Lipid Nanoparticles for Ocular Drug Delivery

The high prevalence and complexity of ocular diseases present significant challenges for drug delivery. Traditional ophthalmic drug delivery methods, such as eye drops or ointments, are often limited by biological barriers (such as the cornea and conjunctiva) and the flushing effect of tears, leading to low bioavailability of the drugs. Lipid nanoparticles (LNPs), as an emerging nanocarrier drug delivery technology, offer innovative solutions for ocular drug delivery due to their unique physicochemical properties and biocompatibility.

Ocular Drug Delivery

Due to the special physiological structure of the eye, there are several barriers such as the corneal barrier, conjunctival barrier, blood-aqueous humor barrier, and blood-retinal barrier. When a drug is dropped into the conjunctival sac, it is continuously diluted by tear fluid and rapidly drained through the nasolacrimal duct, resulting in poor bioavailability. Additionally, blinking and tearing quickly eliminate the drug, and enzymes in the tear fluid may metabolize the drug. Moreover, the poor permeability of the cornea further limits drug absorption. These challenges are faced by most commercially available eye drop and suspension formulations. In addition to traditional ophthalmic solutions, emulsions, suspensions, gels, and ointments, increasing interest is being directed toward the development of new, advanced ophthalmic carriers, including nanomicelles, nanoemulsions, liposomes, nanospheres, in situ gels, and more. Lipid-based nanocarriers, including nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and liposomes, have seen rapid development in ophthalmic applications in recent years. Advances in pharmaceutics, biotechnology, and materials science have promoted the development of novel ophthalmic formulations.

What are Lipid Nanoparticles?

Nanoparticles play a critical role in disease diagnosis, targeted drug delivery, DNA tissue research, drug-induced apoptosis of cancer cells, pharmacological efficacy studies, and tissue engineering. The size and surface properties of nanoparticles enable us to modify their characteristics for continuous drug release during transportation and targeted release at specific locations. Selecting the appropriate matrix for drug delivery is crucial. Modifying the surface properties of nanoparticles helps to clear drugs from the patient's body while significantly reducing side effects. Currently, these particles are combined with drugs or genes and delivered via various routes, including oral, nasal, intraocular, and arterial pathways. Researchers are exploring the use of various polymers to combine drugs and genes to enhance therapeutic efficacy while minimizing side effects.

Fig. 1. Lipid nanoparticles (J Funct Biomater. 2015, 6(2): 379-94).

Lipid nanoparticles, as a key member of nanomedicine, are playing an increasingly important role in the medical field due to their unique structure and functions. LNPs are lipid vesicles with a uniform lipid core, typically around 100 nm in diameter. This unique structure and size give them distinct physical and chemical properties, enabling them to effectively encapsulate and protect nucleic acid drugs such as mRNA, siRNA, and antisense oligonucleotides, and deliver them to target tissues or cells through the bloodstream. Lipid nanoparticles generally have the following characteristics:

• Biocompatibility and low toxicity: Made from natural or synthetic lipids, they effectively reduce ocular irritation.
• High loading capacity: Suitable for a variety of drugs, including small molecule drugs, gene therapy vectors, proteins, and peptides.
• Sustained release properties: By controlling the drug release rate, the duration of drug action can be prolonged.
• Ability to cross biological barriers: Capable of crossing barriers such as the cornea and conjunctiva, improving effective drug delivery.

How to Make Lipid-Based Nanoparticles?

Classic LNPs are primarily composed of ionizable lipids, PEGylated lipids, cholesterol, and neutral auxiliary lipids. The composition and structure are critical factors influencing the properties of lipid nanoparticles, and the preparation technique also significantly affects their characteristics. Since lipid nanoparticles have been considered potential carriers for nucleic acids, various preparation methods have been developed. According to incomplete statistics, there are currently thirteen preparation processes (excluding microfluidic technologies). Based on the characteristics of these processes, lipid nanoparticle preparation methods can be classified into two categories: high-energy dispersion lipid phase methods (such as high-pressure homogenization, high shear, ultrasound, etc.) and homogeneous system nanoparticle precipitation methods (such as microemulsion, solvent-based methods, membrane contact methods, and aggregation methods).

Lipids for Lipid Nanoparticles

BOC Sciences has extensive experience and technical expertise in the preparation of lipid nanoparticles, offering high-quality customized preparation services for our clients. We possess advanced preparation equipment and techniques, covering various processes such as ultrasonic dispersion, high-pressure homogenization, solvent evaporation, and more. Based on the characteristics of different drugs and customer requirements, we optimize preparation conditions to ensure that the particle size, drug loading, stability, and release properties of the lipid nanoparticles meet ideal standards. Additionally, BOC Sciences also provides comprehensive raw material supply services for lipid nanoparticles, including high-purity lipid materials such as phospholipids, cholesterol derivatives, fatty acids, and their derivatives, to meet the needs of clients in the research and production of lipid nanoparticles.

Lipid Nanoparticles for Drug Delivery

LNPs, as an advanced drug delivery system, have become an ideal choice for addressing ocular delivery challenges due to their high drug loading capacity, good biocompatibility, and controllable release properties. Through precise design, lipid nanoparticles can enhance the retention and permeability of drugs in the cornea, conjunctiva, and retina, significantly improving bioavailability. Furthermore, lipid nanoparticles support the encapsulation and delivery of various drug forms, including anti-inflammatory drugs, antibiotics, gene therapy molecules, etc., with wide-ranging applications. With the continuous development of nanotechnology, the potential of lipid nanoparticles in ophthalmic treatments is gradually emerging, providing new solutions for improving the treatment of complex ocular diseases.

Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) are a recently developed drug delivery system composed of natural or synthetic solid lipids such as phospholipids, triglycerides, and others. These nanoparticles can encapsulate or embed active ingredients within the lipid core, forming colloidal particles with a size range of 50-1000 nm. SLNs have advantages such as small volume, large surface area, controlled drug release, stable physicochemical properties, and the prevention of premature drug degradation. Additionally, SLNs are biodegradable and biocompatible, with no biological toxicity, making them particularly suitable for ocular drug delivery. They enhance corneal absorption and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. For example, cyclosporine is commonly used for treating chronic dry eye disease caused by inflammation, and solid lipid nanoparticles loaded with cyclosporine A have been shown to improve drug efficacy in rabbit eyes.

Nanostructured Lipid Carriers

Nanostructured lipid carriers (NLCs) are an improvement of SLNs, achieved by introducing liquid lipids such as medium-chain triglycerides. The main difference between liposomal nanocarriers and solid lipid nanocarriers is that solid lipid nanocarriers are solid, while liposomal nanocarriers are hollow. The simultaneous presence of hydrophilic and hydrophobic regions enables the encapsulation of one or more drugs with different solubilities. The inclusion of liquid lipids has been shown to improve the retention and penetration of therapeutic drugs in the eye. NLCs also demonstrate high drug loading capacity, diverse delivery options, sustained release, and targeting capabilities.

Liposomes

Liposomes are spherical vesicles consisting of lipid bilayers. They can be used as delivery carriers to transport nutrients and drugs into the body. These liposomes can be prepared by disrupting biological membranes using ultrasound, a process that sends sound waves to disrupt particles in the solution. The lipid bilayer mainly consists of phospholipids, which are the primary lipid component. Phospholipids are amphipathic molecules with both hydrophilic (water-attracting, polar) and hydrophobic (lipid-attracting) properties, often described as having a hydrophobic tail and a hydrophilic head. Therefore, liposomes are artificial phospholipid bilayers that possess biocompatibility. This biocompatibility is one of the most important advantages of liposomes as drug carriers: (1) Liposomes are almost non-toxic and have low antigenicity; (2) Liposomes can biodegrade and metabolize in the body; (3) The properties of liposomes, such as membrane permeability, can be controlled to a certain extent. Notably, liposomes can encapsulate and protect drug molecules or nucleic acids on their way to the target site.

Polymer-Lipid Nanoparticles

Polymer-lipid nanoparticles are optimized from SLNs and combine the advantages of liposomes and nanoparticles. They are suitable for hydrophilic drugs that need to be used in their salt forms in clinical practice. Most salt-form drugs are difficult to encapsulate in lipid materials due to their surface cationic charge. Polymer-lipid hybrid nanoparticles solve this issue by introducing negatively charged polymers to form drug-polymer complexes, which are then encapsulated in hydrophobic lipid materials, resulting in higher drug encapsulation rates. Their unique structure can slow the release of drugs and ensure that the drug is completely released in the body without causing toxic side effects from drug accumulation. The polymer-lipid hybridization is typically achieved through hydrophobic interactions, van der Waals forces, electrostatic interactions, or covalent bonds. Currently, lipid-polymer hybrid nanoparticles have broad potential for treating complex ophthalmic diseases such as diabetic retinopathy.

What are the Applications of Lipid Nanoparticles?

LNPs, due to their unique physicochemical properties and biocompatibility, can effectively overcome physiological barriers, enhance drug permeability across the cornea, and prolong the residence time of drugs in the eye, thereby significantly improving therapeutic efficacy. Compared to traditional ocular formulations, LNPs not only can encapsulate a wide range of drug types (such as small molecules and gene therapies), but also possess controllable drug release characteristics, enabling sustained release and targeted delivery. LNPs have shown great potential in the treatment of ophthalmic diseases, including glaucoma, dry eye, ocular infections, and age-related macular degeneration.

Glaucoma

Glaucoma is a chronic progressive optic neuropathy caused by increased intraocular pressure, which can lead to irreversible vision loss in severe cases. Lipid nanoparticle technology significantly improves the corneal permeability of drugs (such as prostaglandin analogs or beta-blockers) that lower intraocular pressure, and extends their retention time in ocular tissues. This improvement not only enhances drug efficacy but also reduces the frequency of administration, thereby improving patient compliance. Additionally, the targeted delivery capabilities of lipid nanoparticles allow for more focused drug action at the site of ocular lesions, effectively reducing systemic side effects.

Dry Eye Disease

Dry eye disease is a multifactorial condition caused by insufficient tear secretion or excessive tear evaporation, leading to ocular inflammation and damage. Symptoms include dry sensation, burning, and foreign body sensation in the eyes. Lipid nanoparticles, as sustained-release carriers, can stably release anti-inflammatory drugs (such as cyclosporine A) to inhibit inflammation, while also carrying lubricants (such as hyaluronic acid) to improve tear film stability and enhance the ocular surface barrier function. This dual action significantly improves the treatment of dry eye disease and reduces the long-term medication burden for patients.

Ocular Infections

Bacterial or fungal eye infections are common ophthalmic emergencies, requiring efficient and precise drug delivery. Lipid nanoparticles have shown excellent capability in loading antibiotics (such as levofloxacin) or antifungal drugs. By increasing the drug concentration at the infection site, lipid nanoparticles enhance the anti-infection effect while significantly reducing adverse reactions caused by systemic drug administration. Moreover, this delivery method can slow the drug release rate, prolong therapeutic effects, and reduce the inconvenience of frequent administration.

Age-Related Macular Degeneration (AMD)

Age-related macular degeneration is one of the leading causes of vision loss in the elderly, characterized by the growth of abnormal blood vessels under the retina. Lipid nanoparticles can encapsulate and deliver anti-angiogenic drugs (such as aflibercept), inhibiting the activity of vascular endothelial growth factor to prevent the formation and expansion of abnormal blood vessels, thus slowing disease progression. This delivery method significantly enhances the bioavailability of the drug, reduces the need for repeated injections, and decreases patient discomfort.

Gene Therapy

Gene therapy has attracted attention as an innovative treatment for hereditary ocular diseases (such as retinitis pigmentosa or Leber's hereditary optic neuropathy). Lipid nanoparticles, as non-viral carriers, are ideal tools for gene delivery due to their low immunogenicity and excellent gene transfer efficiency. By encapsulating small interfering RNA (siRNA), plasmid DNA, or other gene drugs, lipid nanoparticles can effectively cross ocular barriers and deliver therapeutic genes to target cells, enabling gene-level intervention in the disease.

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