Mistretta Katelyn S, Tiche Jane, Chiu Bill, Coburn Jeannine M
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts, USA.
Department of Surgery, Stanford University, Stanford, California, USA.
J Biomed Mater Res A. 2025 Jan;113(1):e37803. doi: 10.1002/jbm.a.37803. Epub 2024 Oct 2.
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. High-risk NB is a subset of the disease that has poor prognosis and requires multimodal treatment regimens, with a 50% rate of recurrence despite intervention. There is a need for improved treatment strategies to reduce high-risk patient mortality. Dinutuximab is an anti-GD2 antibody ideal for targeting GD2 expressing NB cells, but binding of the antibody to peripheral nerve fibers leads to severe pain during systemic administration. Intratumoral delivery of the anti-GD2 antibody would allow for increased local antibody concentration, without increasing systemic toxicity. Chondroitin Sulfate (CS) is a biocompatible glycosaminoglycan that can be methacrylated to form CSMA, a photocrosslinkable hydrogel that can be loaded with therapeutic agents. The methacrylation reaction time can be varied to achieve different degrees of substitution, resulting in different release and degradation profiles. In this work, 4 and 24 h reacted CSMA was used to create hydrogels at 10% and 20% CSMA. Sustained in vitro release of dinutuximab from these formulations was observed over a 24-day period, and 4 h reacted 10% CSMA hydrogels had the highest overall dinutuximab release over time. An orthotropic mouse model was used to evaluate in vivo response to dinutuximab loaded 4 h methacrylated 10% CSMA hydrogels as compared to bolus tail vein injections. Tumor growth was monitored, and there was a statistically significant increase in the days to reach specific tumor size for tumors treated with intratumoral dinutuximab-loaded hydrogel compared to those treated with dinutuximab solution through tail vein injection. This supports the concept that locally delivering dinutuximab within the hydrogel formulation slowed tumor growth. The CSMA hydrogel-only treatment slowed tumor growth as well, an interesting effect that may indicate interactions between the CSMA and cell adhesion molecules in the tumor microenvironment. These findings demonstrate a potential avenue for local sustained delivery of dinutuximab for improved anti-tumoral response in high-risk NB.
神经母细胞瘤（NB）是最常见的小儿颅外实体瘤。高危NB是该疾病的一个亚组，预后较差，需要多模式治疗方案，尽管进行了干预，其复发率仍为50%。需要改进治疗策略以降低高危患者的死亡率。地努图希单抗是一种抗GD2抗体，非常适合靶向表达GD2的NB细胞，但该抗体与外周神经纤维结合会导致全身给药期间出现严重疼痛。抗GD2抗体的瘤内递送可提高局部抗体浓度，而不增加全身毒性。硫酸软骨素（CS）是一种生物相容性糖胺聚糖，可进行甲基丙烯酸酯化形成CSMA，一种可光交联的水凝胶，可负载治疗剂。甲基丙烯酸酯化反应时间可以变化以实现不同程度的取代，从而产生不同的释放和降解曲线。在这项工作中，使用反应4小时和24小时的CSMA以10%和20%的CSMA制备水凝胶。在24天的时间里观察到地努图希单抗从这些制剂中的持续体外释放，反应4小时的10% CSMA水凝胶随着时间推移的地努图希单抗总体释放量最高。使用正交小鼠模型评估与尾静脉推注相比，对负载地努图希单抗的反应4小时甲基丙烯酸酯化10% CSMA水凝胶的体内反应。监测肿瘤生长，与通过尾静脉注射地努图希单抗溶液治疗的肿瘤相比，用瘤内地努图希单抗负载水凝胶治疗的肿瘤达到特定肿瘤大小的天数有统计学上的显著增加。这支持了在水凝胶制剂中局部递送地努图希单抗可减缓肿瘤生长的概念。仅CSMA水凝胶治疗也减缓了肿瘤生长，这一有趣的效果可能表明CSMA与肿瘤微环境中的细胞粘附分子之间存在相互作用。这些发现证明了局部持续递送地努图希单抗以改善高危NB抗肿瘤反应的潜在途径。
