Chitosan in polymer-based nanoparticles for drug delivery to the eye

Eye diseases are difficult to treat due to natural factors such as the blood-eye barrier, cornea or tear film. Polymer-based nanoparticles made of chitosan, among others, can help there to improve drug transport. In this article we would like to summarize a review on this topic.

Haijie Han, Su Li, Mingyu Xu, Yueyang Zhong, Wenjie Fan, Jingwei Xu, Tinglian Zhou, Jian Ji, Juan Ye, Ke Yao, Polymer- and lipid-based nanocarriers for ocular drug delivery: Current status and future perspectives, Advanced Drug Delivery Reviews, Volume 196, 2023, 114770, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2023.114770.

Eye diseases affect the vision and quality of life of approximately 250 million people worldwide. Due to the increasing age of the population and a simultaneous increase in population in the developing regions of the world, the number of blind people could rise from approx. 43.3 million to 115 million people in 2050.

Various options are available for the treatment of eye diseases, such as surgical, laser or drug treatment. The most common therapy is the administration of medication. However, due to the natural barriers in the eye such as the tear film, the cornea, the anterior segment barrier or the blood-ocular barrier, there is only a low accumulation of the drug, insufficient bioavailability and a short residence time in the eye. This could be improved by suitable drug delivery systems. Besides lipid-based nanocarriers (LNCs), polymer-based drug carriers (PNCs) are also promising. Both improve drug penetration, retention and solubility, reduce toxicity, prolong release and allow targeted delivery of the drug. While LNCs have good physiological properties as well as being easy to prepare, PNCs can be specifically modified, allowing targeted control of particle properties. PNCs also include chitosan-based drug delivery systems.

In this article, we want to give you an overview of the current developments in ocular drug delivery with chitosan:

Chitosans for the treatment of corneal neovascularization:

VEGFs are critical mediators of vasculogenesis and angiogenesis and are considered a major cause of various ocular diseases and tumor development. The cornea is an avascular and transparent ocular tissue without capillary and vascular permeability. This is maintained by various angiogenic and anti-angiogenic factors. In case of an imbalance of these, e.g. by VEGFs, a so-called neovascularization of the cornea may occur. Some PNCs, such as chitosan, possess intrinsic VEGF inhibitory properties. For example, Zahir-Jouzdani et al. [1] designed a thiolated derivative of chitosan nanoparticles that has a longer retention time and a more pronounced therapeutic effect compared to conventional nanoparticles due to the high mucoadhesiveness of the thiol group.

Chitosans for the treatment of dry eye syndrome (DED):

DED is a multifactorial ocular surface disease in which the balance of the tear film is disturbed. This results in a cycle of ocular surface inflammation, tear film instability, and hyperosmolarity leading to ocular surface damage. The pathogenesis has not yet been fully elucidated, but inflammation is also thought to play a critical role. To prevent progression of inflammation, non-steroidal anti-inflammatory drugs such as ibuprofen can be used. Since ibuprofen is poorly water soluble, appropriate drug delivery systems are needed for it to exert its optimal effect. Dukovski et al. [2] proposed a functional cationic ibuprofen nanoemulsion with chitosan as the cationic drug and lecithin as the anionic surfactant. This allows the entrapment of chitosan to improve the solubility of the drug, increase the residence time on the ocular surface, and stabilizes the tear film for effective treatment of mild to moderate DED.

Chitosan against cataracts:

Cataract is the disease that most often leads to blindness worldwide. Reasons for cataracts include age, systemic diseases, trauma, or drug-induced changes. The most effective treatment to date is still a surgical procedure in which the clouded lens is removed and a new artificial lens is implanted. However, there are also new drug approaches to prevent or at least delay the onset of cataracts. Many natural and synthetic antioxidant agents, including coenzyme Q10, curcumin, resveratrol, and lutein, are able to reduce oxidative stress and prevent lens damage. Chitosan-modified liposomes containing coenzyme Q10 extended the residence time of the drug in the lens 4.8-fold [3].

When a new lens is implanted, so-called postoperative capsular opacification (PCO) often occurs (adults 20-40%, children 100%) due to proliferation of the remaining lens epithelial cells (LECs). PCO can be postponed or prevented by inhibiting the proliferation of LECs with, for example, drugs such as doxorubicin (DOX) or 5-fluorouracil. For example, intraocular lenses (IOLs) loaded with DOX-loaded chitosan nanoparticles may help in this regard. These improved biocompatibility and efficacy, as well as exhibited significant anti-adhesion and anti-proliferation properties [4]. Another approach is to encapsulate 5-fluorouracil in chitosan nanoparticles to develop a system for controlled and sustained release. When these are used in IOLs, it has been shown that the proliferation of LECs was suppressed [5].

Chitosan for the treatment of retinal vascular diseases:

Retinal diseases such as retinal neovacularization (RNV) result in the abnormal growth of pre-existing blood vessels. This pathological process can be found, for example, as a clinical manifestation of age-related macular degeneration (AMD) or diabetic retinopathy (DR). While AMD is considered the main cause of vision loss in old age, DR is the most common cause of blindness in working age. Most retinal diseases share similar agents and treatment methods such as VEGF inhibitors or corticosteroids. However, poor retinal transport or insufficient drug concentrations are existing challenges in all these methods, which could be overcome by nanocarriers.

To increase delivery efficacy and prolong the release profile, one study used chitosan in PGLA nanoparticles to improve drug payload and achieve prolonged drug release and surface retention. Chitosan-coated PLGA nanoparticles enabled subconjunctival delivery of bevacizumab and improved permeability through the electrostatic interaction between positively charged chitosan and negatively charged ocular surface [6]. In addition, chitosan-nacetyl-l-cysteine (CNAC), a derivative of chitosan, exhibited stronger mucoadhesive properties by forming strong disulfide bonds with cysteine-rich domains of mucus glycoproteins with additional nacetyl-l-cysteine (NAC), resulting in improved mucoadhesive properties [7].

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