Mechanism investigation of ethosomes transdermal permeation.

Ethosomes are widely used to promote transdermal permeation of both lipophilic and hydrophilic drugs, but the mechanism of interaction between the ethosomes and the skin remains unclear. In this work, it was exploded with several technologies and facilities. Firstly, physical techniques such as attenuated total reflectance fourier-transform infrared and laser confocal Raman were used and the results indicated that the phospholipids configuration of stratum corneum changes from steady state to unstable state with the treatment of ethosomes. Differential scanning calorimetry reflected the thermodynamics change in stratum corneum after treatment with ethosomes. The results revealed that the skin of Bama mini-pigs, which is similar to human skin, treated by ethosomes had a relatively low Tm and enthalpy. Scanning electron microscopy and transmission electron microscopy showed that the microstructure and ultrastructure of stratum corneum was not damaged by ethosomes treatment. Furthermore, confocal laser scanning microscopy revealed that lipid labeled ethosomes could penetrate the skin via stratum corneum mainly through intercellular route, while during the process of penetration, phospholipids were retained in the upper epidermis. Cell experiments confirmed that ethosomes were distributed mainly on the cell membrane. Further study showed that only the drug-loaded ethosomes increased the amount of permeated drug. The current study, for the first time, elucidated the mechanistic behavior of ethosomes in transdermal application from molecular configuration, thermodynamic properties, ultrastructure, fluorescent labeling and cellular study. It is anticipated that the approaches and results described in the present study will benefit for better design of drug-loaded ethosomes.

Co-delivery of deferoxamine and hydroxysafflor yellow A to accelerate diabetic wound healing via enhanced angiogenesis.

Nonhealing chronic wounds on foot induced by diabetes is a complicated pathologic process. They are mainly caused by impaired neovascularization, neuropathy, and excessive inflammation. A strategy, which can accelerate the vessel network formation as well as inhibit inflammatory response at the same time, makes it possible for effective diabetic ulcers treatment. Co-delivery of multiple drugs with complementary bioactivity offers a strategy to properly treat diabetic wound. We previously demonstrated that hydroxysafflor yellow A (HSYA) could accelerate diabetic wound healing through promoting angiogenesis and reducing inflammatory response. In order to further enhance blood vessel formation, a pro-angiogenic molecular called deferoxamine (DFO) was topically co-administrated with HSYA. The in vitro results showed that the combination of DFO and HSYA exerted synergistic effect on enhancing angiogenesis by upregulation of hypoxia inducible factor-1 alpha (HIF-1α) expression. The interpenetrating polymer networks hydrogels, characterized by good breathability and water absorption, were designed for co-loading of DFO and HSYA aiming to recruit angiogenesis relative cells and upgrade wound healing in vivo. Both DFO and HSYA in hydrogel have achieved sustained release. The in vivo studies indicated that HSYA/DFO hydrogel could accelerate diabetic wound healing. With a high expression of Hif-1α which is similar to that of normal tissue. The noninvasive US/PA imaging revealed that the wound could be recovered completely with abundant blood perfusion in dermis after given HSYA/DFO hydrogel for 28 days. In conclusion, combination of pro-angiogenic small molecule DFO and HSYA in hydrogel provides a promising strategy to productively promote diabetic wound healing as well as better the repair quality.

Topical application of Hydroxysafflor Yellow A accelerates the wound healing in streptozotocin induced T1DM rats.

To investigate the effects of Hydroxysafflor Yellow A (HSYA), which is derived from safflower, on the proliferation, migration and angiogenesis of cells in vitro and its potential efficacy in vivo when topically applied to a diabetic wound. Human umbilical vein endothelial cells (HUVECs) and mouse macrophage cells (RAW264.7) were used to evaluate angiogenesis and anti-inflammatory activities, respectively. The influence of HSYA on the wound scratch assay was investigated in keratinocytes. A splinted excisional wound model in rats with TIDM induced by streptozotocin was used to assess the effects of wound healing. Collagen disposition and secretion of vascular growth factors (VEGF) as well as transforming growth factor-ß1 (TGF-ß1) were evaluated by an ELISA assay and histological staining. The in vitro results showed that HSYA could significantly enhance both the neovascularization of HUVECs and the migration of keratinocytes. It showed the significant inhibitory effect on nitric oxide production, indicating the anti-inflammatory activity of HSYA. In vivo, the topical application of HSYA significantly enhanced the wound closure rate, and the time to complete wound closure was 17 days, whereas 30 days were needed with PBS treatment. Further, treatment with HSYA exhibited significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis according to Masson's trichrome staining evaluation, VEGE and TGF-ß1 ELISA measurement. In conclusion, HSYA application could be considered a promising therapeutic strategy for treating chronic non-healing diabetic foot ulcers.

Capsaicin-loaded nanolipoidal carriers for topical application: design, characterization, and in vitro/in vivo evaluation.

Capsaicin has been used in clinical applications for the treatment of pain disorders and inflammatory diseases. Given the strong pungency and high oil/water partition coefficient of capsaicin, capsaicin-loaded nanolipoidal carriers (NLCs) were designed to increase permeation and achieve the analgesic, anti-inflammatory effect with lower skin irritation. Capsaicin-loaded NLCs were prepared and later optimized by the Box-Behnken design. The physicochemical characterizations, morphology, and encapsulation of the capsaicin-loaded NLCs were subsequently confirmed. Capsaicin-loaded NLCs and capsaicin-loaded NLCs gel exhibited sustained release and no cytotoxicity properties. Also, they could significantly enhance the penetration amount, permeation flux, and skin retention amounts of capsaicin due to the application of NLCs. To study the topical permeation mechanism of capsaicin, 3,3'-dioctadecyloxacarbocyanine perchlorate (Dio) was used as a fluorescent dye. Dio-loaded NLCs and Dio-loaded NLCs gel could effectively deliver Dio up to a skin depth of 260 and 210 µm, respectively, primarily through the appendage route on the basis of version skin sections compared with Dio solution, which only delivered Dio up to 150 µm. In vivo therapeutic experiments demonstrated that capsaicin-loaded NLCs and capsaicin-loaded NLCs gel could improve the pain threshold in a dose-dependent manner and inhibit inflammation, primarily by reducing the prostaglandin E2 levels in the tissue compared with capsaicin cream and capsaicin solution. Meanwhile, skin irritation was reduced, indicating that application of NLCs could decrease the irritation caused by capsaicin. Overall, NLCs may be a potential carrier for topical delivery of capsaicin for useful pain and inflammation therapy.