Extended Intravitreal Rabbit Eye Residence of Nanoparticles Conjugated With Cationic Arginine Peptides for Intraocular Drug Delivery: In Vivo Imaging

  • Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):4071-4081. doi: 10.1167/iovs.18-24087.
Ignacio Melgar-Asensio  1  2 ,  Irawati Kandela  1 ,  Fraser Aird  1 ,  Soesiawati R Darjatmoko  3 ,  Cristobal de Los Rios  2 ,  Christine M Sorenson  4 ,  Daniel M Albert  5 ,  Nader Sheibani  3 ,  Jack Henkin  1
Affiliations
  • 1. Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois, United States.
  • 2. Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
  • 3. Departments of Ophthalmology and Visual Sciences, Biomedical Engineering, and Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States.
  • 4. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States.
  • 5. Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon, United States.
PMID: 30098194 DOI: 10.1167/iovs.18-24087
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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