KS-133/KS-487 Nanoparticles Exhibit Potent Antitumor Effects through Synergistic LRP1 Targeting and VIPR2 Inhibition: Therapeutic Nanoarchitectonics for Solid Tumors

VIPR2 is associated with psychiatric disorders, breast cancer metastasis, and cancer immunostimulation. The VIPR2 antagonist KS-133 changes the polarity of macrophages to the M1 type, and nanoparticles (NPs) releasing KS-133 exhibit antitumor effects against mouse colon cancer cells (CT26) in vivo. To enhance the antitumor effect of KS-133 NPs, KS-133 NPs are combined with the peptide KS-487 targeting LRP1, which is expressed on CT26 cells. Subcutaneous injection of NPs containing indocyanine green (ICG) fluorescent dye and presenting KS-487 in CT26 subcutaneous tumor-bearing mice resulted in significant accumulation of ICG in the CT26 tumor compared to administration of NPs without KS-487. NPs containing KS-133 and presenting KS-487 (KS-133/KS-487 NPs) exhibited dose-dependent antitumor effects in CT26 subcutaneous tumor-bearing mice; the antitumor effects are more potent than the effects of KS-133 NPs without KS-487. In addition, CD8-positive T cells and macrophages significantly infiltrated into CT26 tumors after injection of KS-133/KS-487 NPs. Thus, KS-133/KS-487 NPs efficiently deliver KS-133 to CT26 tumors via LRP1-targeting and activate immune system cells such as CD8 positive T cells and macrophages via KS-133 inhibition of VIPR2 signaling, resulting in antitumor effects. These results demonstrate the potential of KS-133/KS-487 NPs as a therapeutic candidate for treating solid tumors.