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. 2021 Mar 26;13(4):445.
doi: 10.3390/pharmaceutics13040445.

Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region

Vijayabhaskarreddy Junnuthula  1 , Amir Sadeghi Boroujeni  2 , Shoupeng Cao  3 , Shirin Tavakoli  1 , Roxane Ridolfo  3 , Elisa Toropainen  2 , Marika Ruponen  2 , Jan C M van Hest  3 , Arto Urtti  1   2   4
Affiliations

Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region

Vijayabhaskarreddy Junnuthula et al. Pharmaceutics. .

Abstract

Posterior eye tissues, such as retina, are affected in many serious eye diseases, but drug delivery to these targets is challenging due to various anatomical eye barriers. Intravitreal injections are widely used, but the intervals between invasive injections should be prolonged. We synthesized and characterized (1H NMR, gel permeation chromatography) block copolymers of poly(ethylene glycol), poly(caprolactone), and trimethylene carbonate. These polymers self-assembled to polymersomes and polymeric micelles. The mean diameters of polymersomes and polymeric micelles, about 100 nm and 30-50 nm, respectively, were obtained with dynamic light scattering. Based on single particle tracking and asymmetric flow field-flow fractionation, the polymeric micelles and polymersomes were stable and diffusible in the vitreous. The materials did not show cellular toxicity in cultured human umbilical vein endothelial cells in the Alamar Blue Assay. Pharmacokinetics of the intravitreal nanocarriers in the rabbits were evaluated using in vivo fluorophotometry. The half-lives of the polymersomes (100 nm) and the micelles (30 nm) were 11.4-32.7 days and 4.3-9.5 days. The intravitreal clearance values were 1.7-8.7 µL/h and 3.6-5.4 µL/h for polymersomes and polymeric micelles, respectively. Apparent volumes of distribution of the particles in the rabbit vitreous were 0.6-1.3 mL for polymeric micelles and 1.9-3.4 mL for polymersomes. Polymersomes were found in the vitreous for at least 92 days post-dosing. Furthermore, fundus imaging revealed that the polymersomes accumulated near the optic nerve and retained there even at 111 days post-injection. Polymersomes represent a promising technology for controlled and site-specific drug delivery in the posterior eye segment.

Keywords: drug delivery; intravitreal; optic nerve; polymeric micelle; polymersome; retina.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Asymmetric flow field-flow fractionation (AF4)-dynamic light scattering (DLS) data for (A) polymeric micelles (p22) and (B) polymersomes. Scattered dots indicate the hydrodynamic diameters, and the lines show normalized signal intensities at 280 nm. The measurements were done at 37 °C in porcine vitreous immediately after exposure (black) and after incubation of one day (red) and seven days (blue).
Figure 2
Figure 2
Example fluorophotometer scans of rabbit eyes after injections of (A) polymer micelles and (B) polymersomes into the rabbit vitreous. Relative distance at about 7–18 mm shows the fluorescence levels in the rabbit vitreous. Autofluorescence is shown as blue line. The other lines indicate the fluorescence levels at different times post-injection.
Figure 3
Figure 3
(A) Kinetic profiles of polymeric micelles (n = 4) and (B) polymersomes (n = 2) in rabbit vitreous after intravitreal injections. The dots show the experimental data, and lines are the best fits with one-compartmental model with first-order elimination kinetics.
Figure 4
Figure 4
Fundus imaging in rabbit eyes after intravitreal injection of BODIPY labeled neutral polymersomes (PPP). Upper panel shows full color imaging and lower panel represents fluorescence imaging. (A,B) Polymersome distribution in the rabbit vitreous after 26 days; (C–F) accumulation of polymersomes at the optic nerve head region; (G,H) accumulation of polymersomes at the optic nerve head region (horizontal axis). Without injection fluorescence images would be completely black.
Figure 5
Figure 5
Micrographs (20×) of frozen rabbit vitreous (A), optic nerve polymersome accumulation (B,C) and polymersomes at retinal tissue layers (D). The arrows show localization of the polymersomes.
See this image and copyright information in PMC

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