Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model

Abstract

Introduction Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin. Methods In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium. Results We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release. Conclusion Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs.

Topical Delivery of Tofacitinib in Dermatology: The Promise of a Novel Therapeutic Class Using Biodegradable Dendritic Polyglycerol Sulfates

“…A pilot experiment was therefore performed on intact and barrier-deficient skin models to evaluate the enhanced dermal drug delivery efficacy of dPGS-PCL for hydrophobic active agents within human skin. Three types of conditions were used: 30 times tape-stripped skin (TS) [ 46 ] to model mechanically damaged skin; serine protease (SP) pretreated skin (+SP) to model chemically damaged skin; and saline buffer pretreated skin (−SP) [ 37 ] to model an intact skin barrier. Skin samples were then treated with a low dose of sunitinib, ”as a model of hydrophobic dye”, loaded in dPGS-PCL (0.05 w/w%).…”

“…The skin penetration experiments of sunitinib-loaded dPGS-PCL (dPGS-PCL@SUN) (5 mg/mL) and sunitinib as a model of hydrophobic dye with close molecular weight to TFB (loading: 0.05 w/w%) were performed on freshly excised human skin [ 30 , 37 ]. The commercially available base cream containing (0.05 w/w%) sunitinib was used as a control.…”

“…Then, the distribution of polymeric carriers and their payload drug inside the skin are strongly dependent on the skin interaction with the carrier, drug characteristics, and drug release properties [ 34 , 35 ]. In recent years, immunosuppressive drugs such as tacrolimus and rapamycin were encapsulated in polyglycerol drug delivery systems and were tested as a treatment for inflammatory skin disease [ 36 , 37 ].…”

Chitosan-Rapamycin Carbon Dots Alleviate Glaucomatous Retinal Injury by Inducing Autophagy to Promote M2 Microglial Polarization

“…The utilization of novel nanoparticles as a delivery system for localized RAPA delivery has been previously demonstrated to effectively mitigate skin, vascular inflammation, or promote regeneration, such as in bone tissue. [54][55][56] For retinal applications, though, on top of considerations regarding the biodegradation of intraocular drug carriers, the optical properties of the eye impose significant constraints on nanocarrier size, along with the need to allow light transmission. 33 As a result, CDs, being able to be conjugated to ligands or aptamers for specific applications, despite their relatively small sizes, have become a topic of increasing interest in ophthalmology over the past few years.…”

Anti-inflammatory IL-8 Regulation via an Advanced Drug Delivery System at the Oral Mucosa

“…Several therapeutic avenues concentrate on the development of novel drug delivery systems (DDSs) with increased efficacy and bioavailability of topically applied drug formulations. In dermatology, many of those DDSs are currently under investigation for topical treatment of inflammatory skin diseases. − In the field of ophthalmology, DDS applications are partly already in clinical use. , …”