tretinoin and nile-red

Ultradeformable vesicles are highly promising tools to enhance the percutaneous transport of different drugs such as tretinoin across the skin barrier and also to increase the formulation stability at absorption site and reduce the drug induced irritation.. Topical delivery of tretinoin-loaded ultradeformable vesicles (tretinoin-UDV) was evaluated concerning different studies, such as: the release and permeation profiles (tape stripping); skin penetration (fluorescence analysis); induced electrical changes in skin barrier properties; cytotoxicity (Trypan Blue assay) and skin irritation in in vivo conditions (Draize test). The novel formulation performance was also compared to a commercial tretinoin formulation regarding in vivo studies.. It was obtained a sustained and controlled drug release, as expected for UDV formulation. In addition, a dermal delivery was observed regarding the permeation study since it was not detected any drug amount in the receptor phase after 24h. Nile Red-UDV stained intensively mostly in the stratum corneum, corroborating the tape stripping results. Tretinoin-UDV decreased skin resistance, suggesting its ability to induce skin barrier disruption. Finally, the formulation vehicle (empty UDV) and tretinoin-UDV were not toxic under in vitro and in vivo conditions, at least, at 5×10(-3)mg/mL and 0.5mg/mL of tretinoin, respectively.. Tretinoin-UDV is a promising delivery system for tretinoin dermal delivery without promoting skin irritation (unlike other commercial formulations), which is quite advantageous for therapeutic purpose.

Topics: Administration, Topical; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Drug Carriers; Drug Delivery Systems; Electric Impedance; Epidermis; Humans; Keratinocytes; Light; Liposomes; Nanotechnology; Oxazines; Skin; Skin Absorption; Tretinoin; Trypan Blue

The aim of the present work is to prepare nanoparticulate systems that can target and modulate the functions of mononuclear phagocytes by local administration. All-trans retinoic acid (RA) was chosen as an immunomodulator to be encapsulated in biodegradable nanoparticles (NP). Different formulations were prepared by the nanoprecipitation method and poly(d,l)lactic acid based nanocapsules (NC) were selected to continue the study. RA-NC demonstrated a sustained release profile and an enhanced stability for 7 days. The uptake of fluorescent (NileRed) labeled NP was conducted on bone marrow derived macrophages (BMM) in vitro and xenograft glioma nude mice in vivo. Fluorescent microscopy observations and flow cytometry analysis demonstrated that NR-NC were engulfed by BMM in vitro and lasted inside over 7 days. The intratumoral injection of NR-NC confirmed that NC were efficiently uptaken by infiltrated macrophages. The effects of RA loaded NC on BMM were also evaluated by RT(2)-PCR array. Our results suggest that polymeric nanoparticles are suitable carriers to deliver RA into macrophages and can offer a new strategy in tumor macrophage-based treatment.

Topics: Animals; Biological Transport; Brain Neoplasms; Cell Line, Tumor; Chemical Precipitation; Chemistry, Pharmaceutical; Cytokines; Drug Carriers; Drug Compounding; Drug Stability; Female; Flow Cytometry; Fluorescent Dyes; Glioma; Humans; Immunologic Factors; Injections, Intralesional; Kinetics; Lactic Acid; Macrophages; Mice; Mice, Inbred C57BL; Mice, Nude; Microscopy, Fluorescence; Nanocapsules; Nanotechnology; Oxazines; Phagocytosis; Polyesters; Polymers; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Solubility; Technology, Pharmaceutical; Tretinoin; Xenograft Model Antitumor Assays

To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RAR alpha403) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RAR alpha403 transgene show attenuated responsiveness to topical application of all-trans retinoic acid, in agreement with our previous in vitro data. We also show that the vitamin D3 receptor is unaffected in its ability to transactivate in the presence of the dominant-negative RAR alpha403 transgene, indicating that the RAR alpha403 is unlikely to be functioning through a global sequestration of retinoid X receptors. Additionally, we show that the disruption of epidermal barrier function results in a dramatic 4 C drop in mean body surface temperature, probably accounting for the extremely high incidence of neonatal mortality in severely phenotypic pups. Some severely affected pups do survive and show a pronounced hyperkeratosis at postpartum day 4, consistent with previously documented effects of vitamin A deficiency. Biochemical analysis of the severely phenotypic neonates indicates elevated phospholipids and glycosylceramides in the stratum comeum, which results from altered lipid processing. Taken together with previous studies, these data provide strong evidence linking the retinoid-signaling pathway with modulation of lipid processing required for formation of epidermal barrier function.

Topics: Administration, Topical; Animals; Animals, Newborn; Body Temperature; Ceramides; Epidermis; Fluorescent Dyes; Keratosis; Lipid Metabolism; Mice; Mice, Transgenic; Oxazines; Phospholipids; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Retinoids; Signal Transduction; Skin; Transcription Factors; Transgenes; Tretinoin