Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response

Thackaberry, Evan A.; Farman, Cindy; Zhong, Fiona; Lorget, Florence; Staflin, Karin; Cercillieux, Angelique; Miller, Paul E.; Schuetz, Chris; Chang, Debby P.; Famili, Amin; Daugherty, Ann L.; Rajagopal, K.; Bantseev, Vladimir

doi:10.1167/iovs.16-21334

Cited by 57 publications

(50 citation statements)

References 39 publications

(44 reference statements)

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“…An example of these is the foreign body reaction-a type of cellular inflammation characterized by macrophages, giant cell formation, and fibrosis [17]. Exposure to experimental biomaterials, such as intravitreally injected poly lactic-co-glycolic acid (PLGA) polymer microspheres and rods, has reportedly elicited this kind of reaction [18]. Furthermore, similar inflammatory responses have been reported following the injection of vitreous substitutes such as perfluoro-n-octane (PFO) [19,20], perfluorohexyloctane [21], and silicone oil [22,23].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory responses after vitrectomy with vitreous substitutes in a rabbit model

Barth

Crafoord

Arnér

et al. 2019

Graefes Arch Clin Exp Ophthalmol

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Purpose To investigate the inflammatory response of current and future potential vitreous substitutes in an experimental in vivo vitrectomy model. Methods Twenty-five gauge pars plana vitrectomy was performed in the right eye of 60 pigmented rabbits, with subsequent injection of 0.5-1.0 ml of Healaflow® (cross-linked hyaluronic acid, n = 12), Bio-Alcamid® (polyalkylimide, n = 8), silicone oil (n = 12), or balanced saline solution (BSS, n = 28). Postoperative clinical evaluation was performed; and the rabbits were sacrificed at 1 day, 1 week, or 1 month. The eyecups were then examined macroscopically; the retinas sectioned and stained with hematoxylin and eosin (Htx), and immunohistochemically labeled for glial fibrillary acidic protein (GFAP), CD45, galectin-3, CD68, and CD20. Unoperated left eyes from treated animals as well as eyes from untreated animals were used as controls. Results Vitrectomy without major complications was achieved in 46/60 eyes. The remaining 14 eyes were analyzed separately. One eye developed endophthalmitis after 1 week and was excluded. Eyes treated with Healaflow®, silicone oil, and BSS had a comparable appearance macroscopically and in Htx-stained sections, whereas Bio-Alcamid®-injected eyes exhibited increased macroscopic inflammation and severely affected retinas. GFAP upregulation was present in all treatment groups, most prominent in eyes treated with Bio-Alcamid® and silicone oil. Upregulation of CD45 and CD68 in the inner retina and vitreous space was most prominent with Bio-Alcamid® treatment, and these eyes together with their silicone oil-treated counterparts also displayed a stronger upregulation of CD20-labeled cells compared with remaining groups. General upregulation of galectin-3, mainly in the inner retina, was found in all groups. In eyes with perioperative complications, labeling of CD45, CD68, and especially GFAP was comparably high. Conclusions We here describe differences in the postsurgery inflammatory profiles of existing and potential vitreous substitutes. Bio-Alcamid® and silicone oil display severe signs of gliosis and inflammation, whereas Healaflow® elicits minimal reactions comparable with BSS, highlighting its potential application as a vitreous substitute in a future clinical setting.

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Section: Introductionmentioning

confidence: 99%

Inflammatory responses after vitrectomy with vitreous substitutes in a rabbit model

Barth

Crafoord

Arnér

et al. 2019

Graefes Arch Clin Exp Ophthalmol

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“…Size of the microspheres may have an influence on their intravitreal tolerability. Due to a higher specific surface area, smaller microspheres may show slightly more adverse effects [44]. We suggest fabrication under aseptic conditions to obtain a sterile ocular drug formulation.…”

Section: Discussionmentioning

confidence: 98%

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

et al. 2020

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Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time. Fasudil-loaded microspheres were prepared by double emulsion solvent evaporation technique. The chemical integrity of released fasudil was confirmed by mass spectrometry. The biological activity was measured in cell-based assays using trabecular meshwork cells (TM cells), Schlemm’s canal cells (SC cells), fibroblasts and adult retinal pigment epithelium cells (ARPE-19). Cellular response to fasudil after its diffusion through vitreous humor was investigated by electric cell-substrate impedance sensing. Microspheres ranged in size from 3 to 67 µm. The release of fasudil from microspheres was controllable and sustained for up to 45 days. Released fasudil reduced actin stress fibers in TM cells, SC cells and fibroblasts. Decreased collagen gel contraction provoked by fasudil was detected in TM cells (~2.4-fold), SC cells (~1.4-fold) and fibroblasts (~1.3-fold). In addition, fasudil readily diffused through vitreous humor reaching its target compartment and eliciting effects on TM cells. No negative effects on ARPE-19 cells were observed. Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of ROCK inhibitors could significantly improve current glaucoma therapy particularly for patients with comorbid retinal diseases.

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“… 25 Particle-based delivery of the latter has been reportedly extended for up to 6 months, 26 albeit with movement of visible particulates from the vitreous to the anterior chamber. Observation of foreign body inflammatory responses to IVT-injected, spherical PLGA microspheres in rabbits, 12 with more intense and prolonged such reactions recently seen in nonhuman primates (NHP) 13 drives the search for alternative methods of delivery. Nanotechnology presents opportunities for posterior delivery of drugs and genes, to reduce injection frequency, improve compliance and patient outcome, and includes a variety of devices and materials to enhance access.…”

Section: Discussionmentioning

confidence: 99%

“…Commonly used poly(lactic-co-glycolic) MP (PLGA), though well tolerated in nonocular sites, elicited a foreign body response in rabbit eyes 12 ; such MP have recently led to rabbit eye inflammation, and more severe reaction in primates with potential for damage to critical structures. 13 With risk of causing glaucoma or tissue damage, few size-based carriers are approved for nonsteroid drugs, making long-acting, smaller NP (<100 nm diameter) desirable.…”

mentioning

confidence: 99%

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

Melgar-Asensio

Kandela

Aird

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeDrug 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.MethodsNPC 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.ResultsNPC 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.ConclusionsThis 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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Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response

Abstract: These data demonstrate a lack of tolerability of PLGA microspheres upon intravitreal injection, and suggest that the size, shape, and/or surface area of PLGA depots are critical attributes in determining ocular toxicity.

Cited by 57 publications

References 39 publications

Inflammatory responses after vitrectomy with vitreous substitutes in a rabbit model

Inflammatory responses after vitrectomy with vitreous substitutes in a rabbit model

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

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

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