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 - Funding Information:
Supported by an unrestricted award from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, Retina Research Foundation, P30 EY016665, P30 CA014520, EPA 83573701, R24 EY022883, and R01 EY026078. CMS is supported by the RRF/Daniel M. Albert Chair. NS is a recipient of RPB Stein Innovation Award. Peptides were synthesized by the Peptide Synthesis Core and NP/NPC size and ζ were measured by the Analytical BioNanoTechnology Equipment Core (ANTEC) of Simpson Querrey Institute (SQI) at Northwestern University (NU; Chicago, IL, USA). Also supplied by Erin and Wellington Hsu of SQI were enucleated rabbit eyes for IVIS study. IVIS studies used facilities of the Center for Advanced Molecular Imaging (CAMI), Evanston, Illinois, United States. Charlette M. Caine, DVM, NU, contributed assistance and training in enucleation of euthanized rabbit eyes.
Funding Information:
Supported by an unrestricted award from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, Retina Research Foundation, P30 EY016665, P30 CA014520, EPA 83573701, R24 EY022883, and R01 EY026078. CMS is supported by the RRF/Daniel M. Albert Chair. NS is a recipient of RPB Stein Innovation Award. Peptides were synthesized by the Peptide Synthesis Core and NP/NPC size and ξ were measured by the Analytical BioNanoTechnology Equipment Core (ANTEC) of Simpson Querrey Institute (SQI) at Northwestern University (NU; Chicago, IL, USA). Also supplied by Erin and Wellington Hsu of SQI were enucleated rabbit eyes for IVIS study. IVIS studies used facilities of the Center for Advanced Molecular Imaging (CAMI), Evanston, Illinois, United States. Charlette M. Caine, DVM, NU, contributed assistance and training in enucleation of euthanized rabbit eyes.
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
VL - 59
SP - 4071
EP - 4081
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 10
ER -