Encapsulation of MCC950 in Liposomes Decorated with Anti-Frizzled 1 Improves Drug Bioavailability and Effectiveness in Fatty Liver Disease

Abstract

Inflammasome activation plays a crucial role in the progression to more severe stages of non-alcoholic fatty liver disease (NAFLD), representing a promising therapeutic target. MCC950 is a small molecule acting as a potent and specific inhibitor of the canonical and non-canonical activation of the NLRP3 inflammasome, but its short plasmatic half-life limits its use. Herein, we report, for the first time, the encapsulation of MCC950 in poly(ethylene glycol) (PEG) liposomes (LPs) that are specifically functionalized with an antibody against Frizzled 1 (FZD1), a g-coupled protein involved in the WNT pathway and overexpressed on inflammasome-activated macrophages. MCC950, encapsulated into PEG-LP formulations conjugated with an anti-FZD1 antibody, inhibits the NLRP3 inflammasome activation at concentrations 10 times lower than that of the free drug in THP-1 cells. Luminescent carbon dots (CDs) were also co-encapsulated with MCC950 in LPs to obtain optically traceable nanoformulations that have proved the enhanced ability of the targeted LPs to be internalized into THP-1 cells with respect to their nontargeted counterparts. Our results suggest that MCC950 encapsulation into targeted LPs represents a valuable strategy to achieve reformulation of the NLRP3 inhibitor, able to significantly curtail the threshold of MCC950 doses for inhibiting inflammasome activation, thus offering a new therapeutic approach.

The application strategy of liposomes in organ targeting therapy

“…Wang, Suo, & Zhang, 2023). In addition to paclitaxel, liposomes also play an important role in improving the bioavailability and reducing systemic toxicity of other highly effective anti-cancer drugs, such as silymarin (SL) (Gheybi et al, 2023), curcumin (Negro et al, 2023;, deferoxamine (DFO) (Guo et al, 2023), and catechins (Jin et al, 2023).…”

“…Li et al utilized liposomes with surface modification of glycyrrhetinic acid (GA) and a cell penetrating peptide to load the anti‐tumor drug Pingyangmycin (PYM), achieving hepatocyte surface targeting in liver cancer cells and increasing intracellular drug content (L. Li, Chen, et al, 2022). Additionally, agarose‐based ligands and FZD1 antibodies were also modified on the surface of liposomes to efficiently deliver drugs to the liver (Figure 2c) (Dhawan et al, 2022; Negro et al, 2023). Multiple injections of polyethylene glycol liposomes (PEG‐L) accelerated blood clearance, increasing drug accumulation and activation in the liver, thereby amplifying the therapeutic efficacy of the drug in hepatocellular carcinoma (Zhang, Pan, et al, 2023).…”

“…To overcome paclitaxel resistance in lung cancer, Wang J et al prepared P‐glycoprotein antibody‐conjugated PEG‐coated immunoliposomes (Pab‐PTX‐L) to enhance cellular uptake of paclitaxel in tumor cells, and ultimately achieving the inhibitory effects on tumor growth (Figure 4e) (J. Wang, Suo, & Zhang, 2023). In addition to paclitaxel, liposomes also play an important role in improving the bioavailability and reducing systemic toxicity of other highly effective anti‐cancer drugs, such as silymarin (SL) (Gheybi et al, 2023), curcumin (Negro et al, 2023; Y. Wang, Huang, et al, 2023), deferoxamine (DFO) (Guo et al, 2023), and catechins (Jin et al, 2023).…”

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases

“…In liver-related GIDs, specific proteins from the frizzled (FZD) family, namely FZD1 and FZD7, associated with the Wnt pathway, have been implicated in contributing to the heightened hepatic fibrosis and inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD). These proteins have been identified in the exosomes isolated from the plasma of MASLD-affected subjects [ 42 , 43 ]. In the context of MASLD, recent findings have highlighted an imbalance of specific lipids, specifically oleic and palmitic acid, delivered within circulating exosomes.…”

The ‘speck’-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis

“…Treatment with VI-16, a synthetic flavonoid that tethers NLRP3 and abrogates its binding to Thioredoxin interacting protein (TXNIP), results in a complete NLRP3 inflammasome inhibition, ameliorating colitis [ 83 ]; Compound 6, a novel tetrahydroquinoline which complex with the NACHT domain of NLRP3, inhibits NLRP3 inflammasome and attenuates colitis in in vivo mouse model [ 84 ]. Oral administration of MCC950, the best characterized direct and selective NLRP3 inhibitor, with a half-maximal inhibitory concentration (IC 50 ) within the nanomolar range, Oridonin, which competes for binding to NEK7, or INF39, an irreversible inhibitor of the ATPase domain of NLRP3, have shown efficacy against colitis in animal models [ 85 – 88 ]. OLT1177 (Dapansutrile), developed by Olatec in 2012, was the first specific NLRP3 inhibitor to successfully pass phase II (Clinical Trials Identifier: NCT01636141) in patients with colitis [ 67 , 89 ].…”