Liposome‐encapsulated statins reduce hypertrophic scarring through topical application

Abstract

Hypertrophic scar is an important clinical problem with limited therapeutic options. Aside from their roles as 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors, statins have also been demonstrated to decrease scarring by reducing connective tissue growth factor (CTGF) expression. However, poor penetrative ability limits their utility as topical treatments for hypertrophic scar. Here, we aim to develop novel statin formulations using liposomes to enhance dermal penetrative ability and to evaluate their efficacy against formation of hypertrophic scar utilizing our validated rabbit ear hypertrophic scar model. Liposomal simvastatin or pravastatin were compounded using a novel, flexible liposomal formulation and applied topically to rabbit ear hypertrophic scars daily from postoperation day (POD) 14 until POD 25. Scar color, including erythema and melanin, was measured using reflectance spectrophotometry on POD 28, and scar tissue was harvested for evaluation of scar elevation index as well as gene and protein expression. Human foreskin fibroblasts were also treated with statin formulations and CCN2 expression was determined by quantitative PCR. Both simvastatin and pravastatin were efficiently encapsulated in liposomes, forming nanometer‐scale particles possessing highly negative charges. Topical treatment with liposomal simvastatin and pravastatin at 6.5% concentration significantly reduced scar elevation index and decreased type I/III collagen content and myofibroblast persistence in the wound. The erythema/vascularity of scars was reduced by liposomal statin treatment, with concomitant decrease of CD31 expression as measured histologically. Expression levels of transcripts encoding CTGF, collagen I, and collagen III collagen in scar tissue were also decreased by liposomal pravastatin treatment, as were myofibroblast persistence and the type I/III collagen ratio as assessed by immunofluorescence and picrosirus red staining, respectively. Treatment of human foreskin fibroblasts with simvastatin or with liposome‐encapsulated pravastatin resulted in decreased expression of transcript encoding CTGF. Overall, our novel statin formulations encapsulated in liposomes were successfully delivered through topical application, significantly reducing hypertrophic scarring in a rabbit ear model.

Statin treatment and hypertrophic scarring after cardiac surgery

“…In an animal model, Ko and colleagues have suggested that low dosages of statins (40 mictoM) were associated with significant reductions in the scar elevation index (SEI) compared to an untreated control group, through a mechanism mediated by the reduction of connective tissue growth factor (CTGF) 28 . Recently, Xia et al found that simvastatin seems to inhibit the gene and the protein expression of CTGF and that liposome‐encapsulated statins might reduce hypertrophic scarring though topical application 29 . The same research team then assessed the effectiveness of statin on the wound healing process in an animal model in which the using the SEI, a ratio of cross‐sectional scar area to the area of tissue was assessed 30 .…”

Simvastatin cream alleviates dermal fibrosis in a rabbit ear hypertrophic scar model

“…Previously, our laboratory has demonstrated that application of statins is sufficient to reduce hypertrophic scarring in preclinical rabbit ear models of excisional wounding. We demonstrated amelioration of excisional wound‐induced hypertrophy by application of statins through intradermal injection, 5,6 topical application within emulsifications delivered in transcutol/capmul, 6 and topical application in liposomal formulations 7 . In order to optimize ease‐of‐use clinically in a cost‐effective and traditional drug delivery vehicle, we formulated a statin‐containing cream formulation for topical application.…”

Assessing the Interactions of Statins with Human Adenylate Kinase Isoenzyme 1: Fluorescence and Enzyme Kinetic Studies

“…Moreover, statins demonstrate a promising therapeutic potential in the field of bone tissue engineering and bone regeneration due to their ability to promote the expression of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) [ 8 ]. Statins have been shown to decrease hypertrophic scarring by reducing the expression of connective tissue growth factor (CTGF) and type I/III collagen content [ 9 ]. There is also evidence for the therapeutic potential of statins for the treatment of chronic liver disease and cirrhosis by exerting anti-fibrotic and vasoprotective effects [ 10 ].…”

“…To improve their therapeutic benefits, numerous nanotechnology-based drug delivery systems were developed [ 25 , 26 , 27 , 28 ]. The enhancement of statins’ pharmacological parameters can be achieved by using nano-sized systems and functional nanomaterials, including nanoparticles [ 25 , 27 , 29 ], nanoliposomes [ 9 ], nanocrystals [ 30 ] as well as self-nanoemulsifying systems [ 31 , 32 ]. Due to the wide spectrum of potential benefits of statins, research efforts should also focus on the identification of new targets and deeper understanding of the underlying mechanisms of statin pleiotropy.…”