Extended intravitreal rabbit eye residence of nanoparticles conjugated with cationic arginine peptides for intraocular drug delivery: In vivo imaging

Ignacio Melgar-Asensio, Irawati Kandela, Fraser Aird, Soesiawati R. Darjatmoko, Cristobal de los Rios, Christine M. Sorenson, Daniel Albert, Nader Sheibani, Jack Henkin

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Pages (from-to)4071-4081
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number10
DOIs
StatePublished - Aug 1 2018

Fingerprint

Nanoparticles
Arginine
Rabbits
Peptides
Intravitreal Injections
Pharmaceutical Preparations
Eye Proteins
Photons
Anions
Coloring Agents
Inflammation

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 journalArticle

Melgar-Asensio, Ignacio ; Kandela, Irawati ; Aird, Fraser ; Darjatmoko, Soesiawati R. ; de los Rios, Cristobal ; Sorenson, Christine M. ; Albert, Daniel ; Sheibani, Nader ; Henkin, Jack. / Extended intravitreal rabbit eye residence of nanoparticles conjugated with cationic arginine peptides for intraocular drug delivery : In vivo imaging. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 10. pp. 4071-4081.
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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.",
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author = "Ignacio Melgar-Asensio and Irawati Kandela and Fraser Aird and Darjatmoko, {Soesiawati R.} and {de los Rios}, Cristobal and Sorenson, {Christine M.} and Daniel Albert and Nader Sheibani and Jack Henkin",
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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

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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.

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KW - Nanoparticles

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