Abstract
PURPOSE. Drug delivery by intravitreal injection remains problematic, small agents and macromolecules both clearing rapidly. Typical carriers use microparticles (>2 μm), with size-related liabilities, to slow diffusion. We recently described cationic nanoparticles (NP) where conjugated Arg peptides prolonged residence in rat eyes, through ionic interaction with vitreal poly-anions. Here we extended this strategy to in vivo tracking of NP-conjugate (NPC) clearance from rabbit eyes. Relating t1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. METHODS. NPC carried covalently attached PEG8-2Arg or PEG8-3Arg pentapeptides, having known sequences from human eye proteins. Peptides were conjugated (61–64 per NPC); each NP/NPC also carried a cyanine7 tag (<0.5 dye/particle). In vivo imaging system (IVIS), after intravitreal injection, estimated NPC loss by 800-nm photon emission (745-nm excitation) at 1 to 3-week intervals following initial scan at day 10. RESULTS. NPC of 2Arg-peptides or 3Arg-peptides showed clearance t1/2 of 7 days and 17 days respectively, unconjugated NP t1/2 was <<5 days. Doses of 90, 180, and 360 μg of PEG8-2Arg NPC were compared. The lower doses showed dose-proportional day-10 concentration, and similar clearance. Higher early loss was seen with a 360-μg dose, exceeding rabbit vitreal binding capacity. No inflammation was observed. CONCLUSIONS. This type of cationic NPC can safely increase residence t1/2 in a 1 to 3-week range, with dose <100 μg per mL vitreous. Human drug load may then range from 10 to 100 μg/eye, usefulness depending on individual drug potency and release rate, superimposed on extended intravitreal residence.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4071-4081 |
| Number of pages | 11 |
| Journal | Investigative Ophthalmology and Visual Science |
| Volume | 59 |
| Issue number | 10 |
| DOIs | |
| State | Published - Aug 1 2018 |
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Keywords
- Cationic peptides
- Hyaluronic acid
- Intravitreal drug delivery
- Nanoparticles
- Rabbit eye imaging
ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience
Cite this
Extended intravitreal rabbit eye residence of nanoparticles conjugated with cationic arginine peptides for intraocular drug delivery : In vivo imaging. / Melgar-Asensio, Ignacio; Kandela, Irawati; Aird, Fraser; Darjatmoko, Soesiawati R.; de los Rios, Cristobal; Sorenson, Christine M.; Albert, Daniel; Sheibani, Nader; Henkin, Jack.
In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 10, 01.08.2018, p. 4071-4081.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Extended intravitreal rabbit eye residence of nanoparticles conjugated with cationic arginine peptides for intraocular drug delivery
T2 - In vivo imaging
AU - Melgar-Asensio, Ignacio
AU - Kandela, Irawati
AU - Aird, Fraser
AU - Darjatmoko, Soesiawati R.
AU - de los Rios, Cristobal
AU - Sorenson, Christine M.
AU - Albert, Daniel
AU - Sheibani, Nader
AU - Henkin, Jack
PY - 2018/8/1
Y1 - 2018/8/1
N2 - PURPOSE. Drug delivery by intravitreal injection remains problematic, small agents and macromolecules both clearing rapidly. Typical carriers use microparticles (>2 μm), with size-related liabilities, to slow diffusion. We recently described cationic nanoparticles (NP) where conjugated Arg peptides prolonged residence in rat eyes, through ionic interaction with vitreal poly-anions. Here we extended this strategy to in vivo tracking of NP-conjugate (NPC) clearance from rabbit eyes. Relating t1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. METHODS. NPC carried covalently attached PEG8-2Arg or PEG8-3Arg pentapeptides, having known sequences from human eye proteins. Peptides were conjugated (61–64 per NPC); each NP/NPC also carried a cyanine7 tag (<0.5 dye/particle). In vivo imaging system (IVIS), after intravitreal injection, estimated NPC loss by 800-nm photon emission (745-nm excitation) at 1 to 3-week intervals following initial scan at day 10. RESULTS. NPC of 2Arg-peptides or 3Arg-peptides showed clearance t1/2 of 7 days and 17 days respectively, unconjugated NP t1/2 was <<5 days. Doses of 90, 180, and 360 μg of PEG8-2Arg NPC were compared. The lower doses showed dose-proportional day-10 concentration, and similar clearance. Higher early loss was seen with a 360-μg dose, exceeding rabbit vitreal binding capacity. No inflammation was observed. CONCLUSIONS. This type of cationic NPC can safely increase residence t1/2 in a 1 to 3-week range, with dose <100 μg per mL vitreous. Human drug load may then range from 10 to 100 μg/eye, usefulness depending on individual drug potency and release rate, superimposed on extended intravitreal residence.
AB - PURPOSE. Drug delivery by intravitreal injection remains problematic, small agents and macromolecules both clearing rapidly. Typical carriers use microparticles (>2 μm), with size-related liabilities, to slow diffusion. We recently described cationic nanoparticles (NP) where conjugated Arg peptides prolonged residence in rat eyes, through ionic interaction with vitreal poly-anions. Here we extended this strategy to in vivo tracking of NP-conjugate (NPC) clearance from rabbit eyes. Relating t1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. METHODS. NPC carried covalently attached PEG8-2Arg or PEG8-3Arg pentapeptides, having known sequences from human eye proteins. Peptides were conjugated (61–64 per NPC); each NP/NPC also carried a cyanine7 tag (<0.5 dye/particle). In vivo imaging system (IVIS), after intravitreal injection, estimated NPC loss by 800-nm photon emission (745-nm excitation) at 1 to 3-week intervals following initial scan at day 10. RESULTS. NPC of 2Arg-peptides or 3Arg-peptides showed clearance t1/2 of 7 days and 17 days respectively, unconjugated NP t1/2 was <<5 days. Doses of 90, 180, and 360 μg of PEG8-2Arg NPC were compared. The lower doses showed dose-proportional day-10 concentration, and similar clearance. Higher early loss was seen with a 360-μg dose, exceeding rabbit vitreal binding capacity. No inflammation was observed. CONCLUSIONS. This type of cationic NPC can safely increase residence t1/2 in a 1 to 3-week range, with dose <100 μg per mL vitreous. Human drug load may then range from 10 to 100 μg/eye, usefulness depending on individual drug potency and release rate, superimposed on extended intravitreal residence.
KW - Cationic peptides
KW - Hyaluronic acid
KW - Intravitreal drug delivery
KW - Nanoparticles
KW - Rabbit eye imaging
UR - http://www.scopus.com/inward/record.url?scp=85051533397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051533397&partnerID=8YFLogxK
U2 - 10.1167/iovs.18-24087
DO - 10.1167/iovs.18-24087
M3 - Article
C2 - 30098194
AN - SCOPUS:85051533397
VL - 59
SP - 4071
EP - 4081
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 10
ER -