期刊
INTERNATIONAL JOURNAL OF CANCER
卷 140, 期 3, 页码 726-735出版社
WILEY
DOI: 10.1002/ijc.30479
关键词
neuroblastoma; chemotherapy; sustained-release; orthotopic animal model; tumor recurrence; silk materials
类别
资金
- Warren and Clara Cole Career Development Award (American College of Surgeons), National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000073, UL1 TR001064, P41 EB002520]
Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a small-round-blue cell (SBRC) to predominantly large cell neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors. What's new? Neuroblastoma is the most common extracranial solid tumor in the pediatric population, accounting for 15% of all pediatric oncologic deaths. Treatment of high-risk tumors require intense multi-cycle chemotherapies, resulting in short- and long-term toxicities. Here, the authors describe a new treatment strategy using implantable and injectable chemotherapy-loaded silk materials that leads to improved tumor suppression and decreased systemic toxicity in mice. Additionally, they created a previously unavailable orthotopic animal model of relapsed neuroblastoma, which presents a most aggressive phenotype of large-cell neuroblastoma. The intratumoral treatment strategy and establishment of a relapsed neuroblastoma model represent significant progress in neuroblastoma research.
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