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Description
Although fibrosis is a natural process with a protective function in the body, it can lead to progressive disease and eventual loss of organ function. This pathology can affect different tissues, ranging from skin to the heart; indeed, lung fibrosis has been observed in COVID-19 patients. The proposed root causes of fibrosis are injury, infection and chronic inflammation, which leads to hyperactivation of myofibroblasts. These produce an abundance of collagen to the extracellular matrix (ECM) and are also considered to maintain the inflammatory state in the tissue. Treating fibrosis is complicated because the affected tissues are poorly permeable to pharmaceuticals. Current treatment involves oral intake of medication, which often leads to side effects. We propose an advanced way of delivering an antifibrotic drug directly to the site of affected tissue using a polylactic acid (PLLA)-polycaprolactone (PCL) copolymer. Using this carrier would ensure prolonged and focused release of the pharmaceutical, potentially improving treatment and reducing negative side effects.
WPMY-1 prostate cancer myofibroblasts (ATCC) and primary human myofibroblasts (HMF) were used in this study. The latter was isolated from urethral scar tissue and confirmed to have the α-smooth muscle actin myofibroblast marker via immunocytochemistry. The drug release profile of the copolymers (pure PCL, 10:90, 35:65, 15:85 PCL:PLLA composition) was evaluated over a 4 month period. The antifibrotic drug-laden PLLA-PCL fiber cloth was manufactured by electrospinning; the products were investigated by evaluating their manufacturing capabilities. The effect of the copolymer carrier was analyzed in vitro in two ways. First, the viability of the carrier-drug affected myofibroblast cells was evaluated by the MTT test. Second, gene expression levels of fibrosis-related genes (Tgfb1, Timp1, Pai1, Ctgf, Vegfa and Mmp1) was determined, comparing pre-treatment and post-treatment levels.
The 10:90 PCL:PLLA polymer showed optimal release (concentration and time-wise) of the antifibrotic drug. Our data showed that using this carrier would maintain an effective concentration of the drug in the medium that would be within the therapeutic range, as revealed by the gene expression results. The effect was more pronounced in the WPMY-1 cell line than primary human myofibroblasts, but both showed satisfactory in vitro results.
We conclude that using the drug-laden PCL:PLLA copolymer could be a prospective avenue for treatment. In vivo testing could be the next step for bringing this technology into practice.
This project has received funding from European Regional Development Fund (project No. 01.2.2-LMT-K-718-03-0087) under grant agreement with the Research Council of Lithuania (LMTLT).
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