EXTH-57. EXPLORING NOVEL ROUTES FOR NON-INVASIVE DRUG ADMINISTRATION: INTRADERMAL DELIVERY FOR THE TREATMENT OF BRAIN TUMORS

Abstract Effective non-invasive drug delivery to brain tumors remains challenging, despite extensive exploration of these methods, due to the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a promising alternative approach, as it circumvents limitations on tumor access imposed by the BBB when administering therapeutics systemically and limits the occurrence of systemic toxic responses to treatment. The intranasal route of administration allows therapeutic access to brain tumors through pathways involving the olfactory and trigeminal nerves (TNs) that connect the nasal passage to the brain. However, effective nose-to-brain delivery is impeded by rapid mucosal drug clearance in the nasal cavity, drug aspiration, and ingestion. Since the TN arises from the brainstem and its branches innervate the facial skin, in addition to muscles, meninges, and respiratory mucosa, we tested the hypothesis that facial intradermal administration targeting the V2 branch of the TN could be an alternative strategy to harness TN-mediated brain delivery to bypass the BBB. Here, we developed Spherical Nucleic Acids (SNAs) consisting of a 15nm spherical gold nanoparticle core functionalized with radially oriented fluorophore-tagged ssDNA as a model therapeutic. We observed the delivery of the SNAs to the brain starting 4 hours post intradermal injection, with the SNA accumulation in the tumor persisting over time. Using ex vivo fluorescent imaging, comprehensive immunofluorescence microscopy, and flow cytometry we confirmed the SNA accumulation in the brain, dura, TN, and cervical lymph nodes. In particular, we demonstrated that SNAs were enriched in the neuronal cell bodies of the trigeminal ganglia and within the epineurium and perineurium of the TN. The SNAs were also enriched in CD45-positive immune cells. In conclusion, this study credentialed facial intradermal administration of SNAs as a promising non-invasive method for brain drug delivery to target intracranial tumors.