title: Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition.
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).
  
  
  METHODS
  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 anti-ICAM-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 anti-inflammatory 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Newcastle, Newcastle, Australia; and The University of Queensland, Brisbane, Australia. Susan.Hua@newcastle.
authors.forename: Susan
authors.initials: S
authors.lastname: Hua
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cabot
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000906:Antibodies / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage; D008139:Loperamide / Q000008:administration & dosage; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D009270:Naloxone / Q000008:administration & dosage; D053758:Nanoparticles / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D000890:Anti-Infective Agents; D000906:Antibodies; D015703:Antigens, CD; D016207:Cytokines; D008081:Liposomes; D009292:Narcotic Antagonists; D018799:Intercellular Adhesion Molecule-1; D009270:Naloxone; D008139:Loperamide; D005620:Freund's Adjuvant