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

Tuyet-Nhi Do; Yen-Chin Liu; Yu-Che Chuang; Tsung-Lin Tsai; Ping-Ching Wu

doi:10.2147/IJN.S515452

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.

Authors

Tuyet-Nhi Do¹, Yen-Chin Liu^{2

3

4}, Yu-Che Chuang⁵, Tsung-Lin Tsai^{1

6

7}, Ping-Ching Wu^{1

6

8

9

10}

Affiliations

¹ Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, 701, Taiwan.
² School of Post-Baccalaureate, College of Medicine, Kaohsiung Medical University, Kaohsiung, 812, Taiwan.
³ Department of Anesthesiology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan.
⁴ Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
⁵ Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
⁶ Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 701, Taiwan.
⁷ Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
⁸ Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
⁹ Medical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 701, Taiwan.
¹⁰ University Center of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 701, Taiwan.

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