Pediatric ocular nanomedicines: Challenges and opportunities

Abstract

The eye is a highly complex, yet readily accessible organ within the human body. As such, the eye is an appealing candidate target for a vast array of drug therapies. Despite advances in ocular drug therapy research, the focus on pediatric ocular drug delivery continues to be highly underrepresented due to the limited number of degenerative ocular diseases with childhood onset. In this review, we explore more deeply the reasons underlying the disparity between ocular therapies available for children and for adults by highlighting diseases that most commonly afflict children (with focus on the anterior eye) and existing prognoses, recent developments in ocular drug delivery systems and nanomedicines for children, and barriers to use for pediatric patients.

Keywords: Compliance; Drug administration; Nanomedicine; Ocular drug delivery; Pediatric.

Fig. 1

Illustration that represents the different structures of the eye, divided in the anterior and posterior segments. The different barriers that drugs need to overcome after topical installation are indicated with a red star, and a detailed representation is also provided. The ocular targets to treat a specific disease are indicated with a green star, if they are in the anterior segment, or with a yellow star, if they are located in the posterior segment. Reproduced from Ref. [4] with permission. Copyright 2015, Elsevier.

Fig. 2

Progression of retinopathy of prematurity. (A) Oxygen tension is low in utero and vascular growth is normal. (B) Phase 1: After birth until roughly 30 weeks postmenstrual age, retinal vascularization is inhibited because of hyperoxia and loss of the nutrients and growth factors provided at the maternal–fetal interface. Blood-vessel growth stops and as the retina matures and metabolic demand increases, hypoxia results. (C) Phase 2: The hypoxic retina stimulates expression of the oxygen-regulated factors such as erythropoietin (EPO) and VEGF, which stimulate retinal neovascularization. Insulin-like growth factor 1 (IGF-1) concentrations increase slowly from low concentrations after preterm birth to concentrations high enough to allow activation of VEGF pathways. (D) Resolution of retinopathy might be achieved through prevention of phase 1 by increasing IGF-1 to in-utero concentrations and by limiting oxygen to prevent suppression of VEGF; Alternatively, VEGF can be suppressed in phase 2 after neovascularization with laser therapy or an antibody. EPO = erythropoietin. ω-3 PUFA = ω-3 polyunsaturated fatty acids. Reproduced from Ref. [18] with permission. Copyright 2013, Elsevier.

Fig. 3

Routes of drug administration to eye. Reproduced from Ref. [22] with permission. Copyright 2010, Springer.

Fig. 4

Schematic overview of nanoparticle transport to the RPE. After leaving the fenestrated choriocapillaris the nanoparticle has to cross the five-layered Bruch’s membrane, consisting of a central elastic layer, two collagenous layers and the RPE and choriocapillaris basal laminae. Reproduced from Ref. [20] with permission. Copyright 2015, Elsevier.