Neuropathic pain has a complex etiology and a long course, with the main clinical manifestation being hyperpathia. Currently there are various therapeutic approaches, such as spinal cord stimulation (SCS), pharmacotherapy, acupuncture therapy [49], etc. However, the sustained release and targeted delivery of analgesic drugs remains a critical concern for effective analgesic management [50]. With the consideration of reducing the side effects accompanying therapeutic drugs, the synthesis of nanoparticle formulations has developed rapidly as a new method of pain management. A massive literature reports that many nanoparticles are widely applied in pain drug encapsulation studies, such as liposomes, solid lipid nanoparticles (SLN), PLGA nanoparticles, gelatin, metal organic frameworks (MOF) [51–53] ...... Many experimental researches have elucidated that opioid such as morphine and hydromorphone, non-steroidal anti-inflammatory drugs such as ibuprofen and celecoxib encapsulated in a variety of nanoparticles for the treatment of neuropathic pain [54–55]. Previous studies have shown that nanoparticles can be administered in a variety of ways, such as transdermal, oral and tail vein administration, to achieve analgesic effects in vivio, but that the duration of effect is mostly short and sustained release cannot be achieved over a long period of time [56]. In this study, we used the metal-organic framework nanomaterial MIL-101 (Fe) as a carrier for the non-steroidal anti-inflammatory drug diclofenac sodium in order to obtain analgesic and controlled release effects.
It is well known that MIL-101(Fe) nanoparticles are used as drug carriers due to their large pore size, large specific surface area and high stability [57]. In this study, the large pore size and large specific surface area achieve high drug loading rate and high stability can control the drug release. In this study, the drug loading rate of MIL-101(Fe) loaded with diclofenac sodium was high, and the in vitro release profile and in vivo pharmacokinetic results showed that diclofenac sodium was continuously released from MIL-101(Fe) for three days. These results suggest that the porous structure of MIL-101 (Fe) allows for controlled release of diclofenac sodium, improving the utilisation of diclofenac sodium and prolonging the therapeutic effect. Furthermore, the gradual disintegration of the MIL-101(Fe) form by immersion in PBS for 48 hours demonstrates the good biodegradability of MIL-101 (Fe) and underlines its great potential for practical applications.
We performed cell culture, HE staining, and ELISA tests to detect the safety of the nanomaterial MIL-101(Fe). In vitro cell culture results showed negligible cellular toxicity of MIL-101; a few inflammatory cell aggregates indicated that MIL-101(Fe) did not contribute to an inflammatory response in vivo, and no significant differences in ASL and ALT concentrations between groups suggested that liver function was not impaired in rats. These results indicate the low toxicity of MIL-101(Fe) in vitro and in vivo, confirming the safety of the material and providing feasibility and scientific data to support the development of future clinical trials and new drugs.
In this study, the SNI model was used to induce neuropathic pain in rats. We confirmed that the threshold of mechanical withdrawal threshold (MWT) and cold allodynia in the SNI group were significantly lower than those in the sham group, indicating that our SNI model was successful. On this basis, we tested the effect of diclofenac sodium (DS) on neuropathic pain induced by SNI. We found that diclofenac sodium significantly improved MWT and cold allodynia induced by SNI. This study also found that MIL-101(Fe)-DS not only can significantly reverse neuropathic pain but also extend the analgesia time for three days, this suggests that the nanometer material MIL − 101(Fe) can control the release and improve the utilization rate of the diclofenac sodium in vivo. It found a way out of a stalemate that the existing sustained release agents still need to be taken daily, and provided a theoretical basis for the invention of new sustained-release agents of diclofenac sodium in the future.
Looked up neuropathic pain-related genes from the GEO database, and compared with the differentially expressed genes (DEG) obtained from RNA-sep. In the MOF vs NS group, the genes associated with neuropathic pain such as Adam8, Kdr, Sox9, and like were significantly down-regulated, indicating that the diclofenac sodium (DS) played an analgesic role. The downregulation of the Notch signaling pathway [58–60], which is associated with neuropathic pain, further confirmed that MIL-101 (Fe)-DS was introduced into rats through intraperitoneal injection, and that MIL-101 (Fe) cracked, released DS, and played a peripheral and central analgesic effect.
It is widely known that diclofenac sodium is a non-steroidal anti-inflammatory drug [12, 61], and its mechanism of action in the treatment of neuropathic pain is mainly through the inhibition of COX activity and reduction of prostacyclin production to produce analgesic effects. Studies have shown that high levels of interleukin-6 [62, 63], whose production is regulated by prostaglandins, are associated with the development of neuropathic pain. Diclofenac sodium has also been shown to block NF-κB activation [64, 65], thus affecting the production of pro-inflammatory cytokines such as IL-6. Therefore, diclofenac sodium plays an analgesic role by inhibiting NF-κB activation and downregulating the expression of interleukin-6. Regarding the DS vs NS group, some differentially expressed genes, such as Eda and Il18, were related to the NIK/NF-kappaB signaling pathway, one of the action mechanisms of diclofenac sodium, which proved that DS has an analgesic effect in vivo. The downregulation of the I-kappaB kinase/NF-kappaB signaling pathway confirmed the validity of the DS analgesic mechanism. In summary, the KEGG analysis results were consistent with the GO analysis, further validating the study's findings.