Polypeptide-corticosteroid conjugates as a topical treatment approach to psoriasis
Graphical abstract
Introduction
The skin is the largest and most physiologically complex organ of the human body, creating a barrier between the host and the external environment [1]. Skin barrier integrity is essential for the protection of the whole body; any dysfunction can enhance the risk of developing infective and inflammatory disorders [2], such as psoriasis [3].
Psoriasis is a common inflammatory chronic disease mediated by the immune system with a predominantly cutaneous involvement [4]. There are several clinical phenotypes of psoriasis that are classified based on the characteristics of the disease, including patient age at disease onset, degree of skin involvement, morphologic pattern, and anatomical location [5]. Scaly skin, erythematous plaques, and inflammatory cell infiltration characterize plaque psoriasis, the most prevalent type of psoriasis [6,7]. In recent years, the immune response involved in the onset of the disease has been extensively investigated, uncovering the relative importance of the Interleukin (IL)-23/IL-17 axis [7,8]. The current development of anti-psoriatic therapeutics, mainly IL-17 and IL-23 inhibitors, focuses on systemic treatments that target the immune system [8]. However, topical treatment with corticosteroids remains one of the most widely employed treatments for the approximately 80% of patients affected with mild to moderate psoriasis [9]. Corticosteroids induce anti-inflammatory, antiproliferative, immunosuppressive, and vasoconstrictive effects through binding to intracellular corticosteroid receptors and the modulation of pro-inflammatory cytokine gene transcription [10].
However, many topical corticosteroids that are currently employed or under assessment in clinical trials still require improvements to their physico-chemical properties to promote skin penetration (e.g., solubility in water) and suffer from local cutaneous (e.g., skin atrophy, acne) and systemic side effects (e.g., osteoporosis, diabetes, weight gain) that limit their clinical use [11]. These effects mainly correlate with the high doses required and the elevated frequency of applications, and have been noted for both high and reduced potency corticosteroids. Therefore, any advanced therapeutic approaches that allow a reduction in dose and the avoidance of systemic circulation of corticosteroids could significantly enhance treatment efficacy and patient compliance.
The application of nanomedicines as advanced therapeutics in the field of topical and transdermal delivery of active compounds [[12], [13], [14], [15], [16]] and immunotherapy [17] is currently in exponential growth. Liposomes have been the most used carriers for skin delivery, although their large sizes and heterogeneous size distribution limit their efficiency when acting as skin permeation enhancers [18,19]. The application of controlled polymerization techniques and the tailoring of critical nanocarrier parameters, such as size and Z-potential, can significantly enhance the penetration of active substances into the skin, as has been demonstrated for polypeptide-based nanostructures [20,21]. Furthermore, the mode of the drug encapsulation/entrapment [22] or polypeptide carrier-conjugation [23,24] has a significant influence on the site of drug release and the kinetic profile of drug release. Although currently underexplored for skin delivery, a rationally-designed bioresponsive linker can optimize the therapeutic output of topical treatment by enhancing efficiency and reducing side effects [25,26]. Finally, the vehicle used for the administration of a given therapeutic may also have an essential synergistic effect; formulations with an optimal interaction between the vehicle and the therapeutic agent can enhance penetration and hydration of the skin [27].
We aimed to potentiate the therapeutic capacity of the topical corticosteroid fluocinolone acetonide (FLUO) as a local cutaneous treatment for psoriasis by enhancing its skin permeation and controlling drug release within the epidermis. We proposed the conjugation of FLUO to a biodegradable poly-L-glutamic acid (PGA) carrier via a pH-responsive ester linker, and we now report the synthesis, physico-chemical characterization, and in vitro, ex vivo, and in vivo evaluation of PGA-FLUO for the topical controlled delivery of FLUO. We discovered that this strategy enhanced FLUO skin penetration and provided more significant inhibition of local skin inflammation, and established that the formulation of PGA-FLUO within a hyaluronic acid-poly-L-glutamate cross polymer vehicle (HA-CP; Yalic© [28], previously described as a penetration enhancer [29]) increased the permeation and residence of PGA-FLUO in deeper skin layers.
Overall, our results suggest that our new polypeptide-conjugated corticosteroid approach to the topical treatment of psoriasis can provide for enhanced patient outcomes.
Section snippets
Materials and methods
The materials and physico-chemical characterization methods employed to fully characterize PGA-FLUO can be found in Supplementary Information (SI).
Synthesis and characterization of the poly-L-glutamate-Fluocinolone acetonide conjugate
We aimed to conjugate the poorly water-soluble corticosteroid FLUO to a water-soluble PGA carrier via an ester bond, aiming to improve FLUO bioavailability after topical administration in the skin while also providing a modulated release rate of FLUO in a specific skin layer. We chose PGA based on its successful application in the synthesis of polymer-drug conjugates in terms of cargo loading capacity through the multifunctional carboxylic acid backbone [23], elevated biodegradability of the
Conclusions
Herein, we have demonstrated that the polypeptide conjugation of a corticosteroid used for the topical treatment of psoriasis (PGA-FLUO) provides a significant improvement in the pharmacological activity due to greater bioavailability in the require skin layer. Polypeptide conjugation may contribute to improve the penetration and drug exposure, thereby increasing the amount of corticosteroid in the viable epidermis, and therefore, increasing the effectiveness of the treatment. An adequate drug
Acknowledgements
The authors would like to thank Dr. Stuart P. Atkinson for English revision. This work has been supported by Spanish Ministry of Science, Innovation and Universities (RTC-2017-6465-1 and D.M-B, Grant Industrial PhD DI-14-06926), Generalitat Valenciana (I.DP, Grant VALi+d ACIF-2016-021 and BEFPI/2018/055) and Science development and technology fund - Egypt (STDF grant no. 12362). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with FEDER
Author contributions
- Conception and design: V.J.N, M.J.V.
- Synthesis and characterization of the polymer-drug conjugates: I.DP.
- Ex vivo and In vivo experiments optimization and development: I.DP., E.M., D.M-B., MS, DA, PG.
- Analysis and interpretation of data: I.DP., E.M., V.J.N, M.J.V.
- Writing, review, and/or revision of the manuscript: I.DP., S.H., M.S., V.J.N., M.J.V.
- Study supervision: V.J.N, M.J.V.
Declaration of Competing Interest
D.M-B., V.J.N., and M.J.V. declare that a patent with reference WO2019020344 (A1) has been filed related to the present work.
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