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 M.
AU - Sheibani, Nader
AU - Henkin, Jack
N1 - Publisher Copyright:
© 2018 The Authors.
PY - 2018/8
Y1 - 2018/8
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 t 1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. METHODS. NPC carried covalently attached PEG 8 -2Arg or PEG 8 -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 t 1/2 of 7 days and 17 days respectively, unconjugated NP t 1/2 was <<5 days. Doses of 90, 180, and 360 μg of PEG 8 -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 t 1/2 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 t 1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. METHODS. NPC carried covalently attached PEG 8 -2Arg or PEG 8 -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 t 1/2 of 7 days and 17 days respectively, unconjugated NP t 1/2 was <<5 days. Doses of 90, 180, and 360 μg of PEG 8 -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 t 1/2 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
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U2 - 10.1167/iovs.18-24087
DO - 10.1167/iovs.18-24087
M3 - Article
C2 - 30098194
AN - SCOPUS:85051533397
SN - 0146-0404
VL - 59
SP - 4071
EP - 4081
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 10
ER -