ID #424 CXCR4-Mimicking Nanoparticles Improve Arsenic Trioxide Targeting and Therapeutic Efficacy in Metastatic Neuroblastoma
Jiatong Dai, Jingyi Huang, Xingfei Chen, Jiajie Chen, Jianan Li, Cong Liang, Xiaoyu Lin, Lina Wang, Shiyao Song, Yanlai TangAbstract
Bone and bone marrow metastases in neuroblastoma patients are often associated with high aggressiveness, poor prognosis, and reduced survival. Although arsenic trioxide (ATO) combined with conventional chemotherapy has shown some efficacy in treating high-risk neuroblastoma patients in clinical studies, effective delivery to bone and bone marrow metastatic sites remains a major challenge. Here, we exploit the bone marrow homing capability of the CXCR4–CXCL12 axis to develop a biomimetic nanoparticle for targeted ATO delivery. PEG-modified ATO nanoparticles were coated with neuroblastoma cell membranes overexpressing CXCR4 to construct a biomimetic nanomaterial—BMT-ATO (bone marrow-targeted ATO). Successful coating and CXCR4 functionality were confirmed by Coomassie Brilliant Blue staining and transmission electron microscopy ( TEM ).
In a bone marrow metastasis mouse model, BMT-ATO achieved a 10.177-fold higher accumulation in bone marrow compared to free ATO (p < 0.05, via ICP-MS), leading to significantly increased tumor cell exposure. This induced tumour cell apoptosis via activation of the MAPK/JNK pathway , measured by flow cytometry and western blot. Furthermore, BMT- ATO downregulated CXCR4 expression by approximately 60% in tumor cells (p < 0.05, via western blot), disrupting tumour-bone marrow microenvironment crosstalk that supports metastatic progression. Meanwhile, BMT-ATO prolonged the half-life from 1.743 to 3.93 hours (P < 0.001) and maintained higher plasma concentrations indicating improved pharmacokinetic properties.
These data support further development of BMT-ATO as a clinically translatable strategy for treating bone marrow - metastatic neuroblastoma. Collectively, these findings demonstrate an effective strategy for bone-marrow-targeted drug delivery. This represents the first CXCR4-biomimetic nanoplatform for targeted delivery of ATO to bone marrow metastases, enhancing drug accumulation at metastatic marrow sites and extending systemic exposure, offering a promising therapeutic approach to improve outcomes for patients with bone marrow–metastatic neuroblastoma.