Limits...
Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration.

Amrite AC, Edelhauser HF, Singh SR, Kompella UB - Mol. Vis. (2008)

Bottom Line: These particles did not permeate across the sclera-choroid-RPE in 24 h.The 20 nm particles are transported across the sclera to a minor degree; however, there is no significant transport across the sclera-choroid-RPE.Slow release nanoparticles with low clearance by blood and lymphatic circulations are suitable for prolonged transscleral drug delivery to the back of the eye.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-5840, USA.

ABSTRACT

Purpose: Our previous studies indicated that while 20 nm particles are rapidly cleared from the periocular space of the rat following posterior subconjunctival injection, 200 nm particles persisted for at least two months. To understand faster clearance of 20 nm particles, the purpose of this study was to determine transscleral permeability and in vivo disposition in the presence and absence of circulation. Further, it was the purpose of this study to simulate sustained retinal drug delivery after periocular administration of rapidly cleared and slowly cleared nanoparticles.

Methods: The permeability of 20 and 200 nm particles over 24 h was examined across isolated bovine sclera and sclera-choroid-RPE with or without a surfactant (Tween 20, 0.1% w/v) added to the preparation. The in vivo disposition of nanoparticles was performed using Sprague Dawley rats. The rats, either dead or alive, were administered with 400 microg of the nanoparticles in the periocular space, and the particle disposition in the eye tissues was assessed 6 h later. To evaluate the role of the reticulo-endothelial system and lymphatic circulation, isolated liver, spleen, and cervical, axillary, and mesenteric lymph nodes were analyzed using confocal microscopy. Mathematical simulations with Berkeley Madonna were used to evaluate the effect of nanoparticle size on retinal drug levels following periocular administration. Celecoxib was used as the model drug and the finalized pharmacokinetic model from a previous study was used with some modifications for the simulation.

Results: Transport of 20 nm particles across sclera in the presence and absence of the surfactant were 0.1%+/-0.07% and 0.46%+/-0.06%, respectively. These particles did not permeate across the sclera-choroid-RPE in 24 h. There was no quantifiable transport for 200 nm particles across the sclera or the sclera-choroid-RPE. In live animals, the 20 nm particles were undetectable in any of the ocular tissues except in the sclera-choroid following periocular administration; however, in dead animals, the particle concentrations in the sclera-choroid were 19 fold higher than those in live animals, and particles were detectable in the retina as well as vitreous. The retention of 20 nm particles at the site of administration was two fold higher in the dead animals. In live animals, the particles were clearly detectable in the spleen and to a very low extent in the liver as well. The particles were also detected in the cervical, axillary, and mesenteric lymph nodes of the live animals. Simulations with two particles (20 nm and 200 nm) with different clearance rates demonstrated that the retinal drug levels were affected by particle clearance. Larger nanoparticles sustained retinal drug delivery better than smaller nanoparticles. With an increase in drug release rate from the particles, these differences diminish.

Conclusions: The 20 nm particles are transported across the sclera to a minor degree; however, there is no significant transport across the sclera-choroid-RPE. Periocular circulation (blood and lymphatic) plays an important role in the clearance of the 20 nm particles. The higher particle levels in the ocular tissues in the post-mortem studies indicate a dynamic physiologic barrier to the entry of particles into the ocular tissues after periocular administration. The particle size of the delivery system can play an important role in the observed retinal drug levels after periocular administration. Slow release nanoparticles with low clearance by blood and lymphatic circulations are suitable for prolonged transscleral drug delivery to the back of the eye.

Show MeSH

Related in: MedlinePlus

Dynamic barriers prevent significant entry of 20 nm particles into ocular tissues in live animals. Following periocular administration of 400 µg dose of 20 nm particles to either live (blood and lymphatic circulation present) or dead rats (blood and lymphatic circulation absent) the particle levels in the ocular tissues were quantified. Higher levels of the particles are seen in the sclera-choroid, retina, vitreous, and the cornea of dead rats as compared to live rats. The data are expressed as mean ± SEM for n=4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2254958&req=5

f6: Dynamic barriers prevent significant entry of 20 nm particles into ocular tissues in live animals. Following periocular administration of 400 µg dose of 20 nm particles to either live (blood and lymphatic circulation present) or dead rats (blood and lymphatic circulation absent) the particle levels in the ocular tissues were quantified. Higher levels of the particles are seen in the sclera-choroid, retina, vitreous, and the cornea of dead rats as compared to live rats. The data are expressed as mean ± SEM for n=4.

Mentions: Circulation played a critical role in the disposition of 20 nm particles. The retention in the periocular tissue at the end of 6 h of administration in the live animals was 45%±9% whereas the retention in the dead animals was 77%±3% (Figure 5). The sclera-choroid tissue levels in the live and dead animals at the end of 6 h were 12±16 ng/mg and 214±239 ng/mg, respectively (Figure 6). The particles could not be quantified in the cornea, retina, and the vitreous of live animals; however, the particle levels in the cornea, retina, and the vitreous of the dead animals were 9±8 ng/mg, 13±9 ng/mg, and 22±14 ng/mg, respectively (Figure 6). In both the live and dead animals, the particle levels were below quantification limits in the lens.


Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration.

Amrite AC, Edelhauser HF, Singh SR, Kompella UB - Mol. Vis. (2008)

Dynamic barriers prevent significant entry of 20 nm particles into ocular tissues in live animals. Following periocular administration of 400 µg dose of 20 nm particles to either live (blood and lymphatic circulation present) or dead rats (blood and lymphatic circulation absent) the particle levels in the ocular tissues were quantified. Higher levels of the particles are seen in the sclera-choroid, retina, vitreous, and the cornea of dead rats as compared to live rats. The data are expressed as mean ± SEM for n=4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254958&req=5

f6: Dynamic barriers prevent significant entry of 20 nm particles into ocular tissues in live animals. Following periocular administration of 400 µg dose of 20 nm particles to either live (blood and lymphatic circulation present) or dead rats (blood and lymphatic circulation absent) the particle levels in the ocular tissues were quantified. Higher levels of the particles are seen in the sclera-choroid, retina, vitreous, and the cornea of dead rats as compared to live rats. The data are expressed as mean ± SEM for n=4.
Mentions: Circulation played a critical role in the disposition of 20 nm particles. The retention in the periocular tissue at the end of 6 h of administration in the live animals was 45%±9% whereas the retention in the dead animals was 77%±3% (Figure 5). The sclera-choroid tissue levels in the live and dead animals at the end of 6 h were 12±16 ng/mg and 214±239 ng/mg, respectively (Figure 6). The particles could not be quantified in the cornea, retina, and the vitreous of live animals; however, the particle levels in the cornea, retina, and the vitreous of the dead animals were 9±8 ng/mg, 13±9 ng/mg, and 22±14 ng/mg, respectively (Figure 6). In both the live and dead animals, the particle levels were below quantification limits in the lens.

Bottom Line: These particles did not permeate across the sclera-choroid-RPE in 24 h.The 20 nm particles are transported across the sclera to a minor degree; however, there is no significant transport across the sclera-choroid-RPE.Slow release nanoparticles with low clearance by blood and lymphatic circulations are suitable for prolonged transscleral drug delivery to the back of the eye.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-5840, USA.

ABSTRACT

Purpose: Our previous studies indicated that while 20 nm particles are rapidly cleared from the periocular space of the rat following posterior subconjunctival injection, 200 nm particles persisted for at least two months. To understand faster clearance of 20 nm particles, the purpose of this study was to determine transscleral permeability and in vivo disposition in the presence and absence of circulation. Further, it was the purpose of this study to simulate sustained retinal drug delivery after periocular administration of rapidly cleared and slowly cleared nanoparticles.

Methods: The permeability of 20 and 200 nm particles over 24 h was examined across isolated bovine sclera and sclera-choroid-RPE with or without a surfactant (Tween 20, 0.1% w/v) added to the preparation. The in vivo disposition of nanoparticles was performed using Sprague Dawley rats. The rats, either dead or alive, were administered with 400 microg of the nanoparticles in the periocular space, and the particle disposition in the eye tissues was assessed 6 h later. To evaluate the role of the reticulo-endothelial system and lymphatic circulation, isolated liver, spleen, and cervical, axillary, and mesenteric lymph nodes were analyzed using confocal microscopy. Mathematical simulations with Berkeley Madonna were used to evaluate the effect of nanoparticle size on retinal drug levels following periocular administration. Celecoxib was used as the model drug and the finalized pharmacokinetic model from a previous study was used with some modifications for the simulation.

Results: Transport of 20 nm particles across sclera in the presence and absence of the surfactant were 0.1%+/-0.07% and 0.46%+/-0.06%, respectively. These particles did not permeate across the sclera-choroid-RPE in 24 h. There was no quantifiable transport for 200 nm particles across the sclera or the sclera-choroid-RPE. In live animals, the 20 nm particles were undetectable in any of the ocular tissues except in the sclera-choroid following periocular administration; however, in dead animals, the particle concentrations in the sclera-choroid were 19 fold higher than those in live animals, and particles were detectable in the retina as well as vitreous. The retention of 20 nm particles at the site of administration was two fold higher in the dead animals. In live animals, the particles were clearly detectable in the spleen and to a very low extent in the liver as well. The particles were also detected in the cervical, axillary, and mesenteric lymph nodes of the live animals. Simulations with two particles (20 nm and 200 nm) with different clearance rates demonstrated that the retinal drug levels were affected by particle clearance. Larger nanoparticles sustained retinal drug delivery better than smaller nanoparticles. With an increase in drug release rate from the particles, these differences diminish.

Conclusions: The 20 nm particles are transported across the sclera to a minor degree; however, there is no significant transport across the sclera-choroid-RPE. Periocular circulation (blood and lymphatic) plays an important role in the clearance of the 20 nm particles. The higher particle levels in the ocular tissues in the post-mortem studies indicate a dynamic physiologic barrier to the entry of particles into the ocular tissues after periocular administration. The particle size of the delivery system can play an important role in the observed retinal drug levels after periocular administration. Slow release nanoparticles with low clearance by blood and lymphatic circulations are suitable for prolonged transscleral drug delivery to the back of the eye.

Show MeSH
Related in: MedlinePlus