Biology subjects

Luciani, P.

Publications and source records attributed to Luciani, P..

4 recordsLinked to original sources

bioRxiv2024

A Fibronectin (FN)-Silk 3D Cell Culture Model as a Screening Tool for Repurposed Antifibrotic Drug Candidates for Endometriosis

This study advances sustainable pharmaceutical research for endometriosis by aligning with the UN Sustainable Development Goals on health, gender equality, and responsible consumption in developing in vitro 3D cell culture models of endometriotic pathophysiology. Fibrosis is a key aspect of endometriosis, yet current models to study it remain limited, especially in 3D. This work aims to bridge the translational gap between in vitro fibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-{beta}1) in a physiological manner as probed at the mRNA level. For stromal cells, this response to TGF-{beta}1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-{beta}1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting the drugs potential as a repurposed non-hormonal therapy for endometriosis. This study demonstrates how a sustainable approach - from project conceptualization to material selection - can be integrated into pharmaceutical research for womens health. Table of contentsThis paper presents in vitro 3D cell culture models of fibrosis in endometriosis. Endometrial stromal and epithelial cells cultured in networks of silk protein functionalized with a fibronectin-derived cell adhesion motif showed physiological-like fibrotic behavior. Pirfenidone was able to reverse fibrosis of endometrial stromal cells in vitro, demonstrating this models suitability as a screening tool for antifibrotic drugs for endometriosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/616776v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12727c3org.highwire.dtl.DTLVardef@1a39292org.highwire.dtl.DTLVardef@1ebdb2aorg.highwire.dtl.DTLVardef@181d6ac_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Leveraging machine learning to streamline the development of liposomal drug delivery systems

Drug delivery systems efficiently and safely administer therapeutic agents to specific body sites. Liposomes, spherical vesicles made of phospholipid bilayers, have become a powerful tool in this field, especially with the rise of microfluidic manufacturing during the COVID-19 pandemic. Despite its efficiency, microfluidic liposomal production poses challenges, often requiring laborious, optimization on a case-by-case basis. This is due to a lack of comprehensive understanding and robust methodologies, compounded by limited data on microfluidic production with varying lipids. Artificial intelligence offers promise in predicting lipid behaviour during microfluidic production, with the still unexploited potential of streamlining development. Herein we employ machine learning to predict critical quality attributes and process parameters for microfluidic-based liposome production. Validated models predict liposome formation, size, and production parameters, significantly advancing our understanding of lipid behaviour. Extensive model analysis enhanced interpretability and investigated underlying mechanisms, supporting the transition to microfluidic production. Unlocking the potential of machine learning in drug development can accelerate pharmaceutical innovation, making drug delivery systems more adaptable and accessible.

pharmacology and toxicology↗

bioRxiv2023

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Fibrosis, low-grade inflammation, and increased friction are together with degradation of cartilage key culprits for debilitating pain in osteoarthritis (OA), which is one of the most common chronic diseases of todays aging population. Intraarticular administration of bio-lubricants loaded with a pharmaceutically active component recently showed promise to improve therapy. Liposomes have emerged as exceptional lubricant biomaterial, but their small size leads to rapid clearance from the synovium, causing a need for more frequent administration. We recently developed a liposomal drug delivery system based on aggregation of negatively charged liposomes with physiologically present divalent cations. Here, we expanded our platform by replacing calcium with zinc, reported to exert anti-inflammatory action. The liposomal aggregates extend the release of rapamycin (RAPA) beyond the free liposomes and have a diameter of nearly 100 m, which was previously established to improve retention in synovial joints. Electron microscopy showed that RAPA alters the irregular morphology of liposomal clusters, which are irreversible upon dilution. RAPA recently showed great promise both in vitro and in vivo at protecting the joints from inflammation and cartilage from further degradation. Our study adds to this by showing that RAPA is also able to dampen the fibrotic response in human OA synovial fibroblasts. Finally, the tribological properties were assessed on nano- and macro-scales on silicon surface and ex vivo porcine cartilage, which showed an excellent protective ability of the system against friction on both scales. Taken together, our study shows that liposomal aggregates have the potential of improving local OA therapy.

pharmacology and toxicology↗

bioRxiv2022

Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colonic mucosa. There is no cure for UC and its chronic relapsing/remitting nature strongly affects patient quality of life. Current treatment options frequently have significant side effects and remission rates are limited raising a demand for new treatment strategies. Novel therapeutic approaches that could maximize the drug concentration at the site of inflammation with minimal systemic exposure, like topical applications, would address this unmet clinical need. To date, few drug delivery systems (DDSs) have been designed to topically convey small molecules to the rectum and left-sided colon. Here, we developed and tested a drug delivery platform for topical treatment of UC based on a temperature-triggered in situ forming adhesive lipid gel (TIF-Gel). Due to its soft, gel-like consistency, its high encapsulation efficacy, and its drug-controlled release, TIF-Gel suggests a more patient-friendly and effective application with respect to the rectal formulations currently available. Capitalizing on the biocompatible and biodegradable self-assembled structure of lipid mesophases (LMPs), we loaded TIF-Gel with tofacitinib (TOFA; a hydrophilic inhibitor of the enzymes Janus kinase 1 and 3) or TAC (a hydrophobic immunosuppressive drug), both of which are indicated in the treatment of UC. We designed and fully characterized our biocompatible lipid formulation in vitro and tested it in vivo using two different murine models of inflammatory bowel disease: chemically-induced and T cell transfer-mediated. Both approaches (TIF-Gel-TOFA and TIF-Gel-TAC) led to reductions in colitis disease severity and intestinal inflammation compared to vehicles, therefore showing therapeutic efficacy. Overall, our findings show that TIF-Gel can deliver drugs locally to the colonic mucosa to mitigate intestinal inflammatory disease in a pre-clinical model. They also suggest that, in a clinical setting, TIF-Gel might provide a patient-friendly approach to improve colitis while allowing for a reduction of the adverse effects associated with a systemic therapy.

bioengineering↗