Laser-assisted nanoparticle delivery to promote skin absorption and penetration depth of retinoic acid with the aim for treating photoaging
Graphical abstract
Introduction
The aging sign of skin offers the first mark of the passing time, caused by intrinsic or extrinsic factors. Skin exposure to ultraviolet (UV) irradiation from sunlight is the main source (90 %) of extrinsic factors. The photoaging induced by UV produces DNA and reactive oxygen species (ROS) generation, resulting in increased matrix metalloproteinases (MMPs) and collagen degradation (Lee et al., 2021a, Lee et al., 2014, Lee et al., 2019, Lee et al., 2021b). Photoaged skin shows the appearance of wrinkling, sagging, laxity, discoloration, and roughness. In addition to photodamage on the skin, the aging appearance causes an emotional and psychological impact, reducing life quality (Campione et al., 2021). The topical treatment of retinoic acid (RA), a vitamin A metabolite, is approved for the application of anti-photoaging therapy to mitigate wrinkles, skin damage, and elasticity loss (Spierings, 2021). RA is verified to have the bioactivities of cell differentiation, embryonic development, immune response modulation, and homeostasis of epithelial tissue (de Mendonça Oliveira et al., 2018). Through the RA receptor- and retinoid X receptor-mediated gene activation, RA increases epidermal thickness and inhibits wrinkling via MMP-1 suppression and type I collagen increase in photoaged skin. RA is extensively used to treat skin disorders including psoriasis, acne, ichthyosis, cutaneous cancer, and photoaging (Szymański et al., 2020). Although topical RA is best applied to dermatology, the drawbacks of this drug are the photochemical degradation and cutaneous irritation, such as peeling, erythema, and xerosis (Ferreira et al., 2020). The poor stratum corneum (SC) penetration and insufficient bioavailability in the dermis also restrain the successful therapeutic efficacy of RA (Limcharoen et al., 2020).
The drug delivery into the skin can be enhanced by ablative approaches, such as microneedles, radiofrequency, and laser irradiation (Hsiao et al., 2019). Among these, laser-assisted drug delivery improves dermal bioavailability to accomplish a greater therapeutic effect (Wenande et al., 2020). Ablative lasers partially or completely remove SC and disintegrate skin structure to promote drug permeation. Fractional lasers create an array of microchannels to bypass the SC barrier. The advantages of laser-assisted delivery include the precise control of ablative skin depth with minor cross-contamination risk compared to microneedles and direct SC stripping (Garvíe-Cook et al., 2016). Although the lasers are highly efficient in reducing the cutaneous barriers to enhance drug absorption, the subsequent intracellular drug entrance for exhibiting pharmacological activities is still challenging. Furthermore, conventional vehicles for RA are limited due to poor aqueous solubility, storage instability, and skin damage (Morales et al., 2015). Nanoparticles can be ideal carriers for RA to avoid photochemical degradation and elevate RA internalization into the target cells. The topically applied nanocarriers show the possibility to largely accumulate in the skin, improving the delivery efficiency of the drugs (Carter et al., 2019). The transport of intact nanoparticles into the skin is difficult. Previous studies (Charoenputtakun et al., 2014, Ogunjimi et al., 2021) demonstrate that no intact RA-loaded nanoparticles diffuse into the skin. As evidenced by Bellefroid et al. (2019), the permeation of nanoparticles can only be detected after SC removal. Effective photoaging treatment by RA demands the skin barrier elimination and the facile entrance into the cells. We aimed to investigate the effect of laser-assisted nanoparticle delivery for facile and deeper RA penetration. In particular, a cell-based model estimated the anti-photoaging activity of the nanocarriers.
The most commonly used ablative lasers for drug delivery enhancement are erbium:yttrium-aluminum-garnet (Er:YAG) and CO2 modalities (Haedersdal et al., 2016). In this study, the full-ablative Er:YAG and fractional-ablative CO2 lasers were employed to appraise the laser-mediated transport of RA-loaded nanoparticles. We used poly-l-lactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) as the main materials to produce polymer-based nanocarriers for entrapping RA. Both polymers are approved by USUDA as biocompatible and biodegradable materials with easy surface modification, targeting capability, good stability, and controlled drug leakage (Qi et al., 2019). The animal-based study for drug tests is a matter of controversy concerning animal sentience. The 3R rule (replacement, reduction, and refinement) about animal welfare is globally accepted as the ethical framework when the animal experiment is conducted. For replacement and reduction, the application of in vitro model as the substitution for in vivo study can be cheaper and faster than the animal model (Hubrecht and Carter, 2019). For these reasons, we reduced the animals used in this work. Instead, the in vitro cell study was performed for the evaluation of anti-photoaging efficacy of the nanocarriers. The in vivo anti-photoaging activity was anticipated by calculating the therapeutic index (TI) based on the multiplication of collagen/elastin inhibition percentage in dermal fibroblasts and in vitro RA absorption amount. We only used 24 nude mice to examine the tolerance of nanocarriers on skin. It was because that the real test of the topical drug formulation on skin is still required to explore the cutaneous irritation. The cell-based study is difficult to understand the authentic skin safety of the drug in the clinical condition until now.
Section snippets
Materials
RA, PLA, polyvinyl alcohol (PVA), Nile red, rhodamine B, and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) agent were purchased from Sigma-Aldrich (St. Louis, MO, USA). PLGA (lactide:glycolide = 1:1) was provided by Green Square Materials (Taoyuan, Taiwan). 4′,6-Diamidino-2-phenylindole (DAPI) was obtained from ThermoFisher (Waltham, MA, USA). The anti-collagen I, anti-elastin, and anti-MMP-1 antibodies were purchased from Bioss (Woburn, MA, USA). The secondary anti-rabbit
Physicochemical characterization of the RA-loaded nanoparticles
The polymer-based nanocarriers were fabricated by the emulsion solvent evaporation method. PLA (100 %) nanoparticles were successfully prepared with a mean size of 237 nm obtained from the dynamic laser scattering assay (Table 1). After PLGA incorporation in nanoparticles (PLA/PLGA:3:7), the average diameter (222 nm) was somewhat smaller than that of PLA nanoparticles. The PDI obtained was <0.1, indicating a very narrow size distribution of the nanosystems. The surface charge of PLA and
Discussion
An ideal RA therapy for treating cutaneous photoaging should have an efficient RA transport into the skin, avoidance of RA degradation, and facile RA uptake into the target cells. We investigated the outcomes of ablative laser-assisted delivery of topical RA nanoparticles to treat photoaging. The skin absorption data reported an enhanced RA delivery in the deeper skin strata, achieved by combining the ablative lasers with RA formulated in the polymer-based nanoparticles. Further, we
Conclusions
Our study suggested the possible applicability and safety of laser-assisted nanoparticle delivery for the treatment of skin photoaging. We provided evidence proving that laser-assisted delivery of RA-loaded nanoparticles could be an effective system to facilitate dermal absorption and follicular accumulation. Limited toxicity was found upon nanoparticle internalization by human dermal fibroblasts. The nanocarriers not only reversed the UVA-induced reduction of type I collagen and elastin but
CRediT authorship contribution statement
Woan-Ruoh Lee: Conceptualization, Writing – original draft. Tse-Hung Huang: Investigation, Data curation, Methodology. Sindy Hu: Project administration, Methodology, Formal analysis. Ahmed Alalaiwe: Investigation, Resources. Pei-Wen Wang: Formal analysis, Data curation. Pei-Chi Lo: Methodology, Formal analysis. Jia-You Fang: Funding acquisition, Supervision, Writing – review & editing. Shih-Chun Yang: Conceptualization, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Funding of this work was provided by Ministry of Science and Technology of Taiwan (MOST-110-2330-B-182-011-MY3) and Chang Gung Memorial Hospital (CMRPG2L0111).
Disclosure statement
The authors declare no competing interests.
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