PMID- 35405122 OWN - NLM STAT- MEDLINE DCOM- 20220822 LR - 20220930 IS - 1520-6017 (Electronic) IS - 0022-3549 (Linking) VI - 111 IP - 9 DP - 2022 Sep TI - Hydrophobic Derivatives of Sulfated Hyaluronic Acid as Drug Delivery Systems for Multi-Target Intra-Articular Treatment of Post-Traumatic Osteoarthritis. PG - 2505-2513 LID - S0022-3549(22)00155-1 [pii] LID - 10.1016/j.xphs.2022.04.003 [doi] AB - During osteoarthritis (OA) development, chondrocytes progressively decompensate, upregulating proteolytic enzymes and reducing the key growth factors involved in promoting chondrocyte anabolism. A combined therapeutic approach is needed to address this multifactorial pathology, which affects the whole joint. Based on the literature, three promising targets for OA treatment have been selected: MMP3 (matrix metallopeptidase 3), TRPV4 (transient receptor potential cation channel subfamily V member 4) and mTOR (mammalian target of rapamycin). In this study, a novel water-soluble and biocompatible amphiphilic polymer named "sHA-oleylamide" was synthesized and screened from a series of hyaluronic acid derivatives for its anticatabolic activity. This MMP inhibitor showed no cytotoxicity, and in an in vitro model of inflammatory OA, it reversed the inflammatory outcome at a concentration of 0.011 mg/mL. The ability of sHA-oleylamide to form 20-50 nm micelles in water with a critical micelle concentration of 0.27+/-0.1 mg/mL, was confirmed by TEM images and measured by Nile red staining. RN-1747 and rapamycin molecules were successfully loaded in sHA-oleylamide, previously prepared at 12 mg/mL in PBS; both formulations were stable, sterile and confirmed in vitro to have mTOR inhibition by rapamycin and TRPV4 activation activity by RN-1747. The controlled release of RN-1747 from the micellar formulation with sHA-oleylamide showed that only approximately 60% of the total loaded RN-1747 was released within 7 days. These micellar formulations can potentially increase the bioavailability and pharmaceutical efficacy of the selected active molecules, combining their anti-catabolic and pro-anabolic activities and making them suitable for i.a. administration as OA treatments. CI - Copyright (c) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved. FAU - Guarise, Cristian AU - Guarise C AD - Fidia Farmaceutici, Abano Terme (PD), Italy. Electronic address: cguarise@fidiapharma.it. FAU - Tessari, Martina AU - Tessari M AD - Fidia Farmaceutici, Abano Terme (PD), Italy. FAU - Pavan, Mauro AU - Pavan M AD - Fidia Farmaceutici, Abano Terme (PD), Italy. FAU - Pluda, Stefano AU - Pluda S AD - Fidia Farmaceutici, Abano Terme (PD), Italy. FAU - Di Lucia, Alba AU - Di Lucia A AD - Fidia Farmaceutici, Abano Terme (PD), Italy. FAU - Barbera, Carlo AU - Barbera C AD - Fidia Farmaceutici, Abano Terme (PD), Italy. FAU - Galesso, Devis AU - Galesso D AD - Fidia Farmaceutici, Abano Terme (PD), Italy. LA - eng PT - Journal Article DEP - 20220409 PL - United States TA - J Pharm Sci JT - Journal of pharmaceutical sciences JID - 2985195R RN - 0 (Micelles) RN - 0 (Sulfates) RN - 0 (TRPV Cation Channels) RN - 059QF0KO0R (Water) RN - 9004-61-9 (Hyaluronic Acid) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Drug Delivery Systems MH - Humans MH - *Hyaluronic Acid/therapeutic use MH - Micelles MH - *Osteoarthritis/drug therapy/metabolism/pathology MH - Sirolimus MH - Sulfates MH - TOR Serine-Threonine Kinases/metabolism MH - TRPV Cation Channels MH - Water/metabolism OTO - NOTNLM OT - MMP Inhibition OT - Micellar Formulation OT - Osteoarthritis OT - mTOR Inhibition COIS- Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EDAT- 2022/04/12 06:00 MHDA- 2022/08/23 06:00 CRDT- 2022/04/11 20:10 PHST- 2022/01/17 00:00 [received] PHST- 2022/04/06 00:00 [revised] PHST- 2022/04/06 00:00 [accepted] PHST- 2022/04/12 06:00 [pubmed] PHST- 2022/08/23 06:00 [medline] PHST- 2022/04/11 20:10 [entrez] AID - S0022-3549(22)00155-1 [pii] AID - 10.1016/j.xphs.2022.04.003 [doi] PST - ppublish SO - J Pharm Sci. 2022 Sep;111(9):2505-2513. doi: 10.1016/j.xphs.2022.04.003. Epub 2022 Apr 9.