The use of α-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to α7 nAChR-overexpressing breast cancer

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca²⁺ transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors.