Thursday, April 18, 2024
4/18/2024
Abstract We propose to develop a broad acute/sub-acute opioid drug detoxifying treatment for opioid overdose that can complement & compensate for the deficiencies in nalaxone, using opioid-targeted biomimetic “nanosponges” that absorb overdosed opioids in the body. (Note: if this proof-of-concept is successful here, the approach may be tailored to other drugs-of-abuse.) Called “NarcoBondTM” these 100 nm diameter nanospheres are assembled from a mixture of cholesterol & synthetic choline-based phospholipids that mimic the lipid bilayer cell membranes. Its multifunctional surface displays an optimized milieu of human membrane proteins isolated from: a) erythrocytes to increase half-life in peripheral blood & circulation, b) neurons to increase binding affinity for opioid receptor, & c) purified Mu opioid receptors to bind opioids in circulation. The NarcoBond's repertoire of native opioid receptors broadly binds & captures opioids from microenvironmental niches of cells in tissues & will result in an antagonistic pharmacological effect by rapidly reducing the concentration of the overdosed opioid. Significance. Every 15 min. in the US, a person dies after overdosing on opioids.1 Naloxone, an opioid receptor antagonist, is, to date, the only life-saving treatment for opioid overdose based on its ability to reverse respiratory depression acutely.3 Yet the pharmacodynamic actions of naloxone last for a briefer period than all but the most short acting opioids;3-9 although the elimination half life of naloxone is similar to that of morphine (60–90')9 it is redistributed away from the brain more rapidly.3 Consequently, the patients may become renarcotised after naloxone treatment due to the continued presence of opioids in peripheral blood. In full development, NarcoBond offers a more broad alternative for cost effective & longer lasting means to cleanse the peripheral blood of opioids, reducing the risk of renarcotisation, & assisting in the life-saving reversal of overdose-induced respiratory depression. While prompting acute withdrawal syndrome (AWS) is always a risk in rapid opioid receptor blockade, without renarcotisation's acute risk of recurrent respiratory depression, clinicians will have more time to intervene with gradual weaning protocols to avoid AWS. In addition, NarcoBond's broad capability to mitigate against all opioids including highly potent synthetic acrylfentanyl (i.e., “naloxone resistant” chemical threat agents), addresses unmet need(s) for medical countermeasures in terrorism & hostage scenarios.8,11
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