Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment

Article Article scientifique Article Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment eng 2026-01 author Fernandez Gonzalez Paula 809874 author Morici Luca 0009-0001-7102-1285 824188 author Simula Luca 857442 Département de pathologie et immunologie (PATIM) author Takwa Rajhi author Benabdellah Aya 900065 author Allémann Eric 0000-0002-6598-9521 26730 author Jordan Olivier 0000-0003-3752-2198 133859 Section des sciences pharmaceutiques (FARMA) 114980 10.1016/j.ejpb.2026.114980 41519310 0939-6411 https://linkinghub.elsevier.com/retrieve/pii/S0939641126000019 Osteoarthritis (OA) is the most common joint disease worldwide causing cartilage loss, inflammation and pain. Lorecivivint (LOR) is a new disease-modifying osteoarthritis drug (DMOAD) that targets the Wnt pathway to improve cartilage regeneration and reduce the pro-inflammatory cytokines production. However, its advancement in the clinical evaluation is facing certain challenges due to poor solubility and fast clearance from the joint. Our study is the first to improve LOR delivery using cationic liposomes for intra-articular injection. DSPC-Chol-DOTAP-based liposomes were formulated using microfluidics with an encapsulation efficiency (EE) of 36 % of LOR and increasing the drug solubility over 120-fold in PBS and 100-fold in simulated synovial fluid. In a physiological environment, a prolonged release of 17 % of the LOR over 14 days was achieved, while faster release of 65 to 86 %, respectively, was observed in simulated synovial fluid. The surface charge of + 35 mV and the size of 145 nm were influential in increasing cartilage uptake in bovine explant of 1.4-fold and 3.6-fold compared to free LOR solution and suspension, respectively. In vitro study by flow cytometry revealed there was no cytotoxicity at 10 nM in human chondrocytes (hCHs) and in human mesenchymal stem cells (MSCs). Nevertheless, some toxicity-related morphological changes in hCHs spheroids were observed at 300 nM, which corresponds to the IC80 of LOR. The safer liposomal concentration of 10 nM maintained the drug bioactivity and reduced by half TGF-β and IL-6 levels in two-dimensional hCHs and MSCs cell culture, which confirmed the anti-fibrotic and anti-inflammatory effects. An in vivo pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy. Lorecivivint Adavivint SM04690 DMOADs Liposomes Cartilage MSCs Microfluidic system Intra-articular Dewey 615 Swiss National Science Foundation Synthesis of biopolymers and their application as glucose carriers for osteoarthritis stem cell therapy 192350 CH 31 Section des sciences pharmaceutiques 17 false 883 Technologie pharmaceutique 879 Biopharmacie https://ars.els-cdn.com/content/image/1-s2.0-S0939641126000019-mmc1.docx European journal of pharmaceutics and biopharmaceutics 220 ddb591c3-8ca0-4de2-b550-d0f7628a4436 Article (Published version) Public Gonzalez-Morici_2026_Cationic_lipos.pdf 7480881 application/pdf CC BY-4.0 442e4f06f476114a1ad12975bfb51cb86092d05f8f677ade236d33e3250e49bc Vignette Public 1-s2.0-S0939641126000019-ga1_lrg.jpg 163656 image/png openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment	European journal of pharmaceutics and biopharmaceutics			2026	0	0

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Fernandez Gonzalez, Paula