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LY01005 is an investigational new drug product of goserelin acetate which is formulated as extended-release microspheres for intramuscular injection. To support the proposed clinical trials and marketing application of LY01005, pharmacodynamics, pharmacokinetics and toxicity studies were performed in rats. In the pharmacological study in rats, LY01005 induced an initial supra-physiological level increase of testosterone at 24 h post-dosing which then rapidly fell to castration level. The potency of LY01005 was comparable to the comparator Zoladex® but its effect lasted longer and more stable. A single-dose pharmacokinetics study in rats demonstrated that the Cmax and AUClast of LY01005 increased in a dose-proportional manner in the range of 0.45–1.80 mg/kg and the relative bioavailability was 101.0% between LY01005 and Zoladex®. In the toxicity study, almost all of the positive findings of LY01005 in rats including the changes in hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, progestin) and in reproductive system (uterus, ovary, vagina, cervix uteri, mammary gland, testis, epididymis and prostate) were related to the direct pharmacological effects of goserelin. Mild histopathological changes in foreign body removal reaction induced by excipient were also observed. In conclusion, LY01005 displayed a sustained-release profile of goserelin, and exerted a continuous efficacy in vivo in animal models, which had a comparable potency but with a more sustained effect than that of Zoladex®. The safety profile of LY01005 was largely the same with Zoladex®. These results strongly support the planned LY01005 clinical trials.

Additional file 1: Figure S1 1H NMR hydrogen spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs and (d) Glu-CuInS2 QDs (room temperature, D2O). Figure S2. MS spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs and (d) Glu-CuInS2 QDs. Figure S3. Fluorescence emission spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs synthesized at different dose ratios. (Inset: relationship between dose ratio and luminescence intensity of CuInS2 QDs). Figure S4. Fluorescence emission spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs synthesized under different pH conditions. (Inset: relationship between pH and luminescence intensity of CuInS2 QDs). Figure S5. Fluorescence emission spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs synthesized under different temperature conditions. (Inset: Relationship between temperature and luminescence intensity of CuInS2 QDs). Figure S6. The SEM–EDS analysis of Fru-CuInS2, Gal-CuInS2, Man-CuInS2 and Glu-CuInS2 QDs. Figure S7. The EDX elemental mapping of Fru-CuInS2, Gal-CuInS2, Man-CuInS2 and Glu-CuInS2 QDs. Figure S8. The XPS survey spectra of (a)Fru-CuInS2 QDs, (b)Gal-CuInS2 QDs, (c)Man-CuInS2 QDs, and (d)Glu-CuInS2 QDs. Figure S9. Zeta potential values of glyco-CuInS2 QDs. Figure S10. TEM images of Fru-CuInS2, Gal-CuInS2, Man-CuInS2 and Glu-CuInS2 QDs at a scale of 5 nm after fourteen days. Figure S11. DOS and PDOS of Fructose molecules adsorbed on CuInS2(001) before and after (a) DOS of CuInS2(001) system, (b) Fructose molecules adsorbed on DOS of CuInS2(001) system, (c) PDOS of CuInS2(001) system, (d) Fructose molecules adsorbed on DOS of CuInS2(001) system. Figure S12. The UV–Vis absorption spectra of Fru-CuInS2, Gal-CuInS2, Man-CuInS2 and Glu-CuInS2 QDs, respectively. Figure S13. Fluorescence lifetimes of glyco-CuInS2 QDs. Figure S14. Excitation and emission fluorescence spectra of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs. Figure S15. Fluorescence stabilities of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs and (d) Glu-CuInS2 QDs in solution. The black, red and blue lines refer to the fluorescence spectra of glyco-CuInS2 QDs after 0, 7, and 14 days, respectively. Figure S16. Fluorescence spectra of the pH response of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs. (Inset: relationship between pH and luminescence intensity of CuInS2 QDs). Figure S17. MTT assay to detect changes in cellular activity of cancer cells after the addition of 20,40,60,80,100 μg/mL of (a) Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and (d) Glu-CuInS2 QDs, respectively. Figure S18. Fluorescence intensities of (a)Fru-CuInS2 QDs, (b) Gal-CuInS2 QDs, (c) Man-CuInS2 QDs, and(d) Glu-CuInS2 QDs imaged under fluorescence microscopy after incubation of zebrafish for 1 h, respectively. Table S1. Exploration of optimal synthesis conditions for glyco-CuInS2 QDs. Table S2. The photophysical properties of glyco-CuInS2 QDs.

Fluorescent polymer dots (Pdots) are a new type of efficient fluorophores with superior optical properties. However, their practical applications in bioimaging and biosensing are being hampered by their potential toxicity, poor water-solubility and the aggregation caused quenching effect. Herein, we report an effective strategy for the preparation of a series of new small-size aggregation-induced emission (AIE) active non-conjugated Pdots, which were self-assembled from three amphiphilic block copolymers, 4s-TPE-PCL-b-PNIPAM-Eu(III) (TPNE), 4s-TPE-PCL-b-PAA-Eu(III) (TPAE) and 4s-TPE-PCL-b-PVP-Eu(III) (TPVE). All of the blocks were synthesized by free-radical polymerization using a macroazoinitiator containing AIE fluorophore tetraphenylethene (TPE), poly(e-caprolactone) (PCL) segment and azo group, respectively. The obtained TPNE, TPAE and TPVE Pdots had small diameters down to 5 nm and good monodispersity. The Pdots not only exhibited well-separated dual-wavelength emission by 430 and 615 nm upon excitation at 360 and 395 nm, but also displayed thermo-tunable and pH-dependent fluorescence properties, excellent photostability, good water-solubility, good biocompatibility, favorable photoreversibility and noncytotoxicity. More interestingly, the as-prepared three kinds of Pdots displayed reversibly distinct dual-color (blue-red) fluorescence in the targeted three cancer cells (HepG2, A549 and HeLa cells) by merely tuning the excitation wavelength, indicating their potential applications as sensor and multicolour imaging agents in cell biology and diagnostics.

The cumulative probability distribution of the lightning current amplitude can reflect the lightning activity and is important for the lightning protection engineering technology. Based on the lightning location data from 2009 to 2019, the distribution characteristics of the lightning current amplitude and cumulative probability are studied. The results show that a total of 8,634,858 lightning flashes occurred in Zhejiang province in last 11 years. Negative flashes are much more common than positive ones, accounting for 87.44% of the total. The percentage of the lightning current amplitude between 2 and 100 kA is 94.3%. The average amplitude of positive flashes is significantly higher than that of negative flashes. For the current amplitude of positive flashes, the peak occurs in March and gradually decreases with the increase of the month, reaching its lowest in December. But the monthly distribution of negative flashes is relatively concentrated, especially from February to October. When lightning current amplitude is higher than 25.5 kA, the cumulative probability of positive flashes is significantly higher than that of negative flashes and vice versa. The cumulative probability distribution of negative flashes is closer to that of total flashes and is significantly different from that of positive flashes. In order to get a more suitable cumulative probability formula of lightning current amplitude and corresponding parameters in Zhejiang province, the Levenberg–Marquardt method is used. By fitting the measured data with the formulas recommended by the Institute of Electrical and Electronics Engineers (IEEE) and Electric Power Industry Standard of China (Code for design of overvoltage protection and insulation coordination for AC electrical installations GB/T 50064-2014), respectively, the correlation coefficients of different polarities are obtained. By comparing the aforementioned two fitting results, it is found that the formula recommended by the IEEE can more objectively reflect the probability distribution characteristics in Zhejiang province, and the accuracy of the derived formula is verified by using the lightning current data in 2020. It shows that the curve based on the measured values is consistent with that fitted by the IEEE formula but quite different from that fitted by the GB/T 50064-2014 formula.

Additional file 1: Fig. S1. (A) Tissue chip of TTK expression in ovarian tumor tissues and normal controls. (B) Tissue chip of TTK protein in cisplatin-sensitive and cisplatin-resistant ovarian tumor tissues. (C) TTK expression was reduced after cisplatin treatment in A2780 cells.