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Xiang Li,1,2,* Shu-Jie An,3,* Xiao-Ling Liu,1,* Ai-Ling Ji,4 Yi Cao,5 Ying Xiang,1 Xiang-Yu Ma,1 Qin Hu,1 Zhi-Quan Yuan,1 Ya-Fei Li,1 Yuan-Gang Lu,2 Tong-Jian Cai1 1Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China; 2Department of Plastic & Cosmetic Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China; 3Medical Department, Xijing Hospital, Air Force Medical University (Fourth Military Medical University), Xi’an, People’s Republic of China; 4Department of Preventive Medicine & Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing, People’s Republic of China; 5Department of Health Economics Management, Xijing Hospital, Air Force Medical University (Fourth Military Medical University), Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan-Gang LuDepartment of Plastic & Cosmetic Surgery, Daping Hospital, Army Medical University, 10 Changjiang Branch Road, Daping, Chongqing, 400042, People’s Republic of ChinaTel +86-23-68757597Fax +86-23-68757596Email skin515@163.comTong-Jian Cai Email ctjcsl@fmmu.edu.cnBackground: Post-adolescent acne is a common skin disease faced by adults. However, whether air pollution (AP) serves as a risk factor for post-adolescent acne remains elusive.Aim: To determine the relationship between short-term AP exposure (within 7 days) and outpatient visits for post-adolescent acne.Methods: Daily outpatient visit data for post-adolescent acne and routinely AP data between 2010 and 2013 were collected from Xi’an, China. A generalized additive regression model was used to analyze the relationship between outpatient visits for post-adolescent acne and short-term ambient AP exposure. The gender-specific analyses were conducted as well.Results: Totally, 27,190 outpatient visits for post-adolescent acne were included. The results revealed that a 10 μg/m3 increase in PM10, SO2, and NO2 at lag 0– 7 day was associated with the increase of outpatient visits for post-adolescent acne at 0.84% (95% CI: 0.53%, 1.16%), 1.61% (95% CI: 0.12%, 3.10%), and 3.50% (95% CI: 1.60%, 5.40%), respectively. The significant positive associations of PM10, SO2, and NO2 were found at both single-lag models and moving average models. The gender-specific analyses showed that the effect estimates of PM10 was stronger for females than for males, while there was no observed gender difference in the effects of SO2 and NO2.Conclusion: Short-term exposure to AP was associated with increased outpatient visits for post-adolescent acne, especially for females in the effects of PM10.Keywords: short-term, air pollution, post-adolescent acne, adult acne, time-series analysis

Wei-liang Chen,1 Fang Li,1 Yan Tang,1 Shu-di Yang,1 Ji-zhao Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Xiao-feng Zhou,2 Chun Liu,3 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Ultrasound, Changshu Hospital of Traditional Chinese Medicine, Changshu, 3Department of Pharmacy, The Hospital of Suzhou People’s Hospital Affiliated to Nanjing Medical University, Suzhou, People’s Republic of China Abstract: Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents. Keywords: stepwise pH-responsive, charge reversal, on-demand drug release, efficient delivery

Wen-jing Zhu,1,* Shu-di Yang,1,* Chen-xi Qu,1 Qiao-ling Zhu,1,2 Wei-liang Chen,1 Fang Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Ben-gang You,1 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Clinical Medicine, Nanjing Gulou Hospital, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein–N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy. Keywords: multidrug resistance, micelle, co-delivery, environmentally sensitive, tumor targeting

Wei-liang Chen,1,* Zhi-Qiang Yuan,1,* Yang Liu,1 Shu-di Yang,1 Chun-ge Zhang,1 Ji-zhao Li,1 Wen-jing Zhu,1 Fang Li,1 Xiao-feng Zhou,2,3 Yi-mei Lin,4 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, 2Department of Radiobiology, College of Radiological Medicine and Protection, Soochow University, Suzhou, 3Changshu Hospital of Traditional Chinese Medicine, Changshu, 4The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China *These authors contributed equally to this work Abstract: In this study, harmine liposomes (HM-lip) were prepared through the thin-film hydration–pH-gradient method and then coated with N-trimethyl chitosan (TMC). Particle size, zeta potential, entrapment efficiency, and in vitro release of HM-lip and TMC-coated harmine liposomes (TMC-HM-lip) were also determined. Sprague Dawley rats were further used to investigate the pharmacokinetics in vivo. Retention behavior in mouse gastrointestinal tract (GIT) was studied through high-performance liquid chromatography and near-infrared imaging. Degradation was further evaluated through incubation with Caco-2 cell homogenates, and a Caco-2 monolayer cell model was used to investigate the uptake and transport of drugs. HM-lip and TMC-HM-lip with particle size of 150–170 nm, an entrapment efficiency of about 81%, and a zeta potential of negative and positive, respectively, were prepared. The release of HM from HM-lip and TMC-HM-lip was slower than that from HM solution and was sensitive to pH. TMC-HM-lip exhibited higher oral bioavailability and had prolonged retention time in GIT. HM-lip and TMC-HM-lip could also protect HM against degradation in Caco-2 cell homogenates. The uptake amount of TMC-HM-lip was higher than that of HM and HM-lip. TMC-HM-lip further demonstrated higher apparent permeability coefficient (Papp) from the apical to the basolateral side than HM and HM-lip because of its higher uptake and capability to open tight junctions in the cell monolayers. TMC-HM-lip can prolong the retention time in the GIT, protect HM against enzyme degradation, and improve transport across Caco-2 cell monolayers, thus enhancing the oral bioavailability of HM. Keywords: harmine, liposomes, TMC, bioavailability, Caco-2 cell

Chun-ge Zhang,*,1 Qiao-ling Zhu,*,1 Yi Zhou,*,1,2 Yang Liu,1 Wei-liang Chen,1 Zhi-Qiang Yuan,1 Shu-di Yang,1 Xiao-feng Zhou,3,4 Ai-jun Zhu,1 Xue-nong Zhang,*,1 Yong Jin*,5 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2The Children's Hospital of Wuxi People's Hospital, Nanjing Medical University, Wuxi, 3College of Radiological Medicine and Protection, Soochow University, Suzhou, 4Changshu Hospital of Traditional Chinese Medicine, Changshu, 5Invasive Technology Department, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China *These authors contributed equally to this work Abstract: N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor. Keywords: liver cancer, targeting efficacy, antitumor activity

Yong-Yan Bei,1,* Xiao-Feng Zhou,2,3,* Ben-Gang You,1 Zhi-Qiang Yuan,1 Wei-Liang Chen,1 Peng Xia,1 Yang Liu,1 Yong Jin,4 Xiao-Juan Hu,1 Qiao-Ling Zhu,1 Chun-Ge Zhang,1 Xue-Nong Zhang,1 Liang Zhang5 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s Republic of China; 2College of Radiological Medicine and Protection, Soochow University, Suzhou, People’s Republic of China; 3Changshu Hospital of Traditional Chinese Medicine, Changshu, People’s Republic of China; 4Invasive Technology Department, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 5Department of Biopharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to the paperAbstract: Lactose–palmitoyl–trimethyl–chitosan (Lac-TPCS), a novel amphipathic self-assembled polymer, was synthesized for administration of insoluble drugs to reduce their adverse effects. The central composite design was used to study the preparation technique of harmine (HM)-loaded self-assembled micelles based on Lac-TPCS (Lac-TPCS/HM). Three preparation methods and single factors were screened, including solvent type, HM amount, hydration volume, and temperature. The optimal preparation technique was identified after investigating the influence of two independent factors, namely, HM amount and hydration volume, on four indexes, ie, encapsulation efficiency (EE), drug-loading amount (LD), particle size, and polydispersity index (PDI). Analysis of variance showed a high coefficient of determination of 0.916 to 0.994, thus ensuring a satisfactory adjustment of the predicted prescription. The maximum predicted values of the optimal prescription were 91.62%, 14.20%, 183.3 nm, and 0.214 for EE, LD, size, and PDI, respectively, when HM amount was 1.8 mg and hydration volume was 9.6 mL. HM-loaded micelles were successfully characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a fluorescence-quenching experiment. Sustained release of Lac-TPCS/HM reached 65.3% in 72 hours at pH 7.4, while free HM released about 99.7% under the same conditions.Keywords: harmine, chitosan derivate, self-assembled micelle, central composite design, response surface methodology, characterization