(259) Silver nanoparticles selectively treat neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Objective : Neurofibromatosis type 1 (NF1) is an inherited disorder characterized by loss-of-function mutations in the neurofibromin gene. NF1 patients are susceptible to development of neurofibromas which can transform into deadly malignant peripheral nerve sheath tumors (MPNSTs) after complete loss of neurofibromin. NF1-associated MPNSTs have a generally poor prognosis. Our group and others show that rationally developed nanomedicines show promise in cancer therapy. Here we evaluate silver nanoparticles (AgNPs) as a cancer-selective therapy for NF1-associated MPNSTs to address a significant unmet clinical need.

Methods: A panel of in vitro cell models of NF1-associated MPNSTs, sporadic MPNSTs, and normal Schwann cells were employed to evaluate cancer-selectivity of AgNP relative to standard of care. We then used miRNA or neurofibromin expression vectors to either decrease or restore functional neurofibromin expression, respectively.

Results: Our data show that AgNPs are selectively cytotoxic to NF1-associated MPNSTs relative to sporadic MPNST and normal Schwann cells. Sensitivity to AgNP was potentiated when co-treated with oxidative stress inducing agents. Furthermore, we found that sensitivity to AgNPs is correlated with expression levels of functional neurofibromin. Restoration of neurofibromin expression in NF1-associated MPNSTs decreased AgNP sensitivity, and reducing neurofibromin expression in Schwann cells increased AgNP sensitivity. This finding is unique to AgNP as our alterations in neurofibromin expression did not alter susceptibility to doxorubicin. Using a co-culture model system, we found that AgNP selectively eradicated NF1-associated MPNST at doses allowing normal Schwann cells to remain viable.

Conclusions: We show that NF1-associated MPNSTs are susceptible to AgNP at doses that are tolerated by healthy Schwann cells. These data support the use of AgNP as a novel approach for clinical management of NF1-associated MPNSTs and warrants further preclinical evaluation.