Nanocarriers for Skin Applications: Where Do We Stand?

Abstract

Skin penetration of active molecules for treatment of diverse diseases is a major field of research owing to the advantages associated with the skin like easy accessibility, reduced systemic-derived side effects, and increased therapeutic efficacy. Despite these advantages, dermal drug delivery is generally challenging due to the low skin permeability of therapeutics. Although various methods have been developed to improve skin penetration and permeation of therapeutics, they are usually aggressive and could lead to irreversible damage to the stratum corneum. Nanosized carrier systems represent an alternative approach for current technologies, with minimal damage to the natural barrier function of skin. In this Review, the use of nanoparticles to deliver drug molecules, genetic material, and vaccines into the skin is discussed. In addition, nanotoxicology studies and the recent clinical development of nanoparticles are highlighted to shed light on their potential to undergo market translation.

Keywords: drug delivery; gene expression; nanoparticles; skin penetration; transdermal vaccination.

Figure 1

Simplified schematic illustration of the skin, the skin subdivisions, and the three main penetration pathways, i.e., intracellular, intercellular, and follicular.

Figure 2

Schematic illustration of the most commonly used drug nanocarriers, including liposomes, carbon nanotubes, hybrid nanoparticles, dendrimers, micelles, ionic‐liquid‐based nanoparticles, and polymeric nanogels.

Figure 3

Confocal laser scanning micrographs of porcine skin layers after 1 h incubation with: A) G2‐RITC‐NH₂, B) G2‐ RITC‐COOH, and C) G2‐RITC‐Ac. I) The dendrimer conjugates labeled with rhodamine B isothiocyanate (red); II)  cell membranes stained by WGA‐AF488 (green); III) nuclei stained by DAPI (blue); and IV) merged images. Scale bar: 10 μm. SC: stratum corneum; VE: viable epidermis; DE: dermal layer. Figure adapted with permission from ref. .

Figure 4

Images of protein and lipid distributions across skin samples that were treated with tNGs. The images were obtained with stimulated Raman spectromicroscopy (SRS), measured in stimulated Raman‐loss (SRL) detection mode. A) Fluorescence microscopy image of skin region for SRL (red frame), B) SRL spectra of SC and epidermis (meant is the viable epidermis), and C) optical transmission image (left); distributions of proteins (SRL 2934 cm⁻¹; middle) and lipids (SRL 2850 cm⁻¹; right). Figure adapted with permission from ref. .

Figure 5

Penetration of D₂O in human skin after 1000 min incubation. A–D) Stimulated Raman spectromicroscopy (SRS) images of D₂O (left), fluorescence image of Rhodamine B labeled nanocarriers (middle), and overlap with optical micrographs (right). SC is illustrated by the dashed lines. A) D₂O, B) SiO₂@NG + IR, C) NC − IR, and D) NC + IR; scale bar represents 10 μm. E) Nanocarrier penetration observed by fluorescence intensity. F) D₂O penetration as average from SRS measurements. Figure adapted with permission from ref. .

Figure 6

A) The VPTT and hydrodynamic size of PNIPAM‐co‐PNIPMAM NGs with weight proportion of PNIPMAM. B) Release efficiency of BSA‐FITC from PNIPAM‐co‐PNIPMAM? (1:1) NGs at different temperatures. C) Representative fluorescence images of intradermal BSA delivery by means of the natural thermal gradient (32–37 °C) and D) the corresponding analysis of the mean fluorescence intensity (MFI). E) Representative fluorescence images of intradermal BSA delivery using IR irradiation (25–42 °C) and F) their corresponding MFI analysis. Scale bars: 50 μm. Figure adapted with permission from ref. .

Figure 7

A) Differential permeation of DxPCA from NPs and cream in intact and barrier‐disrupted porcine ear skin. B) Release efficiency of DxPCA from NPs dispersion calculated by simulated EPR spectra under different pH conditions. C) Confocal laser scanning microscopy images of Nile red permeation through the hair follicles (a, b) and glabrous skin (c, d) from NPs (a, c) and cream (b, d). Figure adapted with permission from ref. .

Figure 8

A) Fluorescent microscopy images of siRNA complexed green fluorescently labelled liposomes permeation through the skin layers, a–d) liposome:siRNA complexes at different w/w ratios of siRNA and B) Fluorescent intensity quantification of lipoplexes in the skin. Data are reported as mean values±SD (n=3). Figure adapted with permission from ref. .

Figure 9

SHP/SiRNA nanocomplexes on topical application in melanoma xenograft‐bearing mice. A) Tumor size, B) survival rates of mice, C) H&E, Terminal‐deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) and survivin staining images of mice tumor tissues. Scale bar: 100 μm. Figure adapted with permission from ref. .

Figure 10

Pictorial presentation of transdermal delivery of pDNAs encoding the microRNA‐221 inhibitor gene (Mi221) using AuPT NPs towards treatment of cutaneous melanoma. Four different steps shown are: A) AuPT/Mi221 complex synthesis; B) AuPT/Mi221 topical application; C) penetration into melanoma, and D) gene transfection by AuPT/Mi221 into melanoma cells. Figure adapted with permission from ref. .

Figure 11

Distribution of antigen‐presenting cells (APCs) in skin layers and intradermal injection releasing a vaccine far from the Langerhans cells (LCs).

Figure 12

Characteristics of vaccination with different nanoparticle types.

Figure 13

Systemic humoral immune responses after 4 vaccinations in C57BL/6 mice (n=5). A) OVA‐specific IgG titer in sera after immunization. B) OVA‐specific IgG subclasses 12 days after the last immunization. C) Kinetic analysis of OVA‐specific IgG titer in sera of immunized mice on days 13, 27, 41, and 56. Figure adapted with permission from ref. .

Figure 14

Representative OVA immunohistochemistry (temperature map or red staining) of A) untreated skin biopsies or skin biopsies treated with OVA in B) phosphate‐buffered saline (PBS), C) hydrogels, D) PVCL NGs, or E) film‐forming NGs. Dermal–epidermal boundary is marked by dashed yellow lines. Overlays show OVA staining (red), DAPI staining (blue), and bright field images (gray). Scale bars=50 μm. Figure adapted with permission from ref. .

Figure 15

Photographic images of two examples, before and after patient treatment with FLZ‐SLNs materials. A) Before treatment, B) after 4 weeks treatment, C) before treatment, and D) after 4 weeks of treatment. Figure adapted with permission from ref. .