Drug nanocarrier, the future of atopic diseases: Advanced drug delivery systems and smart management of disease

Highlights

• Lack of versatile choice results in escalation of prevalence of atopic diseases.

• Reduced efficiency of conventional modalities demands newer therapies.

• Nanocarrier-based formulations produced desired anti-dermatitis effects.

• Therapeutic superiority of the nanocarrier-based therapies is proposed.

Abstract

Atopic dermatitis (AD) is a chronically relapsing skin inflammatory disorder characterized by perivascular infiltration of immunoglobulin-E (IgE), T-lymphocytes and mast cells. The key pathophysiological factors causing this disease are immunological disorders and the compromised epidermal barrier integrity. Pruritus, intense itching, psychological stress, deprived physical and mental performance and sleep disturbance are the hallmark features of this dermatological complication. Preventive interventions which include educational programs, avoidance of allergens, exclusive care towards skin, and the rational selection of therapeutic regimen play key roles in the treatment of dermatosis. In last two decades, it is evident from a plethora of studies that scientific focus is being driven from conventional therapies to the advanced nanocarrier-based regimen for an effective management of AD. These nanocarriers which include polymeric nanoparticles (NPs), hydrogel NPs, liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanoemulsion, provide efficient roles for the target specific delivery of the therapeutic payload. The success of these targeted therapies is due to their pharmaceutical versatility, longer retention time at the target site, avoiding off-target effects and preventing premature degradation of the incorporated drugs. The present review was therefore aimed to summarise convincing evidence for the therapeutic superiority of advanced nanocarrier-mediated strategies over the conventional therapies used in the treatment of AD.

Introduction

Atopic dermatitis (AD) is a type of chronic eczematous skin inflammation characterised by an excessive infiltration of IgE, T-lymphocytes and mast cells. The common symptoms of AD include dry inflamed skin, intense pruritus, itching, skin lichenification, sleep disturbance and emotional distress [1], [2]. It is a common, often long-lasting skin disease that affects a large percentage of the world's population. Recent studies demonstrated that the prevalence of AD is continuously increasing while affecting 15–30% of urban children and 1–3% of adults [3], [4], [5]. AD is not restricted to a specific age group, but it can occur in any age. It usually appears during early childhood and periodically relapses throughout the life of a patient [6].

The prime cause of AD is unclear yet; however, it is considered to have a multifactorial pathogenesis accompanying genetic defects [7], [8], [9], immune dysregulation, environmental triggers and impaired skin barrier integrity being the principal causative factors [10], [11], [12]. For many years, an abnormal T-helper cells (T_H2) adaptive immune response to largely innocuous environmental irritants was considered as the major dynamic in the development of AD [13], [14], [15]. Other studies proposed that the skin barrier defects and an abnormal immune response are highly plausible mechanisms underline atopic diseases [16], [17], [18].

To date, there is no absolute therapy for the treatment of AD owing to a complex pathogenic interplay between patient’s susceptible genes, skin barrier abnormalities and immune dysregulation. Nevertheless, various pharmacological and non-pharmacological approaches including, identification and avoidance of causative allergens, skin hydration (e.g., taking baths or using moisturisers), topical anti-inflammatory or immunosuppressant therapies, antipruritic medications, and anti-bacterial measures (e.g., taking bleach baths, applying antiseptics or disinfectants) have been reported very effective either to be used alone or in combination for the treatment for mild-to-severe AD. The mild clinical cases can potentially be managed with skin care or emollient therapy only; however, moderate-to-severe patients require intensive therapy. It is worth mentioning that these approaches can achieve control over AD with varying degree; however, several challenges associated with the use of these conventional therapies which include lack of target-specific delivery [19], systemic toxicity, therapy adherence, and patient compliance are still debatable.

In last two decades, scientific focus has been changing for the development of novel target-specific delivery systems while optimising therapeutic outcome as well as to minimise off-target effects. These advanced strategies include iontophoresis [20], [21], liposomes [22], [23], [24], [25], ethosomes [26], [27], [28], SLNs [29], [30], [31], nanoemulsion [32], [33] and polymeric NPs [34], [35], [36], [37]. Iontophoresis is the process of administering ionic drug molecules across the biological membranes for biological action. This method has been well-employed for the delivery of a number of drugs such as methylprednisolone succinate, dexamethasone phosphate and antibiotics in the treatment of atopic diseases and other dermatological disorders [20], [21]. In contrast to iontophoresis, liposomes have gained remarkable attention as the small spherical vesicles which are composed of cholesterol and natural phospholipids. Owing to their ultra-small size, surface charge, high encapsulation efficiency, biocompatibility, biodegradability, and amphiphilic nature, liposomes are among the promising vesicular delivery systems for the target-specific delivery of the therapeutic payload [22], [23], [24], [25]. Ethosome is another novel vesicular delivery system which have demonstrated remarkable features concomitant to their high deformability. The pharmacological moieties can be transferred across the physicochemical barrier of the skin via ethosomal delivery system more efficiently than the traditional liposomes [26], [27], [28]. Ethosomes-based formulations have shown greater efficiency for the target-specific delivery of drugs into the epidermis and dermis compared to the liposomal formulations [38], [39], [40]. SLNs are another type of nanocarrier that improves transcutaneous absorption of therapeutics for the treatment of skin inflammatory diseases [29], [30], [31]. Small particle size and unique physicochemical properties of the SLNs play important roles in achieving site-specific delivery of the therapeutic payload [29], [30], [31]. SLNs cause greater improvement in the permeation of drugs across the SC and their longer retention into the epidermis and the dermis compared to the conventional delivery [30], [31]. Nanoemulsions have also been developed to overcome the problems of impaired penetration of drugs following the topical application. Despite the nanosized range, a special character of nanoemulsion is their positive charge which further facilitates the penetration of encapsulated drug molecules into the deeper layers of the skin [32]. The physicochemical interaction between positively charged nanoemulsion and negatively charged corneocytes of the SC result into enhanced transcutaneous permeation, longer retention time and improved bioavailability of drugs [33]. In recent years, polymeric NPs have also gained remarkable attention of the scientists both from academia and R&D sectors. The success of these nanocarriers is due to their ultra-small size, surface charge, high entrapment efficiency, biocompatibility and biodegradability [41], [42], [43]. In addition, these delivery systems can; (1) prevent the premature degradation of the labile compounds, (2) provide sustained delivery of the encapsulated drugs, (3) provide efficient triggered release of the therapeutic payload in response to change in pH, presence or absence of enzymes and other physiological stimuli [41], [42], [43], 4) increase localised delivery of the drugs and reduce their systemic toxicity, and 5) prevent off-target effect [26], [27], [28]. These novel delivery systems have also been proposed to augment percutaneous delivery of the drugs without permanent damage to the SC [44], [45].

Despite numerous pharmaceutical and therapeutic benefits, nanocarriers do have a lot of drawbacks and limitations [46]. For instance, small particle size and large surface area of the nanocarriers can cause particle agglomeration and making physical handling difficult. Nanocarrier-drug conjugates can also be phagocytosed by the immune guard cells whereas their intracellular degradation products may cause cytotoxic effects. Limitations to using nanocarrier-based delivery systems are also due to their low drug loading capacity and poor ability to control the size distribution index. Scarcity of technological facilities required for the development of nanocarriers of acceptable quality, also limit their utility. Despite these drawbacks and shortcoming, nanocarrier-mediated delivery systems attained remarkable recognition because of their tremendous advantages over the conventional delivery systems. The current review was therefore aimed to summarise the contents and evidence for the pharmaceutical and therapeutic advantages of the nanocarrier-mediated therapies in the treatment of atopic diseases. The therapeutic superiority of the nanocarrier-mediated systems in accomplishing site-specific delivery of drug, mitigating systemic toxicity, and to optimise therapeutic outcomes in the treatment of atopic diseases has been critically discussed.