Lithium carbonate-loaded polymeric nano-micelles for enhanced antitumor activity against NF1-associated malignant peripheral nerve sheath tumors via improved cellular uptake.
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Malignant peripheral nerve sheath tumors (MPNSTs) are fatal and highly aggressive soft tissue tumors that are associated with patients with neurofibromatosis type 1 (NF1). Traditional treatment methods have limited effects, so new treatment strategies need to be developed. Lithium carbonate (Li2CO3) is a type of psychotropic drug and has also been proven to play an important role in tumor treatment. Its nanoscale structure could achieve better therapeutic effects and reduce toxicity. In this study, we utilized MPNST cells (S462) derived from pediatric patients to develop polymeric nanomicelles loaded with Li2CO3 and determined their effects on the proliferation and apoptosis of MPNST cells and the related signaling mechanisms. The results indicated that LM significantly enhanced cellular uptake when exposed to the same concentration of extracellular Li2CO3. Free Li2CO3 inhibited cell proliferation in a concentration-dependent manner. Using a lower concentration could achieve the same or even stronger antitumor effect. The free drug and LM significantly increased the proportion of cells in the G1 and G2/M phases and inhibited the proportion of cells in the S phase (DNA synthesis phase). The effect of LM on the cell cycle was more significant compared with the free drug group. LM also significantly induced apoptosis in MPNST cells. The mechanism study revealed that LM increased the intracellular reactive oxygen species level and thereby inhibited the phosphorylation of ERK. After treatment with the antioxidant NAC, the expression of p-ERK increased, indicating that LM enhanced antitumor activity against MPNST cells by regulating the ROS-ERK signaling pathway. Our results suggested that encapsulating Li2CO3 in nanocarriers might reduce the required dosage and minimize adverse effects, which would provide a promising strategy for optimizing lithium-based therapies in MPNSTs.