Advances in Nanogels for Topical Drug Delivery in Ocular Diseases

Abstract

Nanotechnology has accelerated the development of the pharmaceutical and medical technology fields, and nanogels for ocular applications have proven to be a promising therapeutic strategy. Traditional ocular preparations are restricted by the anatomical and physiological barriers of the eye, resulting in a short retention time and low drug bioavailability, which is a significant challenge for physicians, patients, and pharmacists. Nanogels, however, have the ability to encapsulate drugs within three-dimensional crosslinked polymeric networks and, through specific structural designs and distinct methods of preparation, achieve the controlled and sustained delivery of loaded drugs, increasing patient compliance and therapeutic efficiency. In addition, nanogels have higher drug-loading capacity and biocompatibility than other nanocarriers. In this review, the main focus is on the applications of nanogels for ocular diseases, whose preparations and stimuli-responsive behaviors are briefly described. The current comprehension of topical drug delivery will be improved by focusing on the advances of nanogels in typical ocular diseases, including glaucoma, cataracts, dry eye syndrome, and bacterial keratitis, as well as related drug-loaded contact lenses and natural active substances.

Keywords: contact lenses; drug delivery systems; nanogels; natural polymers; ocular diseases.

Figure 1

Schematic representation of the ocular structure. The eye consists of two parts: the anterior segment and the posterior segment. The anterior segment includes the cornea, conjunctiva, iris, ciliary body, crystalline lens, and aqueous humor; the posterior segment includes the sclera, choroid, retina, and vitreous humor. They are the main barriers to ocular drug delivery.

Figure 2

The preparation of nanogels is divided into two categories based on the type of bonds in the polymer network. (A) polymer X and polymer Y form physical crosslinked nanogels through noncovalent interactions, which are characterized by simple but unstable preparation; (B) polymer M and polymer N form chemically crosslinked nanogels through covalent interactions, which are characterized by stable structures but require safety considerations.

Figure 3

Overview of creating smart nanogels to control drug delivery. According to their response mechanisms, smart nanogels are classified as chemical, physical, or biological stimuli. Synthetic nanogels are chosen to control drug release based on material properties, disease environment, and drug application. However, for the eye, only temperature, pH, and enzyme responses are currently available.

Figure 4

Schematic representation of drug release from temperature-responsive nanogels based on PNIPAAM. (A) PNIPAAM above 32 °C, which is above LCST, and nanogels are gel phases, show hydrophobic properties, shrink and release drug; (B) PNIPAAM below 32 °C, which is below LCST, nanogels are sol phases, show hydrophilic properties and swell, and release the drug slowly.

Figure 5

Lysine-carbonized nanogels (Lys-CNGs) were prepared as eye drops to treat dry eye syndrome (DES) through controlled pyrolysis of lysine. Lys-CNGs inhibit the overexpression of ROS and proinflammatory cytokines TNF-α & IL-6, which have significant effects on the development of DES. In addition, Lys-CNGs penetrate into the mucin layer to prolong retention time at the ocular surface.

Figure 6

Flowchart for the preparation of two types of drug-loaded nanogel contact lenses (A) Nanodiamond (ND) nanogels are crosslinked with chitosan and loaded with timolol maleate (TM), then embedded in a hydrogel and cast into enzyme-responsive contact lenses. The nanogel contact lenses release TM through lysozyme-triggered mechanisms; (B) levofloxacin (LEV) is encapsulated in poly (sulfobetaine methacrylate) (PSBMA) nanogels to form LEV-loaded nanogels, which are then dispersed in premonomer solutions, polymerized, and pressed into a mold to obtain nanogel contact lenses that sustain drug release.