFN-β治疗的小鼠肾脏内有小结节外，大体上看起来正常。通过荧光成像证实了F3.C1细胞在肿瘤生长部位的积累。重要的是，治疗小鼠体内hIFN-β的全身水平仍低于可检测水平。