Follicular drug delivery is a mechanism that enables the transport of therapeutic agents through the hair follicles present on the skin. This approach leverages the use of nanoparticles, which are widely employed in the broader field of drug delivery, to specifically target and penetrate these follicular pathways. By utilizing follicular delivery, drugs can be delivered in a more targeted and localized manner to treat conditions including acne, alopecia, fungal infections, and skin cancer. This article will explore the anatomy of the hair follicle, various drug carriers and delivery vehicles utilized, relevant in vitro and in vivo models, current clinical applications, and the existing challenges and future directions within this field.
Background Targeted drug delivery is a therapeutic approach designed to concentrate medications at specific sites within the body, enhancing drug concentration at the intended site while minimizing exposure to non-target areas. This approach helps improve treatment outcomes and minimize side effects. Within the various targeted drug delivery approaches, follicular drug delivery specifically targets hair follicles, with the aim of delivering drugs to treat skin-associated infections and conditions.
Key considerations in experimental design for follicular drug delivery include hair follicle anatomy and circulatory proximity, specific target sites for drug delivery, models for follicular delivery, quantitative assessment methods, and formulation design. The target region within the hair follicle must be clearly defined for the formulation and delivery approach.
Hair Follicle Anatomy
Hair is separated into two distinct regions. One region is the hair shaft, which protrudes from the skin's surface. The hair shaft consists of three layers. The inner layer is the medulla. This layer is surrounded by the cortex. The cuticle is a single-cell layer that shields the cortex and medulla from the surrounding skin. The second region is the hair follicle, which rises from the surface of the epidermis and has a structural unit called the pilosebaceous unit. The pilosebaceous unit is made up of the hair follicle, its associated sebaceous gland, and the arrector pili muscle. The hair follicle consists of the inner root sheath and outer root sheath. The inner root sheath protects the growing hair, while the outer root sheath is continuous with the epidermal layer, increasing the surface area for absorption beneath the skin's surface. The arrector pili muscle is a small band of smooth muscle fibers that attaches to the follicle. The sebaceous gland secretes a lipid-rich sebum onto hair follicles which protects the hair and provides a hydrophobic protective barrier over the skin. This lipid-rich environment may provide a lipophilic pathway for potential drug delivery.
Drug Carriers Nanoparticles, including nanocrystals, micelles, lipid, polymeric, and silica nanoparticles, and exosomes are all drug carriers used in follicular drug delivery. When each of these drug carriers are applied to the surface of the skin, they can travel down the hair shaft, bypassing the outer layer of the skin. This section will outline the structure and function of each nanoparticle, and how it lends itself specifically towards follicular drug delivery.
Nanocrystals Nanocrystals are nanosized, inorganic materials that are within thermodynamically stable colloidal solutions. They have a crystalline structure and are between 1 and 1000 μm in diameter. Unlike other nanoparticles, there is no carrier material, meaning that nanocrystals only consist of the drug being delivered. When the drug is dispersed into liquid media, it undergoes surface degradation, with the dispersed particles needing to be stabilized. Nanocrystals are much more drug-saturated, and their dissolution process is significantly faster than that of when the drug is in its normal state, increasing the bioavailability of the drug during delivery.
Nanocrystals interface well with follicular drug delivery because of their small size, their reliance on surface degradation during drug delivery, the establishment of a concentration gradient along the length of the hair follicle, and the high drug saturation within the nanocrystal. Once on the skin, the nanocrystals travel down the hair shaft of the follicle, bypassing the outer layer of the skin due to the concentration gradient, and then form localized depots within the hair follicle, allowing for sustained drug release and therapeutic effects. Once past the outer layer of the skin, the drug can more easily diffuse through the skin, as this layer is more permeable.
Polymeric Micelles Micelles are spherical molecules formed when lipids are placed in a hydrophilic solvent. Lipids are small molecules consisting of a hydrophilic head and at least one hydrophobic tail. When enough lipids are placed into a hydrophilic substance, a concentration known as the Critical Micelle Concentration, they aggregate into spherical molecules, with their hydrophilic heads on the exterior and their hydrophobic tails on the interior.
In drug delivery, polymeric micelles are preferred to classic micelles due to their lower critical micelle concentration and higher stability upon dilution. Polymeric micelles rely on the spontaneous formation of spherical molecules from amphiphilic block copolymers, rather than lipids, when placed in a hydrophilic substance. The exterior of these spherical molecules consists of a hydrophilic shell, with the core being hydrophobic. In drug delivery, the hydrophobic drug of interest is present in the hydrophilic substance when the lipids are added, ensuring that when the micelles form, the hydrophobic drug becomes trapped within the core of the micelle. These copolymers have a customizable size and makeup, allowing for more flexibility in loading capacity, rate of degradation, and therapeutic potential. Polymeric micelles are small enough to access tissues with leaky vasculature, can improve the solubility of poorly water-soluble drugs, and can remain in the blood for a longer period of time, allowing for accumulation of the drug at the desired location.
Polymeric micelles are considered effective in follicular drug delivery due to their small size, high stability, and ability to make water-insoluble drugs soluble. When polymeric micelles make contact with the skin, they can travel down the hair shaft, bypassing the outer layer of the skin, with smaller micelles permeating further into the hair follicle.
Lipid Nanoparticles
Lipid nanoparticles are spherical molecules with a diameter between 10 and 500 nm made up of a lipid bilayer with a hydrophilic core and exterior, and a hydrophobic intermediate layer. The hydrophilic core can contain a hydrophilic drug payload, protecting the drug from degradation in the body, increasing solubility and efficacy, and altering distribution of the drug to the desired sites. The hydrophobic intermediate layer can also contain a hydrophobic drug, increasing its solubility and bioavailability within the body.
Lipid nanoparticles enter the hair follicle via the hair shaft and travel down the length of the follicle, where they sit and deliver the drug over a sustained period of time. The lipid nanoparticles remain in the follicle until slow processes like hair growth, shedding and sebum flow remove the follicles from the pores.
Polymeric Nanoparticles
Polymeric nanoparticles are nanoscale-sized delivery systems composed of drug, polymer, and surfactants. These carriers can be made from hydrophilic natural polymers, like proteins, or from hydrophobic synthetic polymers. Their versatility allows them to be administered through various dosage forms, including topical applications. Polymeric nanoparticles have high encapsulation efficiency and physical stability, which can be optimized based on the method of preparation and the physicochemical properties of the constituent materials. The polymeric coating protects the active drug from premature degradation, improves steric stability, and minimizes irritation upon application. Additionally, these nanoparticles can be mucoadhesive, biodegradable, and provide skin permeation enhancement, improving both therapeutic efficacy and safety.
In general, polymeric nanoparticles exhibit a natural tendency to accumulate within the hair follicle cavities. The targeting efficiency of these systems can be enhanced by modulating their surface properties, including particle size, superficial charge, and aggregation state. These particles can also be functionalized with an antibody or a substance that promotes the targeting of the particle and facilitates site-specific drug delivery.
Silica Nanoparticles Silicon dioxide nanoparticles are inorganic nanoparticles made up of an alternating mixture of silicon and oxygen atoms, with dimensions between 400 and 700 nm. These nanoparticles are hydrophilic, biocompatible, and have low-cost synthesis and dispersive properties. Silica nanoparticles have a porous structure which produces cavities that can store and release a variety of substances and provide a high specific surface area, stable structure, and easy modification.
For follicular drug delivery, the particle surface chemistry influences the effectiveness of the silica nanoparticles. Thiolated silica nanoparticles have demonstrated strong binding affinity to hair shafts and the outer skin stratum corneum. Polyethylene glycol (PEG)-modified silica nanoparticles have demonstrated improved diffusivity and increased follicular penetration. Larger PEGylated particles were observed to penetrate the follicular structure more deeply compared to smaller sizes.
Exosome Therapy
Exosomes, a class of extracellular vehicles (EVs), are nanoscale vesicles with diameters ranging from 30 to 150 nm. These vesicles are secreted by a wide variety of cell types and are characterized by a phospholipid bilayer structure. As mediators of intercellular communication, exosomes play a role in processes including homeostasis, cellular differentiation, and organogenesis. Exosomes encapsulate molecules within the vesicle, providing protection against degradation and allowing for potential targeted delivery to recipient cells. Their ability to transfer bioactive molecules has made them a subject of increasing interest in therapeutic research.
Exosomes have been observed to affect hair follicle cell function, including proliferation, differentiation, and survival. Notably, exosomes are capable of carrying hydrophobic Wnt proteins on their surface over a long distance. These proteins induce the activation of β-catenin, a key signaling pathway in the regulation of hair regeneration and morphogenesis. Exosomes that are derived from mesenchymal stem cells (MSCs) have been used in experimental studies related to hair growth and regeneration. These MSC-derived exosomes offer properties such as lower immunogenicity and greater scalability.
Delivery Vehicles Conventional follicular drug delivery relies on the use of topical delivery vehicles, such as gels and microneedles, to deliver nanoparticles containing the necessary drugs to hair follicles.
Gels