Nanocarriers for Ocular Drug Delivery

Fundus diseases are the most important cause of severe visual impairment or even loss in patients worldwide. Due to various physiological barriers, therapeutic drugs are difficult to enter the fundus, which seriously affects the treatment of fundus diseases. Nanomaterials refer to materials with at least one dimension in the nanometer scale (1-100nm) on the three-dimensional spatial scale, which is a new generation of materials composed of nanoparticles between the size of atoms, molecules and conventional macroscopic systems. In the field of medicine, nanomaterials have developed into important drug delivery systems. The nano drug delivery system has the characteristics of nano size and large surface area/volume ratio, which can load therapeutic drugs with different physical and chemical properties, and modify various surface active substances. It can improve the solubility of drugs and the penetration of physiological barriers, protect biological drugs from degradation, improve drug safety and bioavailability, and deliver therapeutic drugs to specific eye targets, which has great therapeutic potential.

Ocular drug delivery challenges

Common routes of administration for ocular diseases include systemic administration, ocular surface administration, periocular administration, and intravitreal injection. The anatomic factors that reduce ocular penetration of drugs mainly include cornea, conjunctiva, sclera and blood-eye barrier. Among them, the most convenient and widely accepted ocular surface topical dosage form is eye drops. Cornea is a barrier to most hydrophilic and lipophilic drugs. The conjunctiva has rich blood supply and lymphatic circulation, which can clear drug molecules; The permeability of sclera decreased exponentially with the increase of drug molecular radius. Tear diffusion, nasolacrimal duct drainage and blink reflex also reduced the retention time of eye drops on the ocular surface and affected drug availability. Therefore, due to the combined influence of anatomical and physiological barriers, only about 5% of eye drops can enter the eye. The bioavailability of peribulbar injection drugs is slightly higher than that of eye drops, but peribulbar injection is far from meeting the needs of fundus disease treatment due to drug loss caused by periocular space, blood retina barrier (BRB), choroidal circulation, etc. Systemic oral or intravenous administration of drugs is the traditional route of administration for many posterior ocular diseases, but the adverse environment of the gastrointestinal tract, first-pass metabolism, systemic blood dilution, BRB limitation, etc., can lead to a significant reduction in drug efficacy, and more frequent and higher systemic administration of drugs clearly increases the risk of adverse reactions. In recent years, intravitreal injection has been increasingly used for the treatment of posterior ocular diseases. The bioavailability of drugs through vitreous diffusion to fundus is high, but the collagen fibers and hyaluronic acid molecules in vitreous form a network structure. The aperture of the network and the negative charge carried by hyaluronic acid will affect the drug diffusion. At the same time, most of the existing drugs have short half-lives and invasive administration methods, requiring regular and frequent injection by trained ophthalmologists, leading to the risk of retinal detachment, cataract, endophthalmitis, increased intraocular pressure and other eye complications, resulting in poor compliance of patients with this treatment method. Therefore, the research on new fundus disease drug delivery system has aroused wide interest in the industry, and nano drug delivery system deserves attention.

Advantages of nanomaterial for ocular drug delivery

Improved bioavailability: Nanomaterials, due to their ultra-small particle size, are able to penetrate the complex physiological barriers of the eye, such as the cornea and conjunctiva, and act directly on the target tissue. This property significantly improves the bioavailability of the drug, enabling more drug molecules to reach and work at the affected area.

Extended duration of action: Controlled release can be achieved by encapsulating the drug in a nanocarrier. This slow-release system not only reduces the frequency of dosing and improves the patient's treatment experience, but also maintains a stable drug concentration and reduces adverse reactions due to fluctuations in drug concentration.

Enhanced stability and solubility: Some ophthalmic drugs limit their clinical use due to their own instability or low water solubility. Nanomaterials can improve the stability of drugs and increase their solubility under physiological conditions, ensuring the effectiveness of drugs during storage and use.

Targeted delivery ability: Nanocarriers can achieve targeted delivery of specific eye tissues or cells through surface functionalization and other ways. This technique not only improves the therapeutic effectiveness of the drug, but also reduces the distribution of the drug to non-targeted tissues, reducing the risk of systemic side effects.

Multifunctional carrier systems: Nanomaterials can combine multiple functional modules, such as anti-inflammatory, antioxidant, antibacterial, etc., to provide a comprehensive therapeutic strategy. This versatility allows a single nanoparticle to address multiple eye disease pathologies.

Innovative drug delivery routes: Nanomaterials support multiple drug delivery routes (such as local eye drops, intraocular injections, contact lens loading, etc.), providing flexible solutions for the treatment of different eye conditions.

Related services at BOC Sciences

Common ocular nano drug delivery systems

Liposome for ocular drug delivery

Liposomes are lipid vesicles composed of one or more phospholipid bilayers around a hydrous nucleus. The structure of these bilayers gives them unique advantages: (1) The lipid bilayer structure surrounding the hydrous nucleus allows the binding of hydrophilic and lipophilic active substances, easy fusion with biofilms, and the release of drugs through the cornea. (2) Liposomes have low toxicity and immunogenicity, and have good biodegradability. At the same time, liposomes can support a variety of therapeutic drugs with different physical and chemical properties, and the surface is easily modified by polymers, sugar groups, antibodies, proteins and peptides to achieve targeted therapy.

Lipid nanoparticles (LNPs) for ocular drug delivery

The ideal ocular dosage form should release the drug and overcome the eye barrier to ensure that the drug in the tissues inside the eye reaches therapeutic levels. The biocompatibility and adhesion properties of lipid nanoparticles improve their interaction with the eye mucosa. This may increase the residence time of the drug in the cornea, resulting in higher bioavailability. The lipid composition of the lipid nanoparticles can interact with the lipid layer outside the tear film because they exhibit similar properties to the tear film. Therefore, LNP is able to increase the residence time of the vector in the conjunctiva sac, where it acts as a drug reservoir.

According to the different lipid matrix, LNPs can be divided into solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), lipid drug couplings (LDC) and lipid nanocapsules (LNC). SLN refers to a solid colloidal particle with a particle size between 10-1000nm. It is composed of biocompatible solid lipids (triglycerides, pegylated lipids, fatty acids, steroids, etc.) and a stabilizer (surfactants, cosurfactants). Antioxidants, electrolytes, preservatives, viscosity enhancers and other excipients can also be added to formulations and are widely used to encapsulate small molecules, siRNA, DNA, proteins, peptides, etc., to improve biocompatibility and delivery efficiency, and to extend drug action time. The main problems faced by solid lipid nanoparticles are stability, such as particle size growth and gelation trend.

Illustrates the structural differences between SLN and NLC whereas drug expulsion can occur from SLN because of its perfect crystal whereas NLC have better drug loading capacity due to its irregular crystal structure. (Baig, M. S., 2024)

Polysaccharide nanoparticles for ocular drug delivery

Polysaccharide has hydrophilic functional groups, which can enhance adhesion on mucous membranes through hydrogen bonding and electrostatic action, and prolong the residence time of drugs in eyes.

Chitosan based hybrid NPs: Chitosan (CS) is a cationic polysaccharide, which can adhere to mucous membranes through electrostatic action and hydrogen bonding, and has good drug delivery effect and antibacterial ability.

Other polysaccharide NPs: Polysaccharides such as hyaluronic acid (HA), sodium alginate (SA) and pectin can also adhere to mucous membranes via hydrogen bonding for ocular administration.

Polymer nanoparticles for ocular drug delivery

Polymer nanoparticles are one of the most interesting drug delivery systems for the local treatment of eye diseases. The drug can be encapsulated within the polymer core or uniformly dispersed throughout the nanoparticle matrix. Various polymers, such as PLA, PGA, PLGA, chitosan, etc., have been used to manufacture nanoparticle drug delivery systems, but due to the materials and preparation methods employed, these nanoparticles have relatively large sizes (>100nm).

Polymer nanomicelles for ocular drug delivery

Polymer nanomicelles are nanoscale core-shell structures formed by self-assembly of biphasic molecules with hydrophobic groups as the core and hydrophilic groups as the shell, which are known for increasing solubility and maintaining drug release. Compared with solid nanoparticles, polymer nanomicelles are generally easier to prepare, easier to sterilize, and exhibit high thermodynamic stability. The most commonly used hydrophilic block is polyethylene glycol polyethylene oxide (PEG-PEO). PEG is non-toxic and can minimize the attraction of ionic bonds and stabilize the spatial structure of micelles. At the same time, PEG can prevent protein binding in the biological matrix, reduce immunogenicity, and protect micelles from enzymatic degradation.

Dendritic macromolecules for ocular drug delivery

A dendritic macromolecule is a synthetic, highly branched macromolecule with repeating units emanating from the core to form a three-dimensional structure that can be sized by varying the number of branches. Dendrimers can be modified by coupling or attaching other molecules, such as amines, carboxylic acids, polyethylene glycol, phosphoric acid, sulfonic acid, lysine, etc., and continue to release therapeutic effects. At the same time, it has been proved that dendrimer can play a good therapeutic effect and have good biological tolerance through intravenous administration and vitreous injection.