Comparison of normal versus imiquimod-induced psoriatic skin in mice for penetration of drugs and nanoparticles

Lin Sun,1,2 Zeyu Liu,1 Zibei Lin,1 Dongmei Cun,3 Henry HY Tong,4 Ru Yan,1 Ruibing Wang,1 Ying Zheng1 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao Special Administrative Region, People’s Republic of China; 2Department of Pharmaceutical Sciences, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, 519041, People’s Republic of China; 3Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People’s Republic of China; 4School of Health Sciences, Macao Polytechnic Institute, Macao Special Administrative Region, People’s Republic of China Background: As an immune-mediated skin disease, psoriasis encounters therapeutic challenges on topical drug development due to the unclear mechanism, and complicated morphological and physiological changes in the skin. Methods: In this study, imiquimod-induced psoriatic mouse skin (IMQ-psoriatic skin) was chosen as the in vitro pathological model to explore the penetration behaviors of drugs and nanoparticles (NPs). Results: Compared with normal skin, significantly higher penetration and skin accumulation were observed in IMQ-psoriatic skin for all the three model drugs. When poorly water-soluble curcumin was formulated as NPs that were subsequently loaded in gel, the drug’s penetration and accumulation in both normal and IMQ-psoriatic skins were significantly improved, in comparison with that of the curcumin suspension. Interestingly, the NPs’ size effect, in terms of their penetration and accumulation behaviors, was more pronounced for IMQ-psoriatic skin. Furthermore, by taking three sized FluoSpheres® as model NPs, confocal laser scanning microscopy demonstrated that the penetration pathways of NPs no longer followed the hair follicles channels, instead they were more widely distributed in the IMQ-psoriatic skin. Conclusion: In conclusion, the alternation of the IMQ-psoriatic skin structure will lead to the enhanced penetration of drug and NPs, and should be considered in topical drug formulation and further clinical practice for psoriasis therapy. Keywords: imiquimod-induced psoriatic skin, pathological model, topical delivery, penetration, nanoparticle

Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ

The alternative non-homologous end-joining (NHEJ) pathway promotes DNA double-strand break (DSB) repair in cells deficient for NHEJ or homologous recombination, suggesting that it operates at all stages of the cell cycle. Here, we use an approach in which DNA breaks can be induced in G1 cells and their repair tracked, enabling us to show that joining of DSBs is not functional in G1-arrested XRCC4-deficient cells. Cell cycle entry into S-G2/M restores DSB repair by Pol θ-dependent and PARP1-independent alternative NHEJ with repair products bearing kilo-base long DNA end resection, micro-homologies and chromosome translocations. We identify a synthetic lethal interaction between XRCC4 and Pol θ under conditions of G1 DSBs, associated with accumulation of unresolved DNA ends in S-G2/M. Collectively, our results support the conclusion that the repair of G1 DSBs progressing to S-G2/M by alternative NHEJ drives genomic instability and represent an attractive target for future DNA repair-based cancer therapies