The extremely small molecular weight of nanobodies (Nb), their stronger penetration ability, and the hydrophilic amino acids in the Framework Region 2 (FR2) which enhance their water solubility, endow nanobodies with more superior selectivity in the research of transdermal drug delivery for biological agents [1].
As the largest organ of the human body and rich in antigen-presenting cells, the skin provides favorable conditions for the Transdermal Drug Delivery System (TDDS). As a drug delivery method that allows drugs to be absorbed through the skin into local or systemic blood circulation, TDDS avoids the first-pass effect in the liver and the possibility of gastrointestinal inactivation that may occur with traditional oral drugs. It can effectively achieve the therapeutic concentration and duration of action of drugs, and reduce side effects to a certain extent [2]. However, due to the barrier function of the epidermis, most drugs currently cannot effectively penetrate the stratum corneum, resulting in extremely low absorption by the human body. In some cases, drug development is abandoned because the drugs cause skin allergies, inflammation, or other symptoms. Nevertheless, TDDS remains one of the indispensable research directions in current drug delivery strategies and has become the focus of global research and development of external drugs and the cosmetics industry.
Schematic Diagram of Human Epidermal Structure [4]
As early as around 2016, Chinese researchers conducted studies on nanobodies as drugs or drug carriers for transdermal drug delivery. For example, anti-tumor nanobody drug creams targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2), c-Met, CXCR7, and other targets can be absorbed through the skin after being applied to cancerous areas to achieve a certain therapeutic effect; creams containing nanobodies targeting von Willebrand factor (vWF) are used for the treatment of thrombotic thrombocytopenic purpura (TTP); in another case, the anti-ALX-0171 nanobody drug can be applied to the throat, and the drug concentration can be adjusted by changing the application area to neutralize the respiratory syncytial virus [3].
Due to certain limitations of transdermal drug delivery, researchers have developed more transdermal drug delivery methods to penetrate the epidermal stratum corneum, such as microneedle arrays, hair follicle drug delivery, fractional laser, etc. Based on these methods, researchers have carried out more potential studies.
In the research on autoimmune diseases (ADs) conducted by the School of Pharmacy of Zhejiang University of Technology, it was found that transdermal drug delivery technology can provide effective therapeutic approaches using proteins, peptides, and targeted drugs for ADs such as rheumatoid arthritis (RA), type 1 diabetes, psoriasis, and vitiligo. Compared with traditional oral drugs, this technology has a lower risk of carcinogenesis [2].
Researchers from the School of Pharmacy of Sun Yat-sen University found that drug delivery to hair follicles using nanotechnology can directly and effectively treat conditions such as acne, alopecia, and folliculitis. Taking alopecia as an example, the periodic growth changes of the internal environment of hair follicles are affected by a variety of genes and signaling pathways, such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF). Targeted drug delivery to hair follicles via transdermal administration can modify the levels of hormones, inflammation, and other factors [4]. The nanoscale particle size of the drugs used in this study was approximately 300 nm. However, if nanobodies are used as the delivery system, the nanoscale particle size can be significantly reduced, resulting in better coverage and targeting ability. This can be regarded as a more potential strategy.
Schematic Diagram of Follicle-Targeted Drug Delivery System for Acne and Alopecia Treatment [4]
For traditional medicine, transdermal drug delivery technology or similar drug delivery strategies have a history of thousands of years. In the treatment of conditions such as gout, colds, and diarrhea, applying drugs to areas such as bones and joints, muscles and fascia, and acupoints has achieved good results. For instance, in the treatment of gouty arthritis, traditional Chinese medicine holds that hyperuricemia with gouty arthritis is caused by improper diet (excessive consumption of sweet, greasy, and highly nutritious foods), which leads to the accumulation of dampness and heat, blood stasis blocking collaterals, and the accumulation of heat causing organ damage. For such symptoms, Chinese herbal medicines can be ground into ointments and applied to the affected area, combined with decoctions for treatment [5].
In recent years, there have been numerous cases of developing drugs by extracting key active substances from Chinese herbal alkaloids, such as artemisinin and ephedrine. Another example is Morus alba L. Branch Total Alkaloids Tablets, an original drug developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences after 21 years of research. It is a natural Chinese herbal medicine new drug that can effectively treat type 2 diabetes by extracting active substances from Chinese herbal alkaloids [6]. The success of this drug indicates that Chinese herbal ingredients can be used to effectively treat specific diseases. If small molecules of alkaloids are combined with nanobodies, more transdermal drug delivery products can be developed based on different Chinese herbal medicines and applied in fields such as alopecia treatment, scar repair, skin whitening, and health care.
At present, research on transdermal drug delivery technology based on nanobodies is still relatively scarce. In the current environment where various medical methods are increasingly becoming part of daily life, more innovative development and scientific research are needed to explore the opportunities that nanobodies can bring to cosmetic pharmaceutical preparations and epidermal drug delivery.We have reason to believe that nanobodies, with their low immunogenicity, low side effects, small molecular weight, and stronger penetration and binding capabilities, will shine in the field of transdermal drug delivery technology one day.
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