Targeted Nanoparticles that Mimic Immune Cells in Pain Control Inducing Analgesic and Anti-inflammatory Actions: A Potential Novel Treatment of Acute and Chronic Pain Conditions

Abstract

Background: The peripheral immune-derived opioid analgesic pathway has been well established as a novel target in the clinical pain management of a number of painful pathologies, including acute inflammatory pain, neuropathic pain, and rheumatoid arthritis. Objective: Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression, sedation, dependence, tolerance). Study Design: A randomized, double blind, controlled animal trial. Methods: Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated antiICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes, empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 µL Complete Freund’s Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All formulations were administered intravenously via tail vein injection. The dose administered was 200 µL, which equated to 0.8 mg of loperamide HCl for the loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An investigator blinded to the treatment administered assessed the time course of the antinociceptive and antiinflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes via tail vein injection using liquid scintillation counting (LSC). Results: Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic and anti-inflammatory effects over the 48 hour time course studied following intravenous administration in rats with Complete Freund’s Adjuvant-induced inflammation of the paw. All control groups showed no significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into the brain. Limitations: In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. Conclusions: The study presents a novel approach of opioid delivery specifically to injured tissues for pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting, which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles with other therapeutic compounds for use in other painful conditions. Key words: Pain, inflammation; immune cells, opioids, ICAM-1, loperamide, targeted drug delivery, immunoliposomes

Proteome characterization of small extracellular vesicles from spared nerve injury model of neuropathic pain

“…ICAM-1 regulates the homing of opioidproducing cells and the subsequent generation of analgesia within sites of painful inflammation [50]. Loperamide-encapsulated anti-ICAM-1 immunoliposomes exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue [52]. The authors proposed that engineering targeted nanoparticles can be beneficial in treating pain disorders [52].…”

“…Loperamide-encapsulated anti-ICAM-1 immunoliposomes exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue [52]. The authors proposed that engineering targeted nanoparticles can be beneficial in treating pain disorders [52]. Exosomes released by monocytes induce ICAM-1 and cytokines via activation of NFκB [53].…”

An Hypothesis for CXCL1/CXCR2 Signaling Regulating Neutrophil-Derived Opioid Peptides Involved in Acupuncture for Inflammatory Pain

“…Studies have showed that, in early stages of inflammation (6 h after inflammation), both peripheral and central opioid receptors are involved in the antinociceptive effect [21], whereas in later stages (4-6 days after inflammation), endogenous analgesia is mediated exclusively by peripheral opioid and its receptors [19,22]. However, due to the limitations of experimental studies, pharmacological techniques, or other aspects, in peripheral endogenous opioid peptides for treating inflammatory pain, there are still some challenges to recruit more opioid peptide-containing immune cells to the inflammation site and to efficiently promote the release of immune cell-derived opioid peptides and the synthesis of opioid receptors in inflammation site [21,23].…”

Nanotechnology in Chronic Pain Relief

“…To address cancer-induced bone pain, Gdowski et al (2017) modified PLGA with the bone microenvironment targeting amino-bisphosphonate, to deliver cabazitaxel for efficient pain relief in a bone metastatic prostate cancer model. To mimic the endogenous response in inflammatory sites, Hua et al designed opioid loaded liposomes with the capacity to target inflammatory environments and release the corresponding drugs for simultaneous pain relief (Hua and Cabot, 2013). Important research described by Ramírez-García et al (2019) reveals that their novel pH-responsive nanomaterials with the ability to target neurokinin-1 receptors (NK 1 R) in the endosome display excellent capacity for preventing chronic pain.…”