透皮芦荟苦素纳米粒的制备及其对酪氨酸酶活性的抑制作用
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摘要
采用溶胶-凝胶法制备氧化锌量子点(ZnO QDs),表面用3-氨丙基三乙氧基硅烷(APTES)改性,制备氨基化的ZnO QDs。同时,利用N,N′-羰基二咪唑(CDI)活化芦荟苦素(Alo),与氨基化的ZnO QDs反应,将Alo共价连接在ZnO QDs表面,获得芦荟苦素纳米粒(Alo NPs)。采用透射电子显微镜(TEM)、动态光散射仪(DLS)、傅里叶变换红外光谱仪(FTIR)和热重分析仪(TGA)对Alo NPs的形貌、粒径、结构进行了表征。测试表明,ZnO QDs呈类圆形,由于Alo的连接,原本粒径分布在4 nm左右的粒子粒径增加至8 nm左右。TG结果显示Alo NPs中,ZnO QDs和Alo的质量分数分别为39.27%、35.14%。透皮渗透实验结果表明Alo NPs能显著提高Alo的透皮效率。体外释药行为显示,Alo-NPs在酸性条件下(pH=5.0)2 h即能释放87.63%±0.46%的Alo,而在pH=7.4的介质中,2 h内的累积释放率只有1.45%±0.21%。Alo-NPs对酪氨酸酶活性抑制率呈浓度依赖型,当ZnO QDs的当量溶度为12.5μg/mL时,抑制率可高达40.32%±1.57%。这些结果说明Alo NPs作为外用酪氨酸酶活性抑制剂具有潜在的应用价值。
Zinc oxide quantum dots(ZnO QDs) were synthesized by gel-sol method and employed as the transdermal aloesin(Alo) carriers. ZnO QDs were surface-functionalized with amino using aminopropyltriethoxysilane(APTES). Alo was covalently bonded on the surface of ZnO QDs via N,N'-carbonyldiimidazole to obtain Alo NPs, which were characterized by transmission electron microscope(TEM), dynamic light scattering(DLS), Fourier transform infrared spectroscopy(FTIR) and thermal gravimetric analyzer(TGA). TEM images showed that ZnO QDs were analogously sphere and monodisperse with a reasonably narrow size distribution, of which was around 4 nm. The size of Alo NPs increased to around 8 nm due to the surface modification. The intense bands at around 3 400 cm–1 and1 200 cm–1 in the FTIR spectrum of Alo NPs from the vibration of-OH indicated the linkage of Alo on the surface of ZnO QDs. The results of TGA analysis showed that the mass ratio of ZnO QDs and Alo were 39.27% and 35.14%, respectively.The penetration of Alo NPs was much higher than raw Alo according to the passive penetration experiments with Franztype diffusion cells instrument using full-thickness cavy skin, which manifested the improvement of the penetration for Alo delivered by ZnO QDs. The pH-controlled drug release behavior in vitro was investigated. At pH 7.4, only a small amount of Alo(1.45% ± 0.21%) had been released after 2 h. In contrast, as incubation at pH 5.0 of which pH was similar to endosomal environment, Alo was released very fast(87.63% ± 0.46% in 2 h) from Alo NPs, confirming that Alo NPs could response to the pH and realize the intracellular drug release. The inhibitory effect of Alo NPs on tyrosinase was in a dose dependent manner. When the concentration of Alo NPs was 12.5 μg/mL, the inhibition rate was up to 40.32% ± 1.57%. All the results show that the Alo NPs hold a great potential in transdermal tyrosinase inhibition.
Zinc oxide quantum dots(ZnO QDs) were synthesized by gel-sol method and employed as the transdermal aloesin(Alo) carriers. ZnO QDs were surface-functionalized with amino using aminopropyltriethoxysilane(APTES). Alo was covalently bonded on the surface of ZnO QDs via N,N'-carbonyldiimidazole to obtain Alo NPs, which were characterized by transmission electron microscope(TEM), dynamic light scattering(DLS), Fourier transform infrared spectroscopy(FTIR) and thermal gravimetric analyzer(TGA). TEM images showed that ZnO QDs were analogously sphere and monodisperse with a reasonably narrow size distribution, of which was around 4 nm. The size of Alo NPs increased to around 8 nm due to the surface modification. The intense bands at around 3 400 cm–1 and1 200 cm–1 in the FTIR spectrum of Alo NPs from the vibration of-OH indicated the linkage of Alo on the surface of ZnO QDs. The results of TGA analysis showed that the mass ratio of ZnO QDs and Alo were 39.27% and 35.14%, respectively.The penetration of Alo NPs was much higher than raw Alo according to the passive penetration experiments with Franztype diffusion cells instrument using full-thickness cavy skin, which manifested the improvement of the penetration for Alo delivered by ZnO QDs. The pH-controlled drug release behavior in vitro was investigated. At pH 7.4, only a small amount of Alo(1.45% ± 0.21%) had been released after 2 h. In contrast, as incubation at pH 5.0 of which pH was similar to endosomal environment, Alo was released very fast(87.63% ± 0.46% in 2 h) from Alo NPs, confirming that Alo NPs could response to the pH and realize the intracellular drug release. The inhibitory effect of Alo NPs on tyrosinase was in a dose dependent manner. When the concentration of Alo NPs was 12.5 μg/mL, the inhibition rate was up to 40.32% ± 1.57%. All the results show that the Alo NPs hold a great potential in transdermal tyrosinase inhibition.
引文
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2Picardo M, Slominski A. Melanin pigmentation and melanoma.Exp Dermatol, 2017, 26(7):555-556.
3Lijima C, Wong C, Nugroho A, et al. Anti-melanin deposition activity of ceramicines from Chisocheton ceramicus. J Nat Med,2016, 70(4):702-707.
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6Lee S Y, Baek N, Nam T G. Natural, semisynthetic and synthetic tyrosinase inhibitors. J Enzyme Inhib Med Chem, 2016, 31(1):1-13.
7Hsieh P W, Aljuffali I A, Fang C L, et al. Hydroquinone-salicylic acid conjugates as novel anti-melasma actives show superior skin targeting compared to the parent drugs. J Dermatol Sci, 2014,76(2):120-131.
8Candan G, Michiue H, Ishikawa S, et al. Combining poly-arginine with the hydrophobic counter-anion 4-(1-pyrenyl)-butyric acid for protein transduction in transdermal delivery. Biomaterials, 2012,33(27):6468-6475.
9Ookubo N, Michiue H, Kitamatsu M, et al. The transdermal inhibition of melanogenesis by a cell-membrane-permeable peptide delivery system based on poly-arginine. Biomaterials, 2014, 35(15):4508-4516.
10台宗光,朱全刚,戴子渊,等.聚精氨酸及其衍生物作为基因载体应用的研究进展.药学服务与研究, 2014, 14(5):328-332.
11Huang Xiao, Zheng Xi, Xu Zuojuan, et al. ZnO-based nanocarriers for drug delivery application:From passive to smart strategies. Int J Pharm, 2017, 534(1/2):190-194.
12Degim I T, Kadioglu D. Cheap, suitable, predictable and manageable nanoparticles for drug delivery:quantum dots.Current Drug Delivery, 2013, 10(1):32-38.
13He Z, Zhang P, Li X, et al. A targeted DNAzyme-nanocomposite probe equipped with built-in Zn2+arsenal for combined treatment of gene regulation and drug delivery. Scientific Reports, 2016, 6:22737.
14Kim J H, Yoon J Y, Yang S Y, et al. Tyrosinase inhibitory components from Aloe vera and their antiviral activity. J Enzyme Inhib Med Chem, 2017, 32(1):78-83.
15Yu Jiao, Wan Kawai, Sun Xun. Improved transdermal delivery of morin efficiently inhibits allergic contact dermatitis. Int J Pharm,2017, 530(1/2):145-154.
16 Habib B A, Sayed S, Elsayed G M. Enhanced transdermal delivery of ondansetron using nanovesicular systems:Fabrication,characterization, optimization and ex-vivo permeation study BoxCox transformation practical example. European Journal of Pharmaceutical Sciences, 2018, 115:352-361.
17Ghorani B, Goswami P, Blackburn R S. Enrichment of cellulose acetate nanofibre assemblies for therapeutic delivery of Ltryptophan. Int J Biol Macromol, 2018, 108:1-8.
18Abdel-Hafez S M, Hathout R M, Sammour O A. Tracking the transdermal penetration pathways of optimized curcumin-loaded chitosan nanoparticles via confocal laser scanning microscopy. Int J Biol Macromol, 2018, 108:753-764.
19Baroli B, Ennas M G, Loffredo F A, et al. Penetration of metallic nanoparticles in human full-thickness skin. Journal of Investigative Dermatology, 2007, 127(7):1701-1712.
20 Mortensen L J, Oberdorster G, Pentland A P. In vivoskin penetration of quantum dot nanoparticles in the murine model:The effect of UVR. Nano Lett, 2008, 8(9):2779-2787.
21Ilbasmis-Tamer S, Degim I T. A feasible way to use carbon nanotubes to deliver drug molecules:transdermal application.Expert Opin Drug Deliv, 2012, 9(8):991-999.
22Mayr J, Saldias C, Diaz Diaz D. Release of small bioactive molecules from physical gels. Chem Soc Rev, 2018, 47(4):1484-1515.
23 Huang Xiao, Wang Xiaoying, Wang Sichun, et al. UV and darktriggered repetitive release and encapsulation of benzophenone-3from biocompatible ZnO nanoparticles potential for skin protection. Nanoscale, 2013, 5(12):5596-5601.
2Picardo M, Slominski A. Melanin pigmentation and melanoma.Exp Dermatol, 2017, 26(7):555-556.
3Lijima C, Wong C, Nugroho A, et al. Anti-melanin deposition activity of ceramicines from Chisocheton ceramicus. J Nat Med,2016, 70(4):702-707.
4Pillaiyar T, Manickam M, Namasivayam V. Skin whitening agents:medicinal chemistry perspective of tyrosinase inhibitors. J Enzyme Inhib Med Chem, 2017, 32(1):403-425.
5Ullash S, Son S, Yun H, et al. Tyrosinase inhibitors:a patent review(2011-2015). Expert Opinion on Therapeutic Patents, 2016, 26(3):347-362.
6Lee S Y, Baek N, Nam T G. Natural, semisynthetic and synthetic tyrosinase inhibitors. J Enzyme Inhib Med Chem, 2016, 31(1):1-13.
7Hsieh P W, Aljuffali I A, Fang C L, et al. Hydroquinone-salicylic acid conjugates as novel anti-melasma actives show superior skin targeting compared to the parent drugs. J Dermatol Sci, 2014,76(2):120-131.
8Candan G, Michiue H, Ishikawa S, et al. Combining poly-arginine with the hydrophobic counter-anion 4-(1-pyrenyl)-butyric acid for protein transduction in transdermal delivery. Biomaterials, 2012,33(27):6468-6475.
9Ookubo N, Michiue H, Kitamatsu M, et al. The transdermal inhibition of melanogenesis by a cell-membrane-permeable peptide delivery system based on poly-arginine. Biomaterials, 2014, 35(15):4508-4516.
10台宗光,朱全刚,戴子渊,等.聚精氨酸及其衍生物作为基因载体应用的研究进展.药学服务与研究, 2014, 14(5):328-332.
11Huang Xiao, Zheng Xi, Xu Zuojuan, et al. ZnO-based nanocarriers for drug delivery application:From passive to smart strategies. Int J Pharm, 2017, 534(1/2):190-194.
12Degim I T, Kadioglu D. Cheap, suitable, predictable and manageable nanoparticles for drug delivery:quantum dots.Current Drug Delivery, 2013, 10(1):32-38.
13He Z, Zhang P, Li X, et al. A targeted DNAzyme-nanocomposite probe equipped with built-in Zn2+arsenal for combined treatment of gene regulation and drug delivery. Scientific Reports, 2016, 6:22737.
14Kim J H, Yoon J Y, Yang S Y, et al. Tyrosinase inhibitory components from Aloe vera and their antiviral activity. J Enzyme Inhib Med Chem, 2017, 32(1):78-83.
15Yu Jiao, Wan Kawai, Sun Xun. Improved transdermal delivery of morin efficiently inhibits allergic contact dermatitis. Int J Pharm,2017, 530(1/2):145-154.
16 Habib B A, Sayed S, Elsayed G M. Enhanced transdermal delivery of ondansetron using nanovesicular systems:Fabrication,characterization, optimization and ex-vivo permeation study BoxCox transformation practical example. European Journal of Pharmaceutical Sciences, 2018, 115:352-361.
17Ghorani B, Goswami P, Blackburn R S. Enrichment of cellulose acetate nanofibre assemblies for therapeutic delivery of Ltryptophan. Int J Biol Macromol, 2018, 108:1-8.
18Abdel-Hafez S M, Hathout R M, Sammour O A. Tracking the transdermal penetration pathways of optimized curcumin-loaded chitosan nanoparticles via confocal laser scanning microscopy. Int J Biol Macromol, 2018, 108:753-764.
19Baroli B, Ennas M G, Loffredo F A, et al. Penetration of metallic nanoparticles in human full-thickness skin. Journal of Investigative Dermatology, 2007, 127(7):1701-1712.
20 Mortensen L J, Oberdorster G, Pentland A P. In vivoskin penetration of quantum dot nanoparticles in the murine model:The effect of UVR. Nano Lett, 2008, 8(9):2779-2787.
21Ilbasmis-Tamer S, Degim I T. A feasible way to use carbon nanotubes to deliver drug molecules:transdermal application.Expert Opin Drug Deliv, 2012, 9(8):991-999.
22Mayr J, Saldias C, Diaz Diaz D. Release of small bioactive molecules from physical gels. Chem Soc Rev, 2018, 47(4):1484-1515.
23 Huang Xiao, Wang Xiaoying, Wang Sichun, et al. UV and darktriggered repetitive release and encapsulation of benzophenone-3from biocompatible ZnO nanoparticles potential for skin protection. Nanoscale, 2013, 5(12):5596-5601.