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

Vijayabhaskarreddy Junnuthula,Arto Urtti,Elisa Toropainen,Jan C M Van Hest,Shoupeng Cao,Roxane Ridolfo,Amir Sadeghi Boroujeni,Shirin Tavakoli,Marika Ruponen

doi:10.3390/pharmaceutics13040445

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.

Highlights

poly(ethylene glycol) (PEG) was used as a hydrophilic block, whereas the gradient block of PCL and PTMC acted as a hydrophobic domain (Figure S1)
For the positively charged polymersomes, the hydrophilic end of the PEG block was modified with primary amines end to yield positive surface charge, while carboxylic acid end groups were used for negative charge (Figures S2 and S3)
Our finding is important for three reasons: (1) long retention enables prolonged local drug delivery—an important goal, since prolonged injection intervals are needed in the clinics; (2) long vitreal residence increases chances of retinal permeation of the drug delivery particles; (3) polymersomes were well tolerated showing no adverse effects in the rabbit eyes

Summary

Introduction

Many vision impairing diseases affect the tissues of the posterior eye segment, such as retina, choroid, and optic nerve [1]. Age-related macular degeneration, diabetic retinopathy, macular edema, and glaucoma cause visual impairment in millions of patients due to the impaired functionality of the retina and the optic nerve. Drug delivery to these posterior eye tissues is challenging due to the presence of various anatomical eye barriers [2]. Topical ocular drug administration is preferred, but it is effective only in the treatment of anterior eye segment diseases [3] and, as a consequence, Pharmaceutics 2021, 13, 445.

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