INTRODUCTION:

Drug delivery systems has been investigated a long decade to improve therapeutic efficacy, bioavailability and patient acceptability in view of pharmacokinetics through oral route of drug delivery. Moreover, it investigated for stability and degradation of active bio-molecule through various aspects. Current challenging strategy of many molecules are to attain site specific drug delivery and transports high molecular weight drugs through dermal route by reducing side effects encountered by oral route respectively. Skin is the major source for transportation of drugs through it and the well-known stratum corneum (SC) is the outermost barrier layer of it and contains dead keratinocytes combined with corneo-desmosomes, embedded in a lipidic matrix¹.

Generally, desmosomes are specialized cells, which show adhesion property between cell-to-cell. Desmosomes contain two types of cadherins i.e., desmogleins (DSG1-4) and desmocollins (DSC1-3). The DSG/DSC dimers are the basic adhesive unit for desmosomes². These stronger cell adhesions are randomly arranged on the lateral side plasma membranes. In multi-cellular systems, intercellular adhesion junctions are essential to facilitate signal transmission and offer mechanical stability. Desmosomes are the type of specialized intercellular connection that is most committed to mechanical stability among all others. Skin and heart muscle are two examples of tissues that contain them because they are prone to mechanical stress.

Few researchers highlighted on the significance of desmosomes and revealed that these are crucial for tissue morphogenesis as well as tissue integrity. Genetic and autoimmune disorders linked to abnormalities in different desmosomal components have been shown the significance of desmosomes. Desmosomes are sticky intercellular junctions that connect neighboring cells mechanically. They do this phenomenon by connecting the intermediate filament cytoskeletal network to adhesive contact that is mediated by desmosomal cadherins. Plakoglobin and other members of the armadillo gene family, as well as desmoplakin and other members of the plakin family of cytolinkers, are among the densely clustered cytoplasmic plaque proteins that connect desmosomal cadherins to intermediate filaments^3-4.

History of desmosomes: Giulio Bizzozero in between 1846–1901, an Italian pathologist, made the first observation of the desmosome in the spinous layer of the epidermis. Bizzozero's perceptive identification of these structures as adhesive cell to cell contact points was prompted by observations of these little dense nodules, which he later dubbed “nodes of Bizzozero”. Josef Schaffer later used the phrase “desmosome” in 1920. It comes from the Greek terms “desmo”, which means binding or fastening, and “soma”, which means body. Desmosomes function extracellularly by forming physical connections between members of the cadherin family of Ca²⁺dependent transmembrane proteins. These connections are made up of five tandem extracellular domains (EC1-EC5), which are analogous to the extracellular domains of conventional cadherins. Desmosomes are totally different from adherens junctions intracellularly. They are a group of proteins that form an electron-dense plaque that is eventually attached to the cell cytoskeleton⁵.

Structure and morphology: Cell to Cell contact and strong adhesion are mediated by desmosomes, which are highly organized and specialized membrane domains. The intermediate filament cytoskeletons are linked to adhesive contacts at the desmosomes. Desmosomes physically integrate cells inside tissues and hence help the tissues to withstand mechanical stress by mediating both cell-cell adhesion and cytoskeletal connections. Desmosomes are prominently distributed in tissues that are frequently subjected to physical forces, such as heart and skin. At the ultra-structural level, desmosomes appear as electron-dense discs that are about 0.2-0.5mm in diameter and assemble into a mirror image arrangement at cell- cell interfaces^4-5.

Figure 1: Structure of Desmosome (adopted from Wikipedia)

Under basale, desmosomes formed as bridges, the size and numbers of desmosomes are significant from the desmosomal plaques. The lower SC contains corneo-desmosomes, which differs from desmosomes through morphologically. If the junction lost its intercellular portion, then intercellular plaque becomes embedded and the corneo-desmosomes remain functional⁶. Thereby desmosomes preserve tissue integrity during homeostatic and stress condition.

Major Strategies of Desmosomal cadherins:

· Desmosomal cadherins import structural and functional requirements to mutant variants in the study of adhesiveness.

· In view of gene targeting, which has been introduced by an adhesion function, to improve tissue integrity to particular antibodies or peptides, desmosomal cadherins are used⁷.

Clinical Significance:

· Effectively used in auto-immune disease treatment, where the patient clinical findings identified with phenotype muco-cutaneous lesions.

· Used in congenital mutations which effect gene dosage impacts on strong impairment of desmosome function.

· Patients suffering with cutaneous fragility syndrome which effects skin where mutations taken place with PP1 gene.

· Recent investigations found that kidney disease also regulated by desmosomes (polycystin-1) and involved in cystogenesis and then the morphology of desmosomes can be altered.

Table 1: Applications of desmosomes in drug delivery

Type of drug delivery/therapy	Inference
Semisolid dosage forms such as gels, ointments & creams which may adopt passive diffusion for drug permeation through layers of skin.	The SC layer of the skin connected to several cells of desmosomes and it supports cellular communication and leads to maximum permeation of drug through skin⁸.
Ocular drug delivery	Eye surface is directly exposes to outside environment which contains pathogens. Tight junctions, desmosomes, adherent junctions and gap junctions are involving to prevent such incidents. Hence the tears remove debris from the eye by altering the ocular barrier⁹.
Buccal drug delivery	In buccal mucosa tight junctions are absent but the gap junctions are enriched with desmosomes. Furthermore, the buccal mucosa had maximum drug transporting capability than skin. Thus, the molecules interaction with intracellular keratin and intercellular desmosomes may enhance the drug flux¹⁰.
Desmosomes in HNC (head and neck cancer)	Desmosomal cadherins lowers expression of DSG2 and DSC2, thereby it suppresses¹¹.
Nasal drug delivery	Proteins of desmosomes include desmoglein and desmocollins bind to internal cell junctions and these promote adhesion property to nasal epithelium¹².

REFERENCES:

1. Pena juarez MC, Guadarrama-Escobar OR, Escobar-Chavez JJ. Transdermal delivery systems of biomolecules. J Pharm Innov. 2021; 17(2): 319-332.

2. Muller L, Hatzfeld M, Keil R. desmosomes as signaling hubs in the regulation of cell behavior. Front Cell Dev Biol. 2021; 9: 745670.

3. Al-Amoudi A, Frangakis AS. Structural studies on desmosomes. Biochem Soc Trans. 2008; 36(Pt 2): 181-7.

4. Delva E, Tucker DK, Kowalczyk AP. The desmosome. Cold Spring Harb Perspect Biol. 2009; 1(2): a002543.

5. Chidgey M. Desmosomes and disease: an update. HistolHistopathol. 2002; 17(4): 1179-92.

6. Morilla MJ, Romero EL. Ultradeformable phospholipid vesicles as a drug delivery system: A review. Research and reports in transdermal drug delivery. 2015; 15(4): 55-69.

7. Huber O. Structure and function of desmosomal proteins and their role in development and disease. CMLS, Cell. Mol. Life Sci. 2003; 60: 1872–1890.

8. Lee DH, Lim S, Kwak SS, Kim J. Advancements in Skin-Mediated Drug Delivery: Mechanisms, Techniques, and Applications. Adv Healthc Mater. 2023; 27: e2302375.

9. Dubald M, Bourgeois S, Andrieu V, Fessi H. Ophthalmic Drug Delivery Systems for Antibiotherapy-A Review. Pharmaceutics. 2018; 10: 10.

10. Jacob S, Nair AB, Boddu SHS, Gorain B, Sreeharsha N, Shah J. An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems. Pharmaceutics. 2021; 13: 1206.

11. Liu YQ, Zou HY, Xie JJ, Fang WK. Paradoxical Roles of Desmosomal Components in Head and Neck Cancer. Biomolecules 2021; 11: 914.

12. Nur Husna SM, Tan HT, Md Shukri N, Mohd Ashari NS, Wong KK. Nasal Epithelial Barrier Integrity and Tight Junctions Disruption in Allergic Rhinitis: Overview and Pathogenic Insights. Front Immunol. 2021; 12: 663626.

Received on 08.06.2024 Revised on 09.07.2024

Accepted on 19.08.2024 Published on 18.12.2024

Available online on December 21, 2024

Asian J. Pharm. Tech. 2024; 14(4):412-414.

DOI: 10.52711/2231-5713.2024.00065