Non‐porous Versus Mesoporous Polydopamine Nanoparticles For The Skin Delivery Of Retinoic Acid

Objectives: In recent years,self-assembling materials based on polydopamine have attracted much attention due to their convenient preparation and wide range of applications,which provide a new platform for researches in drug delivery.However,the possibility of topical application of polydopamine nanoparticles in the skin,as well as their interaction with the skin remains to be fully studied.In this study,retinoic acid(RA)was used as a model drug to systematically investigate the feasibility of non-porous polydopamine(PDA)and mesoporous polydopamine(m PDA)nanoparticles for topical skin delivery.Methods: PDA and m PDA nanoparticles were respectively prepared by solution oxidation and soft template methods.Transmission electron microscope,scanning electron microscope,ultraviolet visible near-infrared spectroscopy,Fourier transform infrared spectroscopy,as well as nitrogen adsorption and desorption experiments were used to observe the morphology,chemical composition,and other structural information of PDA and m PDA.Using RA as model drug,uniform and stable PDA-RA and m PDA-RA were obtained by prescription screening and process optimization.Based on the optimized preparations,the drug loading capacity,in vitro drug release,free radical scavenging ability,physical stability,and their influence on drug photostability were investigated.The effects of PDA-RA and m PDA-RA on local skin delivery were evaluated by modified Franz diffusion cells using isolated SD rats and miniature pigs as skin models.Laser confocal microscopy(LSCM)and hematoxylin-eosin(HE)staining were used to observe their skin delivery route and the interaction with the skin.Results: PDA and m PDA with particle size of 343.9 ± 1.5 nm and 208.1 ± 12.6 nm were successfully prepared.The particle size and morphology of PDA and m PDA were uniform,and m PDA had clear mesoporous structure.m PDA had a higher drug loading capacity than PDA,and the encapsulation efficiency was also ideal,which could meet the quality requirements of the preparation.The results of free radical scavenging test showed that PDA and m PDA had high scavenging ability towards DPPH and OH free radicals,in which the scavenging rate showed a positive correlation with the concentration of PDA and m PDA,and the scavenging ability of m PDA was more significant.Besides that,PDA-RA and m PDA-RA nanoparticles significantly enhanced DPPH and OH radical scavenging compared with RA(P < 0.05).The drug photostability of the preparation was significantly higher than that of in the drug solution(P < 0.05).The skin penetration results of two different skin models showed that the retention of PDA-RA and m PDA-RA in each skin layer was significantly higher than that in the control group(P > 0.05).For the in vitro SD rat skin model,the greatest drug retention from the preparation group(m PDARA300nm)was 15.57 ± 3.59 μg/g for the stratum corneum and 20.81 ± 2.07 μg/g for the remaining skin layer,which were 4.15 times and 5.62 times of those from the control group,respectively.For the in vitro miniature pig skin model,the drug retention of the preparation group(m PDA-RA500nm)in the stratum corneum,epidermis and dermis were 10.92 ±1.15 μg/g,45.46 ± 13.18 μg/g and 1.79 ± 0.10 μg/g,respectively,which were 3.79 times,8.27 times and 5.11 times of the control group,respectively.The nanoparticles improved the deep skin delivery of drugs without increasing the risk of drugs entering the systemic blood circulation,and had good dermal drug delivery characteristics.LSCM and HE staining results showed that PDA and m PDA specifically delivered drugs into the deep skin through the follicular pathway and the space between keratinocytes.After topical application,the dense structure of the stratum corneum was thinned and the barrier function of the stratum corneum was weakened.Conclusion: This study demonstrated the feasibility and application prospect of PDA and m PDA nanoparticles for skin drug delivery,and provided practical evidence and ideas for their application in other fields.Based on the drug loading capacity,physical stability,and free radical scavenging activity,m PDA is a more ideal candidate for skin drug delivery.