Drug Elimination Kinetics Following Subconjunctival Injection Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Kim, Stephanie H.; Csaky, Karl G.; Wang, Nam Sun; Lutz, Robert J.

doi:10.1007/s11095-007-9408-z

Cited by 64 publications

(50 citation statements)

References 27 publications

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“…For small molecules, their half-lives in the subconjunctival space are in the order of 10–40 min. The main mechanisms of ocular clearance following subconjunctival injection are lymphatic and blood clearance in the periocular space (29,32,33). In the present study, pRNA nanoparticles were distributed from the injection sites to different ocular tissues (conjunctiva, cornea, retina, and sclera) and then cleared from the eyes rapidly.…”

Section: Discussionmentioning

confidence: 99%

Ocular Delivery of pRNA Nanoparticles: Distribution and Clearance After Subconjunctival Injection

Feng

Liu

et al. 2013

Pharm Res

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Purpose RNA nanoparticles derived from the three-way junction (3WJ) of the pRNA of bacteriophage phi29 DNA packaging motor were previously found to be thermodynamically stable. As the nanoparticles could have potential in ocular drug delivery, the objectives in the present study were to investigate the distribution of pRNA nanoparticles after subconjunctival injection and examine the feasibility to deliver the nanoparticles to the cells of cornea and retina. Methods Alexa647-labeled pRNA nanoparticles (pRNA-3WJ and pRNA-X) and double-stranded RNA (dsRNA) were administered via subconjunctival injection in mice. Alexa647 dye was a control. Topical administration was performed for comparison. Ocular clearance of pRNA nanoparticles and dsRNA after the injection was assessed using whole-body fluorescence imaging of the eyes. The numbers of cells in the ocular tissues with nanoparticle cell internalization were determined in fluorescence microscopy of dissected eye tissues. Results After subconjunctival injection, pRNA nanoparticles and dsRNA were observed to distribute into the eyes and cleared through the lymph. pRNA-3WJ, pRNA-X, and dsRNA were found in the cells of the conjunctiva, cornea, and sclera, but only pRNA-X was in the cells of the retina. Topical administration was not effective in delivering the nanoparticles to the eye. Conclusions The pRNA nanoparticles were delivered to the cells in the eye via subconjunctival injection, and cell internalization was achieved in the cornea with pRNA-3WJ and pRNA-X and in the retina with pRNA-X. Only the X-shape pRNA-X could enter the retina.

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Section: Discussionmentioning

confidence: 99%

Ocular Delivery of pRNA Nanoparticles: Distribution and Clearance After Subconjunctival Injection

Feng

Liu

et al. 2013

Pharm Res

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“…Moreover, it is unknown whether the conclusions reached in the rabbit can be directly used in human eyes, as the intravital studies in human beings are limited. Furthermore, these methods fail to sufficiently reveal the theoretical system of drug metabolism in eyes [13,14] .…”

Section: Discussionmentioning

confidence: 99%

“…Some experimental techniques are not clinically suitable due to their invasion and radioactivity. MRI technique can not only provide anatomical information but also make quantitative analyses possible [13] . Our research expands the application of MRI to studies of the permeability of medicines in the eye and found MR technology is superior to other methods in assessing drug permeability in the ocular region.…”

Section: Discussionmentioning

confidence: 99%

Corneal permeability assay of topical eye drop solutions in rabbits by MRI

Mao

Zhang

Hen

et al. 2010

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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This study examined the corneal permeability of topical eye drop solutions added with various corneal penetrating accelerators and gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) by nuclear magnetic resonance imaging (MRI). Twenty-four New Zealand rabbits were randomly divided into 3 groups according to the random digits table: Gd-DTPA group, in which the rabbits received 23.45% Gd-DTPA; hyaluronic acid group, in which 23.45% Gd-DTPA plus 0.2% hyaluronic acid was administered; azone group, in which 23.45% Gd-DTPA with 0.2% azone was given. Fifty microliters of the eye drops was instilled into the conjunctive sac every 5 min, for a total of 6 applications in each group. Contrast medium signals in the cornea, anterior chamber, posterior chamber, and vitreous body were scanned successively by MRI. The morphology and cell density of the corneal endothelium were examined before and 24 h after the treatment. The results showed that the residence time of Gd-DTPA in the conjunctival sac in the hyaluronic acid and azone groups was longer than that in the Gd-DTPA group. The signals in the anterior chamber of the Gd-DTPA and hyaluronic acid groups were increased slightly, and those in the azone group strengthened sharply. The signal intensity continuously rose over 80 min before reaching plateau. The strengthening rate of signals in the anterior chamber was 19.63% in the Gd-DTPA group, 53.42% in the sodium hyaluronate group, and 226.94% in the azone group. No signal was detected in the posterior chamber or vitreous body in all the 3 groups. Corneal morphology and cell density did not show any significant changes after the treatment in all the 3 groups. It was concluded that azone can significantly improve the corneal permeability of drugs that are similar to Gd-DTPA in molecular weight and molecular size, and MRI is a noninvasive technique that can dynamically detect eye drop metabolism in real time.

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“…However, data in the literature have shown that the half-life of small molecules in periocular regions or more specifically in the subconjunctival space is on the order of 10 min after local injection, and the short half-life is presumably caused by considerable drug clearance via both blood and lymph microvessels. 1,18,41,42 These data indicate that after topical application, the majority of ECA molecules are absorbed by the microvessels if they diffuse into the subconjunctival space via conjunctiva. Therefore, we neglected the diffusion of ECA from the subconjunctival space into the sclera.…”

Section: Concentration Boundary Conditionsmentioning

confidence: 90%

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

Lin

Yuan

2010

Ann Biomed Eng

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Topical application of drugs for treatment of intraocular diseases is often limited by inadequate transport and induced toxicity in corneal tissues. To improve the drug delivery, a mathematical model was developed to numerically simulate the transport process of ethacrynic acid (ECA), a potential drug for glaucoma treatment, in the anterior segment of a typical human eye. The model considered diffusion of ECA in all tissues and the aqueous humor (AH) as well as convection of ECA in the AH. The simulation results showed that ECA concentration in the eye depended on the rate of AH production, the half-life of ECA in the precorneal tear film, and the transport parameters in the model. In addition, the main pathway for ECA clearance from the eye was the trabecular meshwork (TM) and the rate of clearance was approximately proportional to the AH production rate. The model predicted that the most effective approach to improving topical drug delivery was to prolong its half-life in the precorneal tear film. These simulation results and model prediction, which could be verified experimentally, might be useful for improving delivery of ECA and other therapeutic agents to the TM as well as other tissues in the anterior segment of the eye.

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Drug Elimination Kinetics Following Subconjunctival Injection Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Cited by 64 publications

References 27 publications

Ocular Delivery of pRNA Nanoparticles: Distribution and Clearance After Subconjunctival Injection

Ocular Delivery of pRNA Nanoparticles: Distribution and Clearance After Subconjunctival Injection

Corneal permeability assay of topical eye drop solutions in rabbits by MRI

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

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