Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases
Maya Kaduri, Mor Sela, Shaked Kagan, Maria Poley, Hanan Abumanhal-Masarweh, Patricia Mora‐Raimundo, Alberto Ouro, Nitsan Dahan, Dov Hershkovitz, Jeny Shklover, Janna Shainsky‐Roitman, Yosef Buganim, Avi Schroeder
Abstract
Neurons within the tumor microenvironment promote cancer progression; thus, their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer cross-talk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration, and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer cell viability. In vivo, bupivacaine-loaded nanoparticles intravenously administered suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.