Advanced nanocarrier- and microneedle-based transdermal drug delivery strategies for skin diseases treatment

Abstract

Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, acting as a global burden and affecting the world economy. Skin diseases severely impact the patients' quality of life and have influenced their physical and mental state. Treatment of these skin disorders with conventional methods shows a lack of therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic side effects due to improper drug delivery. However, these pitfalls can be overcome with the applications of advanced nanocarrier- and microneedle (MN)-based transdermal drug delivery strategies that provide efficient site-specific drug delivery at the target site. These advanced transdermal drug delivery strategies can be more effective than other drug administration routes by avoiding first-pass metabolism, enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. Compared with traditional transdermal delivery methods, nanocarrier- or MN-based drug delivery systems are painless, noninvasive, or minimum-invasive and require no expensive equipment. More importantly, they can introduce more advanced functions, including increased skin penetration efficiency, controlled drug release rates, enhanced targeting abilities, and theranostic functions. Here, the emergence of versatile advanced transdermal drug delivery systems for the transdermal delivery of various drugs is reviewed, focusing on the design principles, advantages, and considerations of nanocarrier- and MN-based transdermal drug delivery strategies and their applications in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery strategies for treating dermatological disorders are summarized.

Keywords: Microneedles; Nanocarriers; Skin diseases; Stratum corneum; Transdermal drug delivery.

Figure 1

Four categories of design principles based on nanocarrier and MN delivery systems with their representative examples.

Figure 2

Skin distribution of NPs. (A) Confocal laser scanning microscopy images (100×) of skin samples treated with free coumarin-6, coumarin-6/nanostructured lipid carries (NLC), and coumarin-6/SLN. (B) Histopathological photomicrographs (200×) of skin treated with (i) normal saline; (ii) Blank-NLC; (iii) Blank-SLN; (iv) TPL-NLC; (v) TPL-SLN. (C) The differential scanning calorimetry (DSC) thermograms of skin tissue were treated with normal saline, Blank-NLC, Blank-SLN, TPL-NLC, and TPL-SLN. Adapted with permission from reference . Copyright 2018 Springer Nature.

Figure 3

Confocal laser scanning microscopy images of the skin cross-sections of microtomed porcine skin layers after treatment with dendrimers. (A) Vehicle (ddH₂O) control. (B) G4-RITC-NH₂. (C) G2-RITC-NH₂. (dendrimer conjugates (red), cell membrane stained by WGA-AF488 (green), and nuclei stained by DAPI (blue)). Scale bar: 10 μm. Adapted with permission from reference . Copyright 2012 American Chemical Society.

Figure 4

(A) Confocal laser scanning microscopy image (200×) of curcumin fluorescence in frozen psoriasis-like mouse skin sections and (B) drug skin retention detected by HPLC (n=5) after treatment with the various curcumin formulations for 8 h. (C) The immunofluorescence images (200×) and (D) semi-quantitative analysis (n=5) show the distribution of CD44 expression in psoriasis-like and normal mouse skin. *p < 0.05, **p < 0.01, ***p < 0.001. Normal, mice treated without any formulations; Model, treated with IMQ only; HA, hyaluronic acid; HA-ES, curcumin-loaded HA-modified ethosomes; ES, curcumin-loaded ethosomes; PGS, curcumin 25% propylene glycol solution; IMQ, imiquimod ointment; IF, immunofluorescence. Adapted with permission from reference . Copyright 2019 Ivyspring International Publisher.

Figure 5

Cell penetration of SPACE-EGF and SPACE-EGF-siRNA. (A-D) Cells were treated for 6 h with PBS, SPACE, EGF, and SPACE-EGF, respectively. (E-F) Cells were incubated for 6 h with siRNA, siRNA-SPACE, siRNA-EGF, and siRNA-SPACE-EGF, respectively. (I, J) The mean fluorescence intensities in melanoma cells after 6 h were compared. SPACE was also labeled fluorescently. Scale bar: 20 μm. Adapted with permission from reference . Copyright 2016 Springer Nature.

Figure 6

Schematic illustration of fabrication and administration of BSP-MNs-QUE@HSF/CDF for topical anti-hypertrophic scar treatment. Adapted with permission from reference . Copyright 2021 American Chemical Society.

Figure 7

Schematic illustration of an HA-based DMN patch loaded with MTX to improve the treatment of psoriasis. Adapted with permission from reference . Copyright 2019 American Chemical Society.

Figure 8

(A) Schematic illustration of the preparation and application of PTX-CTs/Gel as a paintable patch for topical drug delivery. (B) Schematic illustration of enhancement on the transdermal efficiency of PTX by the PTX-CTs/Gel for noninvasive chemotherapy of melanoma. Adapted with permission from reference . Copyright 2018 American Chemical Society.

Figure 9

Schematic illustration showing drug/AuNC-loaded dissolving HA DMN system for the combination of chemotherapy and PTT of treating melanoma. Adapted with permission from reference . Copyright 2018 American Chemical Society.

Figure 10

Characterization of the MNs. (A) Scanning electron microscopy images showing the morphology of the MNs. (B) Drug distribution in the tip of the needle was illustrated by methylene blue. (C) Fluorescence microscopy images of the MNs with fluorescein isothiocyanate isomer (FITC) as a tracer reagent. Adapted with permission from reference . Copyright 2021 Multidisciplinary Digital Publishing Institute.

Figure 11

Schematic illustration of the preparation and functional mechanism of OSA-EV nanospheres. Adapted with permission from reference . Copyright 2020 Ivyspring International Publisher.

Figure 12

Schematic illustration of AGA therapy through a ceria nanozyme (CeNZ)-integrated MNs (Ce-MNs) patch. (A) Fabrication of Ce-MNs. After modification by DSPE-mPEG₂₀₀₀, the CeNZs are encapsulated in the HA-based MNs. The backing layer of the patch is made of PVP-K90. (B) Five minutes after the Ce-MNs are applied to the skin, the PVP patch backing could be detached from the MNs. CeNZs can be delivered into the dermis and epidermis directly to scavenge excessive ROS. The mechanical stimulation induced by the administration of Ce-MNs can remodel the microvasculature in the perifollicular microenvironment. (C) Subsequently, the hostile oxidative microenvironment around the hair follicles is reshaped and angiogenesis is promoted by Ce-MNs, resulting in a fast onset of telogen-to-anagen transition of hair follicles. Adapted with permission from reference . Copyright 2021 American Chemical Society.