Transnasal drug delivery to the brain: circumventing barriers for brain tumor patients

The transnasal route is a novel mode of drug delivery into the brain. It has several advantages of circumventing systemic first-pass metabolism that attenuates bioavailability and bypassing the blood brain barrier that excludes multiple categories of drugs or biologics. These include most compounds that have high molecular weight and low lipid solubility, bioactive neuropeptides, and monoclonal antibodies that have potential neurotherapeutic effects. In this review, we summarized how drugs and biologics can be delivered into the brain via (i) the olfactory/nasal lymphatic route, (ii) the epithelial or other supportive cells by receptor-mediated micropinocytosis for transcellular delivery, and (iii) transneuronal transport through the olfactory and trigeminal neurons. Dexamethasone and neuropeptide corticorelin acetate can be taken up by the lymphatic route, while larger molecular weight entities such as checkpoint inhibitors, bi-specific antibodies, and antibody-drug conjugates may require the slower transepithelial or transneuronal transport system. Tumor Treating Fields may increase the permeability of the tissue near the cribriform plate and therefore facilitate entry of these high-molecular-weight neurotherapeutics into the brain. For brain tumor patients, transnasal delivery holds promise for the delivery of drugs like dexamethasone, neuroactive peptide, and monoclonal antibodies for the treatment of malignancies in the brain while decreasing systemic toxicities.