西红花苷和西红花酸的药动学及制剂学研究进展
|
摘要
西红花苷来源于西红花Crocus sativus柱头和栀子Gardenia jasminoides果实,是一类具长共轭独特水溶性类胡萝卜素,具有显著神经保护、心血管保护及抗肿瘤等药理活性。西红花苷口服不能以原型吸收入血,而是在胃肠道水解为西红花酸后吸收进入血液循环,之后转变为葡萄糖醛酸缀合物,而代谢产物西红花酸主要分布到心、肝、脾、肺等血液充盈组织中。由于西红花苷及代谢物西红花酸体内生物利用度较低、稳定性差,可采用新型递药系统应用于西红花苷(酸),提高其稳定性、生物利用度及药理活性。综述近年西红花苷和西红花酸的体内代谢及制剂学相关研究进展,为该类天然产物进一步深入研究与开发利用提供参考。
Crocin is derived from stigmas of Crocus sativus and fruits of Gardenia jasminoides. It is a type of unique water-soluble carotenoids with long conjugate, possessing remarkable neuroprotection, cardiovascular protection, antitumor, and other pharmacological activities. Data showed that orally administrated crocin couldn't permeate into the bloodstream as the prototype, but it can be absorbed into the blood circulation after being hydrolyzed to crocetin in gastrointestinal tract. Then, crocetin is converted to glucuronic acid conjugate. Moreover, the metabolite crocetin are mainly distributed in heart, liver, spleen, lung, and other blood-rich tissues. In view of the low bioavailability and poor stability of crocin and its metabolite crocetin, researchers have extensively employed novel drug delivery system to study crocin(crocetin) in order to improve its stability, bioavailability, and pharmacological activity. This article reviews in vivo metabolism of crocin(crocetin) in recent years and investigations on drug delivery system, therefore, facilitating further research and development of these natural products.
Crocin is derived from stigmas of Crocus sativus and fruits of Gardenia jasminoides. It is a type of unique water-soluble carotenoids with long conjugate, possessing remarkable neuroprotection, cardiovascular protection, antitumor, and other pharmacological activities. Data showed that orally administrated crocin couldn't permeate into the bloodstream as the prototype, but it can be absorbed into the blood circulation after being hydrolyzed to crocetin in gastrointestinal tract. Then, crocetin is converted to glucuronic acid conjugate. Moreover, the metabolite crocetin are mainly distributed in heart, liver, spleen, lung, and other blood-rich tissues. In view of the low bioavailability and poor stability of crocin and its metabolite crocetin, researchers have extensively employed novel drug delivery system to study crocin(crocetin) in order to improve its stability, bioavailability, and pharmacological activity. This article reviews in vivo metabolism of crocin(crocetin) in recent years and investigations on drug delivery system, therefore, facilitating further research and development of these natural products.
引文
[1]Mehri S,Abnous K,Khooei A,et al.Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress[J].Iran J Basic Med Sci,2015,18(9):902-908.
[2]Sun Y,Xu H J,Zhao Y X,et al.Crocin exhibits antitumor effects on human leukemia HL-60 cells in vitro and in vivo[J].Evid Based Complement Alternat Med,2013,2013(11):690164.
[3]Thushara R M,Hemshekhar M,Santhosh M S,et al.Crocin,a dietary additive protects platelets from oxidative stress-induced apoptosis and inhibits platelet aggregation[J].Mol Cell Biochem,2013,373(1/2):73-83.
[4]Talaei A,Hassanpour M M,Sajadi Tabassi S A,et al.Crocin,the main active saffron constituent,as an adjunctive treatment in major depressive disorder:Arandomized,double-blind,placebo-controlled,pilot clinical trial[J].Affect Disord,2015,174:51-56.
[5]Samarghandian S,Aziminezhad M,Farkhondeh T.Crocin attenuate tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)in streptozotocin-induced diabetic rat aorta[J].Cytokine,2016,88:20-28.
[6]Imenshahidi M,Hosseinzadeh H,Javadpour Y.Hypotensive effect of aqueous saffron extract(Crocus sativus L.)and its constituents,safranal and crocin,in normotensive and hypertensive rats[J].Phytother Res,2010,24(7):990-994.
[7]李声.西红花酸对人食管鳞癌KYSE-150细胞的抑制作用及其机制[D].广州:中山大学,2016.
[8]陶赟,龚国清,钱之玉,等.西红花酸对溃疡性结肠炎大鼠模型的作用及其机制研究[J].中国临床药理学与治疗学,2013,18(3):263-270.
[9]黄艺洪,刘妍,张伟,等.西红花酸对Aβ25-35诱导海马神经元损伤的神经保护作用[J].临床医学工程,2012,19(8):1251-1252.
[10]蔡恒玲,刘应辉,刘娜娜.西红花酸对动脉粥样硬化大鼠血脂及LOX-1表达的影响[J].中国现代医药杂志,2011,13(10):3-5.
[11]Gutheil W G,Reed G,Ray A,et al.Crocetin:An agent derived from saffron for prevention and therapy for cancer[J].Curr Pharm Biotechnol,2012,13(1):173-179.
[12]付小梅,王峥涛.西红花苷-1的稳定性研究[J].食品科学,2012,33(5):71-73.
[13]Giaccio M.Crocetin from saffron:An active component of an ancient spice[J].Crit Rev Food Sci Nutr,2004,44(3):155-172.
[14]金玉燕,张钧寿,张瑛,等.西红花苷大鼠小肠吸收研究及油水分配系数的测定[J].中国药科大学学报,2004,35(3):283-284.
[15]张倩怡,杜守颖,陆洋,等.栀子提取物中栀子苷油水分配系数及大鼠肠吸收动力学研究[J].中国中药杂志,2009,34(14):1840-1844.
[16]杜鹏,钱之玉.西红花苷-1大鼠吸收及排泄的研究[J].中国新药杂志,2004,13(9):801-804.
[17]Lautenschl?ger M,Sendker J,Hüwel S,et al.Intestinal formation of trans-crocetin from saffron extract(Crocus sativus L.)and in vitro permeation through intestinal and blood brain barrier[J].Phytomedicine,2015,22(1):36-44.
[18]冷薇,郑颖,王一涛.莪术油吸收机制及其口服制剂开发[J].中华医药杂志,2007,7(3):221-225.
[19]Karkoula E,Lemonakis N,Kokras N,et al.Trans-crocin4 is not hydrolyzed to crocetin following ip administration in mice,while it shows penetration through the blood brain barrier[J].Fitoterapia,2018,129:62-72.
[20]李向阳,冯伟力,朱俊博,等.藏药佐太对西红花苷-1大鼠体内药动学的影响[J].中草药,2009,40(9):1425-1428.
[21]朱俊博,史彦斌,李向阳.西红花苷-1经大鼠肌肉注射的体内药动学研究[J].中成药,2014,36(9):1983-1985.
[22]刘同征,钱之玉.西红花酸在大鼠的药代动力学研究[J].药学学报,2002,37(5):367-369.
[23]杜鹏,钱之玉,余卫平,等.RP-HPLC法研究西红花酸在大鼠体内的药代动力学和组织分布特性[J].药物分析杂志,2004,24(2):149-153.
[24]Xi L,Qian Z Y,Du P,et al.Pharmacokinetic properties of crocin(crocetin digentiobiose ester)following oral administration in rats[J].Phytomedicine,2007,14(9):633-636.
[25]张颖,刘建勋,林力,等.大鼠口服西红花苷-1后吸收入血成分及药动学[J].中国药学杂志,2012,47(2):136-140.
[26]Umigai N,Murakami K,Ulit M V,et al.The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration[J].Phytomedicine,2011,18(7):575-578.
[27]Baskaran V,Sugawara T,Nagao A.Phospholipids affect the intestinal absorption of carotenoids in mice[J].Lipids,2003,38(7):705-711.
[28]Chryssanthi D G,Lamari F N,Georgakopoulos C D,et al.A new validated SPE-HPLC method for monitoring crocetin in human plasma-Application after saffron tea consumption[J].J Pharm Biomed Anal,2011,55(3):563-568.
[29]Hooshang M A,Mohammad R,Nasim T A,et al.Development and validation of HPLC method for determination of crocetin,a constituent of saffron,in human serum samples[J].Iran J Basic Med Sci,2013,16(1):47-55.
[30]钱之玉,傅健,潘英.西红花甙-I在大鼠体内的药代动力学[J].中国药科大学学报,1996(12):755-757.
[31]Satoh T,Hosokawa M.Structure,function and regulation of carboxylesterases[J].Chem Biol Interact,2006,162(3):195-211.
[32]Asai A,Nakano T,Takahashi M A,et al.Orally administered crocetin and crocins are bbsorbed into blood plasma as crocetin and its glucuronide conjugates in mice[J].J Agric Food Chem,2005,53(18):7302-7306.
[33]冯晓宾,周桂芬,钱晓东,等.西红花水提液在大鼠血中的移行成分分析[J].中草药,2017,48(4):747-752.
[34]Zhang Y,Fei F,Zhen L,et al.Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats[J].JChromatogr B Analyt Technol Biomed Life Sci,2016,1044-1045:1-7.
[35]楚溪,张园园,张一昕,等.西红花苷对异丙肾上腺素所致大鼠心肌缺血保护作用研究[J].亚太传统医药,2017,13(23):25-27.
[36]肖小华,徐丽瑛,周艳艳,等.栀子苷和西红花苷Ⅰ对ANIT致小鼠肝损伤的保肝作用研究[J].时珍国医国药,2014(7):1600-1601.
[37]Oruc S,G?nül Y,Tunay K,et al.The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats[J].Life Sci,2016,154:79-86.
[38]张灵芝.脂质体制备及其在生物医学中的应用[M].北京:北京医科大学,中国协和医科大学联合出版社,1998.
[39]Mousavi S H,Moallem S A,Mehri S,et al.Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form[J].Pharm Biol,2011,49(10):1039-1045.
[40]Rastgoo M,Hosseinzadeh H,Alavizadeh H,et al.Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma[J].Planta Med,2013,79(6):447-451.
[41]殷平华.水栀子番红花甙及其脂质体对肝脏的生物活性研究[D].南京:中国药科大学,1997.
[42]Zhou H,Yuan X,Zhao Q,et al.Determination of oxygen transmission barrier of microcapsule wall by crocetin deterioration kinetics[J].Eur Food Res Technol,2013,237(4):639-646.
[43]Kyriakoudi A,Tsimidou M Z.Properties of encapsulated saffron extracts in maltodextrin using the Büchi B-90nano spray-dryer[J].Food Chem,2018,266:458-465.
[44]魏慧贤,钟芳,麻建国.初乳乳化工艺对W/O/W型复乳稳定性和药物包埋率的影响研究[J].高校化学工程学报,2008,22(4):659-665.
[45]Faridi E A,Jafari S M,Assadpour E.Preparation of a multiple emulsion based on pectin-whey protein complex for encapsulation of saffron extract nanodroplets[J].Food Chem,2017,221:1962-1969.
[46]Vandamme T F,Lenourry A,Charrueau C,et al.The use of polysaccharides to target drugs to the colon[J].Carbohydr Polym,2002,48(3):219-231.
[47]Mehrnia M A,Jafari S M,Makhmal-Zadeh B S,et al.Crocin loaded nano-emulsions:Factors affecting emulsion properties in spontaneous emulsification[J].Int J Biol Macromol,2016,84:261-267.
[48]Mehrnia M A,Jafari S M,Makhmal-Zadeh B S,et al.Rheological and release properties of double nano-emulsions containing crocin prepared with Angum gum,Arabic gum and whey protein[J].Food Hydrocolloids,2017,66:259-267.
[49]Kim D G,Jeong Y I,Choi C,et al.Retinol-encapsulated low molecular water-soluble chitosan nanoparticles[J].Int J Pharm,2006,319(1):130-138.
[50]Dudhani A R,Kosaraju S L.Bioadhesive chitosan nanoparticles:Preparation and characterization[J].Carbohydr Polym,2010,81(2):243-251.
[51]Rahaiee S,Shojaosadati S A,Hashemi M,et al.Improvement of crocin stability by biodegradeble nanoparticles of chitosan-alginate[J].Int J Biol Macromol,2015,79:423-432.
[52]Rahaiee S,Hashemi M,Shojaosadati S A,et al.Nanoparticles based on crocin loaded chitosan-alginate biopolymers:Antioxidant activities,bioavailability and anticancer properties[J].Int J Biol Macromol,2017,99:401-408.
[53]El-Kharrag R,Amin A,Hisaindee S,et al.Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles[J].Int J Oncol,2017,50(1):212-222.
[54]Vijayakumar R,Devi V,Adavallan K,et al.Green synthesis and characterization of gold nanoparticles using extract of anti-tumor potent Crocus sativus[J].Physica,2012,44(3):665-671.
[55]Hoshyar R,Khayati G R,Poorgholami M,et al.A novel green one-step synthesis of gold nanoparticles using crocin and their anti-cancer activities[J].J Photochem Photobiol B,2016,159:237-242.
[56]Freiberg S,Zhu X X.Polymer microspheres for controlled drug release[J].Int J Pharm,2004,282(1):1-18.
[57]Langroodi F A.Evaluation of the effect of crocetin on antitumor activity of doxorubicin encapsulated in PLGAnanoparticles[J].Nanomedicine,2016,3(1):23-34.
[58]Ghahestani Z H,Langroodi F A,Mokhtarzadeh A,et al.Evaluation of anti-cancer activity of PLGA nanoparticles containing crocetin[J].Artif Cells Nanomed Biotechnol,2016,45(5):955-960.
[59]Mary T A,Shanthi K,Vimala K,et al.PEGfunctionalized selenium nanoparticles as a carrier of crocin to achieve anticancer synergism[J].Rsc Adv,2016,27(6):22936-22949.
[60]Esposito E,Drechsler M,Mariani P,et al.Nanostructured lipid dispersions for topical administration of crocin,a potent antioxidant from saffron(Crocus sativus L.)[J].Mater Sci Eng C Mater Biol Appl,2017,71:669-677.
[61]王震.西红花总苷卵磷脂复合物自乳化软胶囊的研制[D].南京:中国药科大学,2004.
[62]金玉燕.西红花多甙自微乳化肠溶胶囊的研制[D].南京:中国药科大学,2004.
[63]钟慧.藏红花酸固体分散缓释片的研究[D].镇江:江苏大学,2014.
[64]Soltani F,Ramezani M,Farzad S A,et al.Comparison study of the effect of alkyl-modified and unmodified PAMAM and PPI dendrimers on solubility and antitumor activity of crocetin[J].Artif Cells Nanomed Biotechnol,2016,45(7):1-7.
[65]Selim K,Tsimidou M,Biliaderis C G.Kinetic studies of degradation of saffron carotenoids encapsulated in amorphous polymer matrices[J].Food Chem,2000,71(2):199-206.
[2]Sun Y,Xu H J,Zhao Y X,et al.Crocin exhibits antitumor effects on human leukemia HL-60 cells in vitro and in vivo[J].Evid Based Complement Alternat Med,2013,2013(11):690164.
[3]Thushara R M,Hemshekhar M,Santhosh M S,et al.Crocin,a dietary additive protects platelets from oxidative stress-induced apoptosis and inhibits platelet aggregation[J].Mol Cell Biochem,2013,373(1/2):73-83.
[4]Talaei A,Hassanpour M M,Sajadi Tabassi S A,et al.Crocin,the main active saffron constituent,as an adjunctive treatment in major depressive disorder:Arandomized,double-blind,placebo-controlled,pilot clinical trial[J].Affect Disord,2015,174:51-56.
[5]Samarghandian S,Aziminezhad M,Farkhondeh T.Crocin attenuate tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)in streptozotocin-induced diabetic rat aorta[J].Cytokine,2016,88:20-28.
[6]Imenshahidi M,Hosseinzadeh H,Javadpour Y.Hypotensive effect of aqueous saffron extract(Crocus sativus L.)and its constituents,safranal and crocin,in normotensive and hypertensive rats[J].Phytother Res,2010,24(7):990-994.
[7]李声.西红花酸对人食管鳞癌KYSE-150细胞的抑制作用及其机制[D].广州:中山大学,2016.
[8]陶赟,龚国清,钱之玉,等.西红花酸对溃疡性结肠炎大鼠模型的作用及其机制研究[J].中国临床药理学与治疗学,2013,18(3):263-270.
[9]黄艺洪,刘妍,张伟,等.西红花酸对Aβ25-35诱导海马神经元损伤的神经保护作用[J].临床医学工程,2012,19(8):1251-1252.
[10]蔡恒玲,刘应辉,刘娜娜.西红花酸对动脉粥样硬化大鼠血脂及LOX-1表达的影响[J].中国现代医药杂志,2011,13(10):3-5.
[11]Gutheil W G,Reed G,Ray A,et al.Crocetin:An agent derived from saffron for prevention and therapy for cancer[J].Curr Pharm Biotechnol,2012,13(1):173-179.
[12]付小梅,王峥涛.西红花苷-1的稳定性研究[J].食品科学,2012,33(5):71-73.
[13]Giaccio M.Crocetin from saffron:An active component of an ancient spice[J].Crit Rev Food Sci Nutr,2004,44(3):155-172.
[14]金玉燕,张钧寿,张瑛,等.西红花苷大鼠小肠吸收研究及油水分配系数的测定[J].中国药科大学学报,2004,35(3):283-284.
[15]张倩怡,杜守颖,陆洋,等.栀子提取物中栀子苷油水分配系数及大鼠肠吸收动力学研究[J].中国中药杂志,2009,34(14):1840-1844.
[16]杜鹏,钱之玉.西红花苷-1大鼠吸收及排泄的研究[J].中国新药杂志,2004,13(9):801-804.
[17]Lautenschl?ger M,Sendker J,Hüwel S,et al.Intestinal formation of trans-crocetin from saffron extract(Crocus sativus L.)and in vitro permeation through intestinal and blood brain barrier[J].Phytomedicine,2015,22(1):36-44.
[18]冷薇,郑颖,王一涛.莪术油吸收机制及其口服制剂开发[J].中华医药杂志,2007,7(3):221-225.
[19]Karkoula E,Lemonakis N,Kokras N,et al.Trans-crocin4 is not hydrolyzed to crocetin following ip administration in mice,while it shows penetration through the blood brain barrier[J].Fitoterapia,2018,129:62-72.
[20]李向阳,冯伟力,朱俊博,等.藏药佐太对西红花苷-1大鼠体内药动学的影响[J].中草药,2009,40(9):1425-1428.
[21]朱俊博,史彦斌,李向阳.西红花苷-1经大鼠肌肉注射的体内药动学研究[J].中成药,2014,36(9):1983-1985.
[22]刘同征,钱之玉.西红花酸在大鼠的药代动力学研究[J].药学学报,2002,37(5):367-369.
[23]杜鹏,钱之玉,余卫平,等.RP-HPLC法研究西红花酸在大鼠体内的药代动力学和组织分布特性[J].药物分析杂志,2004,24(2):149-153.
[24]Xi L,Qian Z Y,Du P,et al.Pharmacokinetic properties of crocin(crocetin digentiobiose ester)following oral administration in rats[J].Phytomedicine,2007,14(9):633-636.
[25]张颖,刘建勋,林力,等.大鼠口服西红花苷-1后吸收入血成分及药动学[J].中国药学杂志,2012,47(2):136-140.
[26]Umigai N,Murakami K,Ulit M V,et al.The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration[J].Phytomedicine,2011,18(7):575-578.
[27]Baskaran V,Sugawara T,Nagao A.Phospholipids affect the intestinal absorption of carotenoids in mice[J].Lipids,2003,38(7):705-711.
[28]Chryssanthi D G,Lamari F N,Georgakopoulos C D,et al.A new validated SPE-HPLC method for monitoring crocetin in human plasma-Application after saffron tea consumption[J].J Pharm Biomed Anal,2011,55(3):563-568.
[29]Hooshang M A,Mohammad R,Nasim T A,et al.Development and validation of HPLC method for determination of crocetin,a constituent of saffron,in human serum samples[J].Iran J Basic Med Sci,2013,16(1):47-55.
[30]钱之玉,傅健,潘英.西红花甙-I在大鼠体内的药代动力学[J].中国药科大学学报,1996(12):755-757.
[31]Satoh T,Hosokawa M.Structure,function and regulation of carboxylesterases[J].Chem Biol Interact,2006,162(3):195-211.
[32]Asai A,Nakano T,Takahashi M A,et al.Orally administered crocetin and crocins are bbsorbed into blood plasma as crocetin and its glucuronide conjugates in mice[J].J Agric Food Chem,2005,53(18):7302-7306.
[33]冯晓宾,周桂芬,钱晓东,等.西红花水提液在大鼠血中的移行成分分析[J].中草药,2017,48(4):747-752.
[34]Zhang Y,Fei F,Zhen L,et al.Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats[J].JChromatogr B Analyt Technol Biomed Life Sci,2016,1044-1045:1-7.
[35]楚溪,张园园,张一昕,等.西红花苷对异丙肾上腺素所致大鼠心肌缺血保护作用研究[J].亚太传统医药,2017,13(23):25-27.
[36]肖小华,徐丽瑛,周艳艳,等.栀子苷和西红花苷Ⅰ对ANIT致小鼠肝损伤的保肝作用研究[J].时珍国医国药,2014(7):1600-1601.
[37]Oruc S,G?nül Y,Tunay K,et al.The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats[J].Life Sci,2016,154:79-86.
[38]张灵芝.脂质体制备及其在生物医学中的应用[M].北京:北京医科大学,中国协和医科大学联合出版社,1998.
[39]Mousavi S H,Moallem S A,Mehri S,et al.Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form[J].Pharm Biol,2011,49(10):1039-1045.
[40]Rastgoo M,Hosseinzadeh H,Alavizadeh H,et al.Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma[J].Planta Med,2013,79(6):447-451.
[41]殷平华.水栀子番红花甙及其脂质体对肝脏的生物活性研究[D].南京:中国药科大学,1997.
[42]Zhou H,Yuan X,Zhao Q,et al.Determination of oxygen transmission barrier of microcapsule wall by crocetin deterioration kinetics[J].Eur Food Res Technol,2013,237(4):639-646.
[43]Kyriakoudi A,Tsimidou M Z.Properties of encapsulated saffron extracts in maltodextrin using the Büchi B-90nano spray-dryer[J].Food Chem,2018,266:458-465.
[44]魏慧贤,钟芳,麻建国.初乳乳化工艺对W/O/W型复乳稳定性和药物包埋率的影响研究[J].高校化学工程学报,2008,22(4):659-665.
[45]Faridi E A,Jafari S M,Assadpour E.Preparation of a multiple emulsion based on pectin-whey protein complex for encapsulation of saffron extract nanodroplets[J].Food Chem,2017,221:1962-1969.
[46]Vandamme T F,Lenourry A,Charrueau C,et al.The use of polysaccharides to target drugs to the colon[J].Carbohydr Polym,2002,48(3):219-231.
[47]Mehrnia M A,Jafari S M,Makhmal-Zadeh B S,et al.Crocin loaded nano-emulsions:Factors affecting emulsion properties in spontaneous emulsification[J].Int J Biol Macromol,2016,84:261-267.
[48]Mehrnia M A,Jafari S M,Makhmal-Zadeh B S,et al.Rheological and release properties of double nano-emulsions containing crocin prepared with Angum gum,Arabic gum and whey protein[J].Food Hydrocolloids,2017,66:259-267.
[49]Kim D G,Jeong Y I,Choi C,et al.Retinol-encapsulated low molecular water-soluble chitosan nanoparticles[J].Int J Pharm,2006,319(1):130-138.
[50]Dudhani A R,Kosaraju S L.Bioadhesive chitosan nanoparticles:Preparation and characterization[J].Carbohydr Polym,2010,81(2):243-251.
[51]Rahaiee S,Shojaosadati S A,Hashemi M,et al.Improvement of crocin stability by biodegradeble nanoparticles of chitosan-alginate[J].Int J Biol Macromol,2015,79:423-432.
[52]Rahaiee S,Hashemi M,Shojaosadati S A,et al.Nanoparticles based on crocin loaded chitosan-alginate biopolymers:Antioxidant activities,bioavailability and anticancer properties[J].Int J Biol Macromol,2017,99:401-408.
[53]El-Kharrag R,Amin A,Hisaindee S,et al.Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles[J].Int J Oncol,2017,50(1):212-222.
[54]Vijayakumar R,Devi V,Adavallan K,et al.Green synthesis and characterization of gold nanoparticles using extract of anti-tumor potent Crocus sativus[J].Physica,2012,44(3):665-671.
[55]Hoshyar R,Khayati G R,Poorgholami M,et al.A novel green one-step synthesis of gold nanoparticles using crocin and their anti-cancer activities[J].J Photochem Photobiol B,2016,159:237-242.
[56]Freiberg S,Zhu X X.Polymer microspheres for controlled drug release[J].Int J Pharm,2004,282(1):1-18.
[57]Langroodi F A.Evaluation of the effect of crocetin on antitumor activity of doxorubicin encapsulated in PLGAnanoparticles[J].Nanomedicine,2016,3(1):23-34.
[58]Ghahestani Z H,Langroodi F A,Mokhtarzadeh A,et al.Evaluation of anti-cancer activity of PLGA nanoparticles containing crocetin[J].Artif Cells Nanomed Biotechnol,2016,45(5):955-960.
[59]Mary T A,Shanthi K,Vimala K,et al.PEGfunctionalized selenium nanoparticles as a carrier of crocin to achieve anticancer synergism[J].Rsc Adv,2016,27(6):22936-22949.
[60]Esposito E,Drechsler M,Mariani P,et al.Nanostructured lipid dispersions for topical administration of crocin,a potent antioxidant from saffron(Crocus sativus L.)[J].Mater Sci Eng C Mater Biol Appl,2017,71:669-677.
[61]王震.西红花总苷卵磷脂复合物自乳化软胶囊的研制[D].南京:中国药科大学,2004.
[62]金玉燕.西红花多甙自微乳化肠溶胶囊的研制[D].南京:中国药科大学,2004.
[63]钟慧.藏红花酸固体分散缓释片的研究[D].镇江:江苏大学,2014.
[64]Soltani F,Ramezani M,Farzad S A,et al.Comparison study of the effect of alkyl-modified and unmodified PAMAM and PPI dendrimers on solubility and antitumor activity of crocetin[J].Artif Cells Nanomed Biotechnol,2016,45(7):1-7.
[65]Selim K,Tsimidou M,Biliaderis C G.Kinetic studies of degradation of saffron carotenoids encapsulated in amorphous polymer matrices[J].Food Chem,2000,71(2):199-206.