The efficiency of ultrasonic glymphatic manipulation-based intrathecal drug delivery depends on the physiological states

Abstract

Recently, for the first time, we discovered that brain-wide application of low-pressure transcranial focused ultrasound can be used to enhance the parenchymal penetration of intrathecally administered imaging agents to a large portion of the brain through the glymphatic pathway. This proof-of-concept study only investigated the delivery efficiency in fully anesthetized animals (2.5% isoflurane). Here, we aim to determine how different anesthetic conditions affect the delivery efficiency as the glymphatic system is altered by the physiological states. We assigned three rat experimental groups: heavy-3% isoflurane (n = 4), moderate-2.5% isoflurane (n = 4), and light-1.5% isoflurane (n = 5), co-delivered two different-sized imaging tracers intrathecally (IRDye + trypan blue, IRDye labeled IgG antibody + trypan blue), and exposed ultrasound (650 kHz, 0.2 MPa for 10 min). We measured heart rate, respiratory rate, oxygen level, perfusion, and body temperature during the test and imaged the ex vivo brain using an optical imaging system. We observed that the distribution of the delivered agents in the brain parenchyma is higher in light anesthetic groups as compared to moderate and higher ones, and it depends on the molecular size of the agents as well. Future work is to increase the number of animals in each group, perform statistical analysis to confirm the preliminary findings, and determine the delivery efficacy of the technique on metastatic cancer model. M. Aryal et al., J Control Release (2022), PMID:35798095.