Use of a Noninvasive Brain-Penetrating Peptide-Drug Conjugate Strategy to Improve the Delivery of Opioid Pain Relief Medications to the Brain

Abstract

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the Angiopep-2 peptide (An2) that crosses the bloodbrain-barrier (BBB) by LRP1 receptor-mediated transcytosis, with either morphine or M6G. We demonstrated improvement of BBB permeability of these new entities compared with that of unconjugated M6G and morphine. Intravenous or subcutaneous administration of the An2-M6G conjugate exerted greater and more sustained analgesic activity than equivalent doses of either morphine or M6G. Likewise, subcutaneous An2-morphine induced a delayed but prolonged antinociceptive effect. The effects of these conjugates on the gastrointestinal tract motility were also evaluated. An2-morphine significantly reduced the intestinal transit time while An2-M6G exhibited a reduced constipation profile, as compared to an equimolar dose of morphine. In summary, we have developed new brain-penetrant opioid conjugates exhibiting improved analgesia to side-effect ratios. These results thus support the use of An2 carrier peptides as an innovative BBB targeting technology to deliver effective drugs such as M6G for the pain management.

An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors

“…TAT has been shown to penetrate the BBB in a non-facilitated process [31,34]. Angiopep-2 (An2), derived from aprotinin, has emerged more recently as a valid alternative [35][36][37][38]. Importantly, this peptide exploits the low density lipoprotein receptor related protein-1 (LRP-1)-expressed both by brain microcapillary endothelial cells and by glioma-to gain access to the brain parenchyma via receptor-mediated transcytosis [39].…”

Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

“…Similarly, the K in of the Morphine‐Ang (2.7 × 10 −3 ml/s/g) was 12‐fold higher than that of unconjugated morphine (2.2 × 10 −4 ml/s/g). Importantly, both conjugates exhibited potent and more prolonged analgesic effects than equivalent doses of unconjugated drugs, supporting the utility of Angiopep‐2 BBB shuttle peptide in CNS delivery (Eiselt et al, 2020).…”

Biomaterials and Regenerative Medicine in Pain Management

“…Sustained release of ADSC-derived exosomes regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response. Reproduced with permission significantly lower brain penetration of M6G following more conventional delivery methods limits its application in pain management [65]. Eiselt and colleagues conjugated M6G with a brain-targeting peptide angiopep-2 peptide (An2), which crosses the blood-brain barrier by low-density lipoprotein receptor-related protein 1 (LRP1)-receptor mediated transcytosis and demonstrated significantly improved brain penetration and analgesic potency of M6G.…”

“…The targeted delivery facilitated the elimination of both pro-inflammatory cytokines and ROS in microglia and ameliorated mechanical allodynia in a spinal nerve transection-induced neuropathic pain mouse model. Other novel ROS scavenging materials have been proposed for various applications, including ceria nanocrystals decorated Targeted delivery: uterus Liposomes conjugated with anti-oxytocin receptor antibody Indomethacin Increased localization to the uterus by sevenfold; for the prevention of inflammation-induced preterm labor pain [64] Targeted delivery: brain Angiopep-2 peptide Morphine-6-glucuronide Greater and more sustained analgesic activity than equivalent doses M6G [65] Targeted delivery: endosome Composite polymeric nanoparticles, encapsulating aprepitant N/A Inhibited substance P-induced activation of spinal neurons; complete and persistent relief from nociceptive, inflammatory, and neuropathic nociception [66] Mesoporous silica nanoparticle core with DADLE-conjugated liposome shell N/A Achieve long-lasting activation of DOPr in endosomes; provided sustained inhibition of nociceptor excitability and relief from inflammatory pain [67] ROS scavenging Ceria-zirconia nanoparticles conjugated with anti-CD11b antibody N/A Facilitated elimination of both pro-inflammatory cytokines and ROS in microglia; greatly ameliorated mechanical allodynia in neuropathic pain [70] mesoporous silica nanoparticles [71], movable hemin-loaded mesoporous silica nanoparticles [72], poly(NIPAAm-co-VPco-MAPLA-co-MATEMPO) hydrogel [73], and enzymemimicking ultrasmall Cu 5.4 O nanoparticles [74]. Table 1 lists current research a clinical application of biomaterials for pain management.…”

“…Brain-targeting carriers have been developed to enhance drug penetration across blood–brain barrier which has the potential to improve the analgesic response while maintaining, or reducing, dose and minimizing adverse side effects. The analgesic potency of the morphine metabolite morphine-6-glucuronide (M6G) is 50-fold higher than morphine when administered via intracerebral injection, but the significantly lower brain penetration of M6G following more conventional delivery methods limits its application in pain management [ 65 ]. Eiselt and colleagues conjugated M6G with a brain-targeting peptide angiopep-2 peptide (An2), which crosses the blood–brain barrier by low-density lipoprotein receptor-related protein 1 (LRP1)-receptor mediated transcytosis and demonstrated significantly improved brain penetration and analgesic potency of M6G.…”