Synthesis of Chitosan-Modified Diclofenac Acid Prodrug Nanoparticles and Evaluation of Their Anti-Inflammatory Effects in a Preclinical Model

Diclofenac acid (DA) is widely employed in various clinical settings for pain management. However, prolonged use of DA can induce various adverse effects on the gut, including ulcers and intestinal bleeding. There is also a possible link between the extended use of DA and its increased susceptibility to cardiovascular diseases. Prodrug-based nanoparticles (NPs) have emerged as a promising approach for drug delivery and overcome side effects. In this investigation, a diclofenac acid-based prodrug (DA-P) was synthesized and subsequently used for developing NPs (DA-P-NPs). The developed NPs were further modified with chitosan (DA-P-NPs-CHI) to achieve stability and sustained release of the drug. The DA-P was chemically synthesized and confirmed with EI-mass spectrometry, ¹H-NMR, and ¹³C-NMR spectroscopic techniques. The characterization of DA-P-NPs and DA-P-NPs-CHI involved several techniques, such as atomic force microscopy (AFM and SEM), DLS, FTIR, TGA, and DSC. DA-P demonstrated a reduced critical micelle concentration (CMC) of 0.07 mg/mL and effectively encapsulated more drug within the NPs. DA-P-NPs and DA-P-NPs-CHI exhibited average particle sizes of 130.7 ± 0.6 and 230.2 ± 5.3 nm, and surface charges of -36.2 ± 2.0 and 41.2 ± 0.9 mV, respectively. DA-P-NPs-CHI exhibited a drug-release rate remarkably greater at acidic pH. A paw-edema model was induced via formalin exposure to evaluate the anti-inflammatory effect of DA-P-NPs-CHI. Assessment of anti-inflammatory activity demonstrated that the use of DA-P-NPs-CHI resulted in a substantial reduction in edema compared to diclofenac-treated rats. These findings demonstrate that the proposed DA-P-NPs possess the promising attributes that make them a possible alternative therapy for pain and inflammation.