壳聚糖季铵盐微球作为注射疫苗佐剂的安全性评价
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摘要
以小鼠、大鼠、豚鼠、家兔等为动物模型,对壳聚糖季铵盐微球作为注射疫苗佐剂进行安全性评价.结果表明,小鼠急性毒性实验中50倍临床拟给药剂量(5.0 mg/只)下动物耐受性良好;大鼠重复毒性实验中即使50倍高剂量多次注射微球,动物各组织器官仍无病理性变化;异常毒性实验中小鼠给药后体征正常、体重明显增加,壳聚糖微球注射豚鼠后未见过敏反应及症状;家兔注射部位未发生肌肉组织溃烂、化脓等,佐剂未引起红细胞溶血.
The safety evaluation of N-(2-hydroxy)propyl-3-trimethylammonium chitosan chloride(HTCC) microspheres as parenteral vaccine adjuvant was carried out in mice, rats, guinea pigs, rabbits. Mouse acute toxicity test showed that they have a high tolerance for over 50 times given clinical dose(5.0 mg/dose). Even high dosage of microspheres was injected in SD rats for many times, no pathological changes were found in their organ. The symptoms of mice in abnormal toxicity test were normal after injection. And the weight of mice increased significantly. In allergy test, no allergic reaction and symptoms were found in guinea pigs. And no fester and suppuration were found in muscle stimulation test. In the hemolysis results, red blood cell did not aggregate. All the tests proved good security of the HTCC microspheres.
The safety evaluation of N-(2-hydroxy)propyl-3-trimethylammonium chitosan chloride(HTCC) microspheres as parenteral vaccine adjuvant was carried out in mice, rats, guinea pigs, rabbits. Mouse acute toxicity test showed that they have a high tolerance for over 50 times given clinical dose(5.0 mg/dose). Even high dosage of microspheres was injected in SD rats for many times, no pathological changes were found in their organ. The symptoms of mice in abnormal toxicity test were normal after injection. And the weight of mice increased significantly. In allergy test, no allergic reaction and symptoms were found in guinea pigs. And no fester and suppuration were found in muscle stimulation test. In the hemolysis results, red blood cell did not aggregate. All the tests proved good security of the HTCC microspheres.
引文
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[3]岳华,马光辉.基于纳微米颗粒和凝胶佐剂的新型疫苗传递体系[J].中国材料进展,2015,34(3):216-224.
[4]Singh M,Chakrapani A,O'Hagon D.Nanoparticles and Microparticles as Vaccine-delivery Systems[J].Expert Review of Vaccines,2007,6(5):797-808.
[5]Peek L J,Middaugh C R,Berkland C.Nanotechnology in Vaccine Delivery[J].Adv.Drug Delivery Rev.,2008,60(8):915-928.
[6]Vyas S P,Gupta P N.Implication of Nanoparticles/Microparticles In Mucosal Vaccine Delivery[J].Expert Review of Vaccines,2007,6(3):401-418.
[7]Cui Z,Mumper R J.Microparticles and Nanoparticles as Delivery Systems for DNA Vaccines[J].Critical Reviews in Therapeutic Drug Carrier Systems,2003,20(2):103-137.
[8]Vasiliev Y M.Chitosan-based Vaccine Adjuvants:Incomplete Characterization Complicates Preclinical and Clinical Evaluation[J].Expert Review of Vaccines,2015,14(1):37-53.
[9]Wu J,Wei W,Wang L Y,et al.A Thermosensitive Hydrogel Based on Quaternized Chitosan and Poly(ethylene glycol)for Nasal Drug Delivery System[J].Biomaterials,2007,28(13):2220-2232.
[10]Behera T,Swain P.Antigen Encapsulated Alginate-coated Chitosan Microspheres Stimulate Both Innate and Adaptive Immune Responses in Fish Through Oral Immunization[J].Aquacult.Int.,2013,22(2):673-688.
[11]Kim J J,Nam J P,Nah J W,et al.Immunoadjuvant Efficacy of N-Carboxymethyl Chitosan for Vaccination via Dendritic Cell Activation[J].J.Med.Food,2014,17(2):268-277.
[12]Verheul R J,Hagenaars N,van Es T,et al.A Step-by-step Approach to Study the Influence of N-Acetylation on the Adjuvanticity of N,N,N-Trimethyl Chitosan(TMC)in an Intranasal Nanoparticulate Influenza Virus Vaccine[J].Eur.J.Pharm.Sci.,2012,45(4):467-474.
[13]Jiang H L,Kang M L,Quan J S,et al.The Potential of Mannosylated Chitosan Microspheres to Target Macrophage Mannose Receptors in an Adjuvant-Delivery System for Intranasal Immunization[J].Biomaterials,2008,29(12):1931-1939.
[14]Wang Y Q,Wu J,Fan Q Z,et al.Novel Vaccine Delivery System Induces Robust Humoral and Cellular Immune Responses Based on Multiple Mechanisms[J].Adv.Healthcare Mater.,2014,3(5):670-681.
[15]Vasiliev Y M.Chitosan-based Vaccine Adjuvants:Incomplete Characterization Complicates Preclinical and Clinical Evaluation[J].Expert Review of Vaccines,2015,14(1):37-53.
[16]Neimert-Andersson T,Binnmyr J,Enoksson M,et al.Evaluation of Safety and Efficacy as an Adjuvant for the Chitosan-based Vaccine Delivery Vehicle Viscogel in a Single-blind Randomised Phase I/Iia Clinical Trial[J].Vaccine,2014,32(45):5967-5974.
[17]Bernstein D I,Atmar R L,Lyon G M,et al.Norovirus Vaccine against Experimental Human GII.4 Virus Illness:A Challenge Study in Healthy Adults[J].The Journal of Infectious Diseases,2015,211(6):870-878.
[18]国家药典委员会.中华人民共和国药典[S].2015.
[19]国家食品药品监督管理局药品审评中心.预防用生物制品临床前安全性评价技术审评一般原则[S].2005.
[20]张若明.疫苗的临床前安全性评价[J].中国新药杂志,2008,17(13):1176-1179.
[21]European Medicines Agency.Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines[S].1997.
[22]Cha E,Lee J,Lee S,et al.Single-dose Toxicity of Shin Yang Hur Herbal Acupuncture[J].J.Pharma.,2015,18(2):67-75.
[23]Nam I F,Zhuk V V.Preclinical Animal Acute Toxicity Studies of New Developed MRI Contrast Agent Based on Gadolinium[J].IOP Conference Series:Materials Science and Engineering,2015,81(1):012092.
[24]Greaves P.Histopathology of Preclinical Toxicity Studies:Interpretation and Relevance in Drug Safety Evaluation[M].New York:Elsevier Science,1990.76-77.
[25]Ross T.Fundamentals of Toxicologic Pathology[J].Australian Veterinary Journal,2010,88(6):235-236.
[26]Tryphonas L,Schwartz L W,Levin S,et al.Toxicologic Pathology:Modern Challenges and the Need for a New Educational Strategy[J].Veterinary Pathology,1995,32(2):208-210.
[27]国家食品药品监督管理局.化学药物刺激性、过敏性和溶血性研究技术指导原则[S].2005.
[28]Seubert A,Monaci E,Pizza M,et al.The Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells[J].J.Immunol.,2008,180(8):5402-5412.