鬼臼毒素纳米脂质载体的靶向分布
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摘要
目的观察西藏小型猪宫颈外用鬼臼毒素(POD)纳米脂质载体(POD-NLC)后POD黏膜分布情况和系统毒性作用。方法应用随机数字表将西藏小型猪分为实验组和对照组,实验组宫颈涂0.5%POD-NLC,对照组涂0.5%POD酊剂。观察24 h不同时间宫颈黏膜刺激性、POD荧光强度及血中鬼臼毒素含量。结果实验组用药后未发现局部刺激,对照组出现红肿,水疱、血疱、糜烂、破溃等严重局部刺激反应;药物分布显示对照组在涂药4 h后黏膜组织中荧光值达到最高;实验组POD荧光值上升较慢,在16 h达最大值。实验组用药6 h后POD的血药浓度达峰值(14.28±0.33 ng/m L),对照组用药4 h后即达峰值(42.46±0.32 ng/m L),在所有测试时间点,实验组的血药浓度均低于对照组(P<0.05)。对照组的浓度曲线下面积是实验组的1.38倍。结论 POD-NLC具有缓释性、在黏膜较长时间蓄积,动物实验显示无局部刺激性且系统吸收低。
Objective To assess the distribution and systemic toxicity of podophyllotoxin- loaded nanostructured lipid carriers(POD- NLC) after topical application on the cervical mucosa in Tibet minipigs. Methods Twelve Tibet mini- pigs were randomized into test group and control group to receive topical application of 0.5% POD- NLC and 0.5% POD tincture,respectively, on the cervical mucosa. Cervical mucosal irritation, targeted distribution and systemic absorption of POD were observed at different time points within 24 h after the drug application. Results No local inflammation reaction was observed in the test group, while serious local irritations(swelling, blisters, blood blisters, erosion and ulceration) occurred in the control group. The fluorescence intensity of POD in the mucosal tissue reached the peak level at 4 h after drug application in the control group, while the POD fluorescence intensity increased slowly and reached the peak level at 16 h in the test group. The peak blood POD concentration occurred at 6 h after POD-NLC application in the test group(14.28±0.33 ng/m L), as compared to 4 h in the control group(42.46 ± 0.32 ng/m L). At all the time points within 24 h, blood POD concentration remained significantly lower in the test group than in the control group(P<0.05), and the area under curve of blood POD concentration in the control group was 1.38-fold greater than that in the test group. Conclusion POD-NLC allows sustained release of POD and achieves a higher POD concentration in the mucosal tissue without causing local irritation or obvious systemic toxicity in Tibet minipigs.
Objective To assess the distribution and systemic toxicity of podophyllotoxin- loaded nanostructured lipid carriers(POD- NLC) after topical application on the cervical mucosa in Tibet minipigs. Methods Twelve Tibet mini- pigs were randomized into test group and control group to receive topical application of 0.5% POD- NLC and 0.5% POD tincture,respectively, on the cervical mucosa. Cervical mucosal irritation, targeted distribution and systemic absorption of POD were observed at different time points within 24 h after the drug application. Results No local inflammation reaction was observed in the test group, while serious local irritations(swelling, blisters, blood blisters, erosion and ulceration) occurred in the control group. The fluorescence intensity of POD in the mucosal tissue reached the peak level at 4 h after drug application in the control group, while the POD fluorescence intensity increased slowly and reached the peak level at 16 h in the test group. The peak blood POD concentration occurred at 6 h after POD-NLC application in the test group(14.28±0.33 ng/m L), as compared to 4 h in the control group(42.46 ± 0.32 ng/m L). At all the time points within 24 h, blood POD concentration remained significantly lower in the test group than in the control group(P<0.05), and the area under curve of blood POD concentration in the control group was 1.38-fold greater than that in the test group. Conclusion POD-NLC allows sustained release of POD and achieves a higher POD concentration in the mucosal tissue without causing local irritation or obvious systemic toxicity in Tibet minipigs.
引文
[1]姜飞,田海妍,张建龙,等.八角莲的化学成分研究[J].中草药,2011,42(4):634-9.
[2]Lacey CJ,Woodhall SC,Wikstrom A,et al.2012 European guideline for the management of anogenital warts[J].J Eur Acad Dermatol Venereol,2013,27(3):e263-70.
[3]Workowski KA,Bolan GA.Sexually transmitted diseases treatment guidelines,2015[J].MMWR Recomm Rep,2015,64(Rr/03):1-137.
[4]Handley J,Dinsmore W.Treatment of anogenital warts[J].J Eur Acad Dermatol Venereal,1994(3):251-65.
[5]Hermanns-LêT,Arrese JE,Goffin V,et al.Podophyllotoxininduced acantholysis and cytolysis in a skin equivalent model[J].Eur J Morphol,1998,36(3):183-7.
[6]Lacey CJ,Goodall RL,Tennvall GR,et al.Randomised controlled trial and economic evaluation of podophyllotoxin solution,podophyllotoxin cream,and podophyllin in the treatment of genital warts[J].Sex Transm Infect,2003,79(4):270-5.
[7]Pardeike J,Hommoss A,Müller RH.Lipid nanoparticles(SLN,NLC)in cosmetic and pharmaceutical dermal products[J].Int J Pharm,2009,366(1/2):170-84.
[8]Müller RH,Shegokar R,Keck CM.20 years of lipid nanoparticles(SLN and NLC):present state of development and industrial applications[J].Curr Drug Discov Technol,2011,8(3):207-27.
[9]韩凯,王春慧,种树彬,等.0.5%鬼臼毒素纳米脂质载体的制备及理化性质考察[J].皮肤性病诊疗学杂志,2012,19(1):10-3.
[10]王春慧,韩凯,种树彬,等.0.5%鬼臼毒素纳米脂质载体包封率的测定[J].皮肤性病诊疗学杂志,2012,19(1):14-6.
[11]郑商联,周珏.女性尖锐湿疣115例调查[J].浙江预防医学,1999,35(2):19-20.
[12]Heath A,Mellstrand T,Ahlmén J.Treatment of podophyllin poisoning with resin hemoperfusion[J].Hum Toxicol,1982,1(4):373-8.
[13]Maia CS,Mehnert W,Sch?fer-Korting M.Solid lipid nanoparticles as drug carriers for topical glucocorticoids[J].Int J Pharm,2000,196(2):165-7.
[14]武志强,管宇,何宏华,等.小型猪皮肤组织结构及其初期收缩的研究[J].实用美容整形外科杂志,1997,8(3):113-5.
[15]Jenning V,Gysler A,Schafer-Korting M,et al.Vitamin a loaded solid lipid nanoparticles for topical use:occlusive properties and drug targeting to the upper skin[J].Eur J Pharm Biopharm,2000,49(3):211-8.
[16]Müller RH,Radtke M,Wissing SA.Solid lipid nanoparticles(SLN)and nanostructured lipid carriers(NLC)in cosmetic and dermatological preparations[J].Adv Drug Deliv Rev,2002,54(Suppl 1):S131-55.
[17]曾抗,张三泉,江彬彬,等.脂质体鬼臼毒素混悬液在大鼠表皮及真皮的分布规律初探[J].中华皮肤科杂志,2003,36(6):329-31.
[18]Boddupalli BM,Mohammed ZN,Nath RA,et al.Mucoadhesive drug delivery system:An overview[J].J Adv Pharm Technol Res,2010,1(4):381-7.
[19]林东海,李刚,孙秀燕.药物微粒载体在黏膜给药中的黏液屏障与传递策略[J].国际药学研究杂志,2010,37(6):435-8,445.
[20]Gainza G,Bonafonte DC,Moreno B,et al.The topical administration of rh EGF-loaded nanostructured lipid carriers(rh EGF-NLC)improves healing in a porcine full-thickness excisional wound model[J].J Control Release,2015,197(9):41-7.
[2]Lacey CJ,Woodhall SC,Wikstrom A,et al.2012 European guideline for the management of anogenital warts[J].J Eur Acad Dermatol Venereol,2013,27(3):e263-70.
[3]Workowski KA,Bolan GA.Sexually transmitted diseases treatment guidelines,2015[J].MMWR Recomm Rep,2015,64(Rr/03):1-137.
[4]Handley J,Dinsmore W.Treatment of anogenital warts[J].J Eur Acad Dermatol Venereal,1994(3):251-65.
[5]Hermanns-LêT,Arrese JE,Goffin V,et al.Podophyllotoxininduced acantholysis and cytolysis in a skin equivalent model[J].Eur J Morphol,1998,36(3):183-7.
[6]Lacey CJ,Goodall RL,Tennvall GR,et al.Randomised controlled trial and economic evaluation of podophyllotoxin solution,podophyllotoxin cream,and podophyllin in the treatment of genital warts[J].Sex Transm Infect,2003,79(4):270-5.
[7]Pardeike J,Hommoss A,Müller RH.Lipid nanoparticles(SLN,NLC)in cosmetic and pharmaceutical dermal products[J].Int J Pharm,2009,366(1/2):170-84.
[8]Müller RH,Shegokar R,Keck CM.20 years of lipid nanoparticles(SLN and NLC):present state of development and industrial applications[J].Curr Drug Discov Technol,2011,8(3):207-27.
[9]韩凯,王春慧,种树彬,等.0.5%鬼臼毒素纳米脂质载体的制备及理化性质考察[J].皮肤性病诊疗学杂志,2012,19(1):10-3.
[10]王春慧,韩凯,种树彬,等.0.5%鬼臼毒素纳米脂质载体包封率的测定[J].皮肤性病诊疗学杂志,2012,19(1):14-6.
[11]郑商联,周珏.女性尖锐湿疣115例调查[J].浙江预防医学,1999,35(2):19-20.
[12]Heath A,Mellstrand T,Ahlmén J.Treatment of podophyllin poisoning with resin hemoperfusion[J].Hum Toxicol,1982,1(4):373-8.
[13]Maia CS,Mehnert W,Sch?fer-Korting M.Solid lipid nanoparticles as drug carriers for topical glucocorticoids[J].Int J Pharm,2000,196(2):165-7.
[14]武志强,管宇,何宏华,等.小型猪皮肤组织结构及其初期收缩的研究[J].实用美容整形外科杂志,1997,8(3):113-5.
[15]Jenning V,Gysler A,Schafer-Korting M,et al.Vitamin a loaded solid lipid nanoparticles for topical use:occlusive properties and drug targeting to the upper skin[J].Eur J Pharm Biopharm,2000,49(3):211-8.
[16]Müller RH,Radtke M,Wissing SA.Solid lipid nanoparticles(SLN)and nanostructured lipid carriers(NLC)in cosmetic and dermatological preparations[J].Adv Drug Deliv Rev,2002,54(Suppl 1):S131-55.
[17]曾抗,张三泉,江彬彬,等.脂质体鬼臼毒素混悬液在大鼠表皮及真皮的分布规律初探[J].中华皮肤科杂志,2003,36(6):329-31.
[18]Boddupalli BM,Mohammed ZN,Nath RA,et al.Mucoadhesive drug delivery system:An overview[J].J Adv Pharm Technol Res,2010,1(4):381-7.
[19]林东海,李刚,孙秀燕.药物微粒载体在黏膜给药中的黏液屏障与传递策略[J].国际药学研究杂志,2010,37(6):435-8,445.
[20]Gainza G,Bonafonte DC,Moreno B,et al.The topical administration of rh EGF-loaded nanostructured lipid carriers(rh EGF-NLC)improves healing in a porcine full-thickness excisional wound model[J].J Control Release,2015,197(9):41-7.