Hollow copper sulfide nanoparticle-mediated transdermal drug delivery

Abstract

A photothermal ablation-enhanced transdermal drug delivery methodology is developed based on hollow copper sulfide nanoparticles (HCuSNPs) with intense photothermal coupling effects. Application of nanosecond-pulsed near-infrared laser allows rapid heating of the nanoparticles and instantaneous heat conduction. This provides very short periods of time but extremely high temperatures in local regions, with focused thermal ablation of the stratum corneum. The depth of skin perforations can be controlled by adjusting the laser power. Skin disruption by HCuSNP-mediated photothermal ablation significantly increases the permeability of human growth hormone. This technique offers compelling opportunities for macromolecular drug and vaccine delivery.

Figure 1

A) Transmission electron micrograph of HCuSNPs. B) Experimental absorbance spectrum of HCuSNPs in water. Bar, 50 nm.

Figure 2

A) Thermographic images of nude mice under the NIR laser treatment. Nude mice received 50 μL of gel with or without HCuSNPs followed by NIR laser irradiation. Arrows, skin area treated with gel and laser. B) Plots of average temperature in the laser-shining area as a function of irradiation time.

Figure 3

H&E staining of the skin sections from the anesthetic nude mice pretreated with A) HCuSNP gel, B) blank gel plus laser (2.6 W/cm²), C) HCuSNP gel plus laser (1.3 W/cm²), D) HCuSNP gel plus laser (2.6 W/cm²), E) HCuSNP solution plus laser (1.3 W/cm²), or F) HCuSNP solution plus laser (2.6 W/cm²). Asterisks, epidermis without stratum corneum; Arrowheads, stratum corneum layers stripped from epidermis; Arrows, dermis with removal of both stratum corneum and viable epidermis. Bars, 50 μm.

Figure 4

Representative Nile red staining of the skin sections from the anesthetic nude mice pretreated with A) HCuSNP gel, B) blank gel plus laser (2.6 W/cm²), C) HCuSNP gel plus laser (1.3 W/cm²), or D) HCuSNP gel plus laser (2.6 W/cm²). EP, epidermis; SC, stratum corneum; Arrowheads, epidermis without stratum corneum; Asterisk, densely packed stratum corneum; Arrow, loss of epidermis. Inner graphs are the enlargement of the stratum corneum area. Bars, A) and B) 10 μm; C) and D) 20 μm.

Figure 5

Fluorescence micrographs of the dextran-FITC (MW 20 k)-applied skin sections from the anesthetic nude mice pretreated with A) HCuSNP gel, B) blank gel plus laser (2.6 W/cm²), C) HCuSNP gel plus laser (1.3 W/cm²), or D) HCuSNP gel plus laser (2.6 W/cm²). EP, epidermis; DM, dermis; Asterisks, stratum corneum; Arrow, loss of epidermis. Bar, 100 μm.

Figure 6

A) Cumulative delivery of hGH solution across nude mouse skin pretreated with HCuSNP gel alone, laser alone, or HCuSNP gel with laser. “Untreated” group, the intact skin without pretreatment. “5% Azone” group, hGH solution containing 5% Azone was applied to the intact skin without pretreatment. Each value represents Mean ± S.D. (n=5). B) hGH levels in serum after s.c. injection or transdermal delivery with different pretreatment, at a dose of 10 μg hGH. For transdermal delivery, hGH gel was applied to the skin for 3 h starting at time 0. In “5% Azone” group, hGH gel containing 5% Azone was directly applied to the intact mice skin without pretreatment. Each data point represents the mean ± SD of 3 nude mice.

Figure 7

A) Ear swelling as a result of topical application of different agents through measurement of the increase of thickness of ear pinnae before and after treatment. Bars represent Mean ± SD of five mice (10 ears) per group. **, p < 0.01 as compared to other groups. B) Representative histology of ear skin following different treatment by H&E staining. Top side was the application site. Arrow represents area of dermatitis, i.e. squamous cell hyperplasia and polymorphonuclear cell infiltration at the application site. Bar, 100 μm.

Scheme 1

Illustration of NIR laser-triggered photothermal ablation of skin mediated by HCuSNPs.