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In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid, used for the potential treatment of inflammatory diseases. The LDCs 1–2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain viaan ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1–2were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization viadynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1–2exhibited excellent stability for about a month, with good polydispersity (around 0.2) and a negative zeta potential between −20 mV and −34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1–2surpassed 90 %, as determined by HPLC analysis. In vitrocytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1–2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1–2effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1–2was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1–2were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1–2compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1–2exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1–2as potential drug candidates in future pre-clinical and clinical trials.

We have synthesized lipidic prodrugs of celecoxib by grafting aliphatic chains to celecoxib through acyl sulfonamide (1), aryl sulfonyl carbamate (2) and aryl sulfonyl urea (3) chemical linkages. Their molecular formulas were confirmed through HR-MS and the formation of ester bond by FTIR and NMR spectroscopy. Nanoparticles of the different prodrugs were successfully formulated using emulsion evaporation method and DSPE-PEG2000as the only excipient. All nanoparticles were spherical and had a size between 130 and 160 nm, PdI ≤0.2 and negative Zeta potential values from −25 to −35 mV. In addition, they were stable upon storage at 4 °C and/or at room temperature for about a month (in shelf). Morphology of all nanoparticles were spherical-type as observed in transmission electron microscopy and scanning electron microscopy. The encapsulation efficiency of the prodrug was as high as 99% for all three corresponding prodrugs NPs. The nanoscale prodrugs 1–3,is reported for the first time. Moreover, all the characterization data (physicochemical and biological) regarding NPs is also unique. In addition, all prodrug nanoparticles have preserved in vitroanti-inflammatory activity when incubated with the THP-1 cell line activated with lipopolysaccharide (LPS). In vivostudies on a collagen induced arthritis murine model showed results: Prodrug 3NPs showed activity but were not as efficient as celecoxib in its free form, this might be due to no or very slow release of celecoxib form the prodrug 3NPs. To promote the reduction of inflammation using NPs would require to explore the possible administration of other prodrugs 1and 2in the future.