Targeting neurons in breast cancer with anesthetic nanoparticles inhibits nerve-cancer stimulation and tumor progression.

No abstract

Males and females respond differently to medications due to physiologic, metabolic, and genetic factors. At times, sex‐related differences cannot be mitigated by dose adjustment to body mass, and are evident from the tissue level to the single cell. The rising number of clinically approved nanotechnologies calls for assessing how their activity is affected by the patient's sex. Herein, sex differences in nanotechnology are scoped, with emphasis on molecular considerations. Sex‐specific pharmacokinetics of nanocarriers is influenced by the nanoparticle's composition, its size, and architecture. The biodistribution and immune response to nanoparticles in males and females, and the influence nanoparticles have on hormones, fertility, and toxicity, are discussed. Despite its importance, the effect of sex on the design and implementation of nanomedicines is underresearched. Herein, it is aimed to raise awareness of sex differences in the preclinical and clinical evaluation of nanotechnologies.

Many cases of heritable environmental responses have been documented but the underlying mechanisms are largely unknown. Recently, inherited RNA interference has been shown to act as a multigenerational genome surveillance apparatus. We suggest that inheritance of regulatory RNAs is at the root of many other epigenetic phenomena, the trigger that induces other epigenetic mechanisms, such as the depositing of histone modifications and DNA methylation. In addition, we explore the possibility that interacting organisms influence each other's transcriptomes by exchanging heterologous non-coding RNAs.

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 crosstalk. 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 administered intravenously, 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.