Thermodynamically and chemically stable RNA nanoparticles derived from the three-way junction (3WJ) of the pRNA from bacteriophage phi29 DNA packaging motor were examined previously for ocular delivery. It was reported that, after subconjunctival injection, RNA nanoparticles with tri-way shape entered the corneal cells but not the retinal cells, whereas particle with four-way shape entered both corneal and retinal cells. The present study evaluated ocular delivery of RNA nanoparticles with various shapes and sizes, and assessed the effect of thermosensitive hydrogels (poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid); PLGA-PEG-PLGA) for increasing the retention of RNA nanoparticles in the eye. Fluorescence imaging of mouse eyes and fluorescence microscopy of dissected eye tissues from the conjunctiva, cornea, retina, and sclera were performed to determine the distribution and clearance of the nanoparticles in the eyes after subconjunctival injection in vivo. RNA nanoparticles entered the cells of the conjunctiva, cornea, retina, and sclera after subconjunctival delivery. The clearance of RNA pentagon was slower than both RNA square and triangle of the same designed edge length (10nm) in the eye, and the clearance of RNA squares of the longer edge lengths (10 and 20nm) was slower than RNA square of the shorter edge length (5nm), thus indicating that the size could affect ocular pharmacokinetics of the nanoparticles. At 24h after the injection, approximately 6-10% of the fluorescence signal from the larger nanoparticles in the study (RNA square of 20nm edge length and RNA pentagon of 10nm edge length) remained in the eye, and up to 70% of the retinal cells contained the nanoparticles. The results suggest that the larger nanoparticles were "gulped" in conjunctival, corneal, retinal, and scleral cells, similar to the behavior observed in macrophages. Additionally, the combination of RNA nanoparticles with the thermosensitive polymers increased the retention of the nanoparticles in the eye.
In the present study, terpene composited lipid nanoparticles and lipid nanoparticles were developed and evaluated for dermal delivery of all-trans-retinoic acids (ATRA). Terpene composited lipid nanoparticles and lipid nanoparticles were investigated for size, size distribution, zeta potential, entrapment efficiency, photostability, and cytotoxicity. In vitro skin permeation of ATRA lipid formulations were also evaluated. To explore the ability of lipid nanocarriers to target the skin, the distribution of rhodamine B base in the skin was investigated using confocal laser scanning microscopy (CLSM). The results indicated that the physicochemical characteristics of terpene composited lipid nanoparticles influenced skin permeability. All lipid nanocarriers significantly protected ATRA from photodegradation and were non-toxic to normal human foreskin fibroblast cells in vitro. Solid lipid nanoparticles containing 10% limonene (10% L-SLN) had the highest ATRA skin permeability. Terpene composited SLN and nanostructured lipid carriers (NLC) showed higher epidermal permeation of rhodamine B across the skin based on CLSM image analysis. Our study suggests that terpene composited SLN and NLC can be potentially used as dermal drug delivery carriers for ATRA.Key words lipid nanoparticle; terpene; dermal delivery; all-trans-retinoic acid Transdermal drug delivery has been chosen as a feasible alternative route of drug delivery due to its various advantages over conventional oral and intravenous routes such as reduction of drug metabolism via first pass effect, minimization of pain, and possible controlled drug release.1,2) However, the effectiveness of transdermal drug delivery depends on the capability of drugs to penetrate across the skin in sufficient amounts to reach therapeutic levels.3) The stratum corneum is an important barrier of the skin for drug absorption. 4,5) To facilitate drug delivery through the skin, penetration enhancers, which ideally cause a temporary reversible reduction in the barrier function of the stratum corneum, are extensively used to increase percutaneous absorption. 6) Terpenes are a series of naturally occurring compounds consisting of isoprene (C 5 H 8 ) units. They have been used in transdermal research since 1960s as skin permeation enhancers. They are reported to be a very safe and are an effective class of penetration enhancers that has been classified by the Food and Drug Administration (FDA) as generally regarded as safe (GRAS).7) Limonene is a hydrocarbon lipophilic terpene obtained from the lemon peel of citrus lemon.8) Previous studies have demonstrated that permeability enhancement by limonene can occur through multiple possible mechanisms, which may have contributed to the enhanced permeability of ketoprofen.9) 1,8-Cineole, a terpene, has also been used to promote percutaneous absorption of several lipophilic drugs through hairless mouse skin 10,11) and was recently reported to have an enhancing effect on percutaneous Zidovudine (AZT) absorption across rat skin.12) The mechanism o...
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