Combination of Ketorolac Tromethamine and Prednisolone-Loaded PLGA Nanocomposite for Effective Chronic Pain Relief in Mice

Int J Nanomedicine. 2025 Jun 27:20:8343-8357. doi: 10.2147/IJN.S515452. eCollection 2025.

Abstract

Introduction: Chronic pain is a complex condition that requires timely and effective management to prevent long-term emotional, social, and economic consequences. This study aims to develop a poly(lactic-co-glycolic acid) (PLGA)-based nanocomposite co-loaded with ketorolac tromethamine (KT) and prednisolone (PRED) to improve therapeutic efficacy and reduce systemic side effects associated with conventional treatments.

Methods: KT-PRED-PLGA nanoparticles were synthesized via a double emulsion method and characterized for their physicochemical properties and biocompatibility. A chronic inflammatory pain model was established in ICR mice using Complete Freund's Adjuvant (CFA). Mechanical pain thresholds were evaluated using Dixon's up-and-down method. Histopathological and immunohistochemical analyses were performed to evaluate systemic toxicity and inflammation-related protein expression.

Results: The KT-PRED-PLGA nanoparticles exhibited favorable characteristics, including a mean particle size of 166.2 ± 8.0 nm, a polydispersity index of 0.14, a zeta potential of -15.8 ± 0.3 mV, and encapsulation efficiency exceeding 80%. The nanoparticles sustained drug release up to 92.5% over 120 h. In vitro assays demonstrated the KT-PRED-PLGA nanoparticles revealed high biocompatibility in Vero cells after 72 h of exposure. In vivo experiments demonstrated significantly reduced pain behaviors and tissue inflammation, with minimal toxicity. Behavioral assessments confirmed enhanced analgesic and anti-allodynic effects over the free drugs. Reduced expression of cyclooxygenases (COX-1 and COX-2) and prostaglandin E2 (PGE2) in hind paw tissues confirmed improved anti-inflammatory activity.

Conclusion: KT-PRED-PLGA nanoparticles offer safe, sustained analgesia with enhanced therapeutic efficacy and reduced systemic toxicity, highlighting their strong potential for future clinical translation in chronic pain therapy.

Keywords: PLGA nanoparticle drug delivery; chronic inflammatory pain relief; double emulsion strategy; ketorolac tromethamine and prednisolone encapsulation; nanomedicine.

MeSH terms

  • Animals
  • Chronic Pain* / drug therapy
  • Disease Models, Animal
  • Drug Carriers / chemistry
  • Drug Liberation
  • Ketorolac Tromethamine* / administration & dosage
  • Ketorolac Tromethamine* / chemistry
  • Ketorolac Tromethamine* / pharmacokinetics
  • Ketorolac Tromethamine* / pharmacology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Nanocomposites* / administration & dosage
  • Nanocomposites* / chemistry
  • Particle Size
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
  • Prednisolone* / administration & dosage
  • Prednisolone* / chemistry
  • Prednisolone* / pharmacokinetics
  • Prednisolone* / pharmacology
  • Vero Cells

Substances

  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Ketorolac Tromethamine
  • Prednisolone
  • Drug Carriers