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蛋白质基生物材料的生物医学应用进展

史乾坤 王玉鹏 张浩 周东方

引用本文:
Citation:

蛋白质基生物材料的生物医学应用进展

    作者简介: 史乾坤(1995—),男,硕士生,主要研究方向为蛋白质基生物材料。E-mail:2896205221@qq.com;周东方,博士,南方医科大学药学院教授,博士生导师。主要从事高分子药物(金属、基因、蛋白)可控递送系统的纳米医学研究以及生物医用高分子材料的再生医学研究。2013~2019年任中国科学院长春应用化学研究所高分子物理与化学国家重点实验室助理研究员,副研究员;2020年起任南方医科大学药学院教授(第三层次人才引进)。近年来以通讯作者/第一作者在Advanced Materials、Nano Letters、ACS Nano、Progress in Polymer Science、Coordination Chemistry Review、Small、Journal of Controlled Release、Bioactive Materials等学术期刊上发表论文40余篇;主持国家自然科学基金面上、青年科学基金项目,中国科学院-威高研究发展计划项目子课题,吉林省科技发展计划优秀青年人才基金项目以及南方医科大学高层次人才引进科研启动项目等;申请中国发明专利8件,其中授权6件;获中/韩国生物材料协会青年科学家奖;入选 Journal of Materials Chemistry B 2020年新锐研究者;担任Bioactive Materials (IF=8.72)的专刊编辑.
    通讯作者: 张浩; 周东方, dfzhou@smu.edu.cn
  • 中图分类号: O636.9

Advances in Protein-Based Biomaterials for Biomedical Applications

    Corresponding author: ZHANG HaoZHOU Dongfang, dfzhou@smu.edu.cn
  • CLC number: O636.9

  • 摘要: 尽管合成生物材料具有巨大的潜力和多样性,但其生物医学应用仍然受到生物相容性、生物降解性及生物再吸收性等问题的限制。天然高分子尤其是蛋白质基生物材料能够较好地解决合成材料存在的问题,在药物递送、组织工程、伤口修复和生物传感器等生物医学领域有着广泛应用。本文重点综述了动物、植物来源的蛋白质基材料在生物医学领域的已有和潜在临床应用,并对其未来应用前景进行了展望。
  • 图 FIG. 600.  FIG. 600.

    Figure FIG. 600..  FIG. 600.

    图 1  蛋白质基材料在生物医学上的应用

    Figure 1.  Protein-based materials for biomedical applications

    表 1  来自动物,植物和微生物的蛋白质

    Table 1.  Proteins from animal, plant and microorganism

    AnimalPlantMicroorganism
    Heat shock proteinsWheat glutenLactate dehydrogenase
    CollagenZeinBrome mosaic virus
    AlbuminSoy proteinChymotrypsin
    KeratinCamellia proteinFumarase
    SilkPeanut proteinAdenovirus
    GelatinRice brain proteinCowpea mosaic virus
    Myofibrillar proteinsCottonseed proteinMS2 bacteriophage
    下载: 导出CSV

    表 2  完成人体临床试验的丝素蛋白基产品

    Table 2.  Silk-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and
    completion date
    Clinical trial identifier
    1SERI surgical scaffoldSoft tissue support and repair10026 months, August 2013NCT01389232
    2Silk surgical meshBreast reconstruction1733 months, March 2016NCT01914653
    3Sericin scaffoldSkin graft, impaired wound healing3020 months, March 2014NCT01539980
    4Restylane silk with lidocaineLip augmentation and correction of perioral rytidis6017 months, August 2016NCT02703948
    5Restylane silkLip rejuvenation2021 months, June 2017NCT03241862
    6Restylane silkPhotoaged thinned hands2512 months, October 2016NCT02780258
    7Silk fibroin with bioactive coating layerdressingSplit-thickness skin graft2914 months, May 2015NCT02091076
    8Silk-like linensPressure ulcer333212 months, March 2015NCT02925741
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV

    表 3  已经完成人体临床试验的角蛋白基产品

    Table 3.  Keratin-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and completion dateClinical trial identifier
    1Keratin dressingsVaricose ulcer14330 months, September 2019NCT02896725
    2Topical keratinBreast carcinoma255 months, November 2018NCT03374995
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV

    表 4  已经完成人体临床试验的人血清白蛋白基产品

    Table 4.  HSA-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and
    completion date
    Clinical trial identifier
    1sEphB4-HSAKaposi sarcoma6518 months, June 2022NCT03993106
    2Pembrolizumab + sEphB4-HSAMetastatic urothelial carcinoma3860 months, December 2025NCT04486781
    3Succinylated human serum albuminHIV infections612 months, June 2006NCT00128063
    4Human albuminGastric cancer anastomotic leak1 04948 months, December 2019NCT04490668
    5Interferonbeta-1a HSA-free biosimilarMultiple sclerosis241 month, August 2015NCT02517788
    6HSA-GCSFChemotherapy-induced neutropenia21620 months, April 2016 NCT02465801
    7Human serum AL bumin/Interferon alpha2aChronic hepatitis B3212 months, November 2014NCT01997944
    8 rHSA-GCSFChemotherapy-induced neutropenia8022 months, April 2019NCT02925741
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV

    表 5  已经完成人体临床试验的转铁蛋白基产品

    Table 5.  Transferrin-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of
    participants
    Study period and
    completion date
    Clinical trial
    identifier
    1Transferrin saturation coefficientIron-deficiency1364 months, September 2019 NCT04139265
    2 Carbohydrate deficient transferrinAlcohol abuse1946 months, October 2016NCT02822911
    3Iron acetyl-transferaseIron deficiency anemia5832 months, October 2010NCT00802139
    4Ferritinand transferrin saturationAnemia40836 months, September 2017NCT02276690
    5Ferrous sulphateIron-deficiency anemia349 months, March 2016NCT02498886
    6Ferric citrateChronic kidney disease6030 months, March 2019NCT02888171
    7Heme-iron polypeptideAnemia8011 months, November 2012NCT01733979
    8Monoclonal antibody A27.15Chronic myeloproliferative disorders2736 months, February 2001NCT00003082
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV

    表 6  已经完成人体临床试验的血红蛋白基产品

    Table 6.  Hemoglobin-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of
    participants
    Study period and
    completion date
    Clinical trial
    identifier
    1HBOC-201Coronary occlusion512 months, April 2008 NCT00479895
    2HBOC-201Angina pectoris4544 months, July 2007 NCT00317512
    3HBOC-201Wounds and injuries5352 months, December 2008 NCT00301483
    4HBOC-201Anemia5080 months, July 2020NCT01881503
    5Hemoglobin glutamer 250 - bovinePeripheral vascular disease1624 months, June 2008NCT00300040
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV

    表 7  已经完成人体临床试验的植物蛋白基产品

    Table 7.  Plant protein-based products completed for human clinical trials

    NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and completion dateClinical trial identifier
    1 ZeinAmino acid2833 months, July 2020 NCT03279211
    2 ZeinBiological availability108 months, January 2019 NCT04207372
    3Milk protein-carbohydrate-soy proteinHypertension35260 months, April 2008 NCT00107744
    4Soy protein dietMetabolic syndrome X154 months, December 2012NCT01694056
    5Soy protein + IsoflavonesGestational diabetes4033 months, September 2016 NCT02806739
    6Soy proteinHypercholesterolemia6036 months, June 2012NCT00945737
    7Soy proteinOsteoporosis20336 months, January 2004NCT00661856
    8Seaweed and soy proteinBreast cancer336 months, March 1999NCT01204957
    9GlutenCeliac disease169 months, May 2019NCT03409796
    10GlutenGluten sensitivity10862 months, April 2016NCT01485341
    11GlutenCeliac disease6012 months, October 2018NCT03288831
    12AN-PEPGluten digestion129 months, May 2012NCT01335503
    Data sources:https://clinicaltrials.gov/
    下载: 导出CSV
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  • 收稿日期:  2020-12-01
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  • 刊出日期:  2021-04-01

蛋白质基生物材料的生物医学应用进展

    通讯作者: 张浩; 
    通讯作者: 周东方, dfzhou@smu.edu.cn
    作者简介: 史乾坤(1995—),男,硕士生,主要研究方向为蛋白质基生物材料。E-mail:2896205221@qq.com;周东方,博士,南方医科大学药学院教授,博士生导师。主要从事高分子药物(金属、基因、蛋白)可控递送系统的纳米医学研究以及生物医用高分子材料的再生医学研究。2013~2019年任中国科学院长春应用化学研究所高分子物理与化学国家重点实验室助理研究员,副研究员;2020年起任南方医科大学药学院教授(第三层次人才引进)。近年来以通讯作者/第一作者在Advanced Materials、Nano Letters、ACS Nano、Progress in Polymer Science、Coordination Chemistry Review、Small、Journal of Controlled Release、Bioactive Materials等学术期刊上发表论文40余篇;主持国家自然科学基金面上、青年科学基金项目,中国科学院-威高研究发展计划项目子课题,吉林省科技发展计划优秀青年人才基金项目以及南方医科大学高层次人才引进科研启动项目等;申请中国发明专利8件,其中授权6件;获中/韩国生物材料协会青年科学家奖;入选 Journal of Materials Chemistry B 2020年新锐研究者;担任Bioactive Materials (IF=8.72)的专刊编辑
  • 1. 南方医科大学药学院,广州 510515
  • 2. 吉林农业大学食品科学与工程学院, 小麦和玉米深加工国家工程实验室,长春 130118

摘要: 尽管合成生物材料具有巨大的潜力和多样性,但其生物医学应用仍然受到生物相容性、生物降解性及生物再吸收性等问题的限制。天然高分子尤其是蛋白质基生物材料能够较好地解决合成材料存在的问题,在药物递送、组织工程、伤口修复和生物传感器等生物医学领域有着广泛应用。本文重点综述了动物、植物来源的蛋白质基材料在生物医学领域的已有和潜在临床应用,并对其未来应用前景进行了展望。

English Abstract

  • 推进生物医用材料这一学科领域发展的关键是开发可以与生物系统相互作用的生物材料以适用于各种医疗健康需求。这些生物材料可以直接来自自然界,也可以人工合成(如通过化学反应制备的聚(乳酸-羟基乙酸)共聚物(PLGA)[1]、聚乳酸(PLA)和聚己内酯(PCL)[2]等)。尽管合成生物材料具有巨大的潜力和多样性,但其生物医学应用仍然受到生物相容性、生物降解性及生物再吸收性等问题的限制[3]。由于天然材料在生物相容性、降解性和吸收性方面固有的优势,目前已经成为生物医学工程中应用的可行替代品[4, 5]。在众多的天然、可再生和可生物降解材料中,蛋白质基生物材料正引起人们的极大兴趣。蛋白质是所有生物领域中普遍存在的重要生物分子,广泛分布于体内并参与几乎所有的生命活动,从单细胞原核生物到单细胞和多细胞真核生物(表1),每一种蛋白质都发挥着自己的作用,共同维持正常的生命活动[6]。例如,白蛋白有助于维持血液的渗透压,并负责输送亲脂物质,如维生素和激素等[7];血红蛋白(Hb)负责体内的气体(氧气、二氧化碳、一氧化碳等)输送;转铁蛋白(Tf)负责运输体内的铁离子。同时,蛋白质具有以下优点:(1)良好的生物相容性;(2)丰富的官能团,如―NH2、―COOH、―SH等,使蛋白质具有较好的功能扩展性能;(3)固有的生物活性,不需要过多的功能化修饰,简化了合成步骤。虽然蛋白质基生物材料具有诸多优点,但是也会引起一定的炎症反应。针对存在的免疫原性问题,可以通过特定的加工方法除去引起免疫原性的成分,如通过提纯的方法制备脱胶丝素蛋白[8],通过酶解法切除胶原蛋白[9]特定的片段,从而使材料表现出最小的炎症反应。因此,蛋白质基生物材料凭借其多种优势,被广泛应用于组织再生的支架、药物递送系统和生物传感器等生物医学工程领域[10]。最近已有不少基于蛋白质生物医学应用的综述文献,例如Abbas等[11]综述了自组装肽和蛋白质基纳米材料用于抗肿瘤光动力和光热治疗;Defrates等[12]综述了植物蛋白作为组织工程的支架研究;Misawa等[13]综述了基于蛋白质的生物传感器的最新进展。区别于上述综述,本综述将重点总结常用动物和植物来源的蛋白质基生物材料在组织工程、生物电子工程、药物递送、伤口修复和制药等领域已有的临床应用情况和潜在的应用前景(图1)。

    AnimalPlantMicroorganism
    Heat shock proteinsWheat glutenLactate dehydrogenase
    CollagenZeinBrome mosaic virus
    AlbuminSoy proteinChymotrypsin
    KeratinCamellia proteinFumarase
    SilkPeanut proteinAdenovirus
    GelatinRice brain proteinCowpea mosaic virus
    Myofibrillar proteinsCottonseed proteinMS2 bacteriophage

    表 1  来自动物,植物和微生物的蛋白质

    Table 1.  Proteins from animal, plant and microorganism

    图  1  蛋白质基材料在生物医学上的应用

    Figure 1.  Protein-based materials for biomedical applications

    • 用于医疗方向的天然材料有着悠久而丰富的历史,例如玛雅人使用珍珠层作为牙种植体,使用肠线作为缝合线。近年来,随着药物递送和组织工程研究的快速发展,在生物相容性和生物可降解性方面具有独特优势的蛋白质基生物材料有着不可或缺的地位。

    • 丝素蛋白作为蚕丝的重要组成部分[14],是一种低密度的结构蛋白,β-折叠和α-螺旋含量高,核心结构域无规则卷曲,使得其强度坚韧[15]。另外,丝素蛋白的氨基酸序列因合成蚕丝的物种而异,赋予其独特的物理和化学性质。丝素蛋白较好的生物相容性和低免疫原性、易加工性、热稳定性和机械强度使得其在组织工程、药物输送和生物光学器件等应用中发挥了重要作用。

      临床上使用的基于天然丝素蛋白的产品包括手术缝合线,韩国世丽(SERI)外科手术支架[16],用于治疗腹壁重建、乳房重建[17, 18]和伤口及皮肤病学状况的丝素蛋白基敷料等。在临床伤口治疗上,与传统的敷料(药用石蜡纱布敷料;Bactigras®)相比,丝素蛋白基敷料不会使伤口黏连且可以很好地吸收渗出液[16, 19]。还有由Sofregen公司开发上市的基于丝素蛋白的3D可注射支架声带,可以提高音量并且能够在体内持续存在12个月以上,并随着时间的推移被新生组织替代。另外,以丝素蛋白为基质的许多产品还处于临床试验阶段。表2列举了部分FDA记录的临床试验产品,主要应用于组织修复、伤口治疗以及医美整形领域,包括软组织修复、乳房重建和唇部修整等。丝素蛋白在生物医学领域还有多种其他的潜在应用,例如,丝素蛋白作为细胞黏附和增殖的载体和支持基质,有助于组织再生[20-24];丝素蛋白基质的生物材料在伤口愈合方面的性能已有许多研究,如纳米纤维垫[25, 26]、涂层[27-29]、水凝胶[30]和多孔支架[31]等,与商业上可用的产品相比,显示出更好的愈合性能[32, 33],以及作为皮肤替代物的潜力。

      NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and
      completion date
      Clinical trial identifier
      1SERI surgical scaffoldSoft tissue support and repair10026 months, August 2013NCT01389232
      2Silk surgical meshBreast reconstruction1733 months, March 2016NCT01914653
      3Sericin scaffoldSkin graft, impaired wound healing3020 months, March 2014NCT01539980
      4Restylane silk with lidocaineLip augmentation and correction of perioral rytidis6017 months, August 2016NCT02703948
      5Restylane silkLip rejuvenation2021 months, June 2017NCT03241862
      6Restylane silkPhotoaged thinned hands2512 months, October 2016NCT02780258
      7Silk fibroin with bioactive coating layerdressingSplit-thickness skin graft2914 months, May 2015NCT02091076
      8Silk-like linensPressure ulcer333212 months, March 2015NCT02925741
      Data sources:https://clinicaltrials.gov/

      表 2  完成人体临床试验的丝素蛋白基产品

      Table 2.  Silk-based products completed for human clinical trials

    • 角蛋白是富含半胱氨酸(4%~17%,质量分数)的纤维蛋白,与中间细丝结合形成大量的细胞骨架和表皮附肢结构,如头发、角、羽毛、羊毛、指甲等[34]。角蛋白由不同氨基酸的多肽链构成,这些多肽链可作为分子间或分子内键合的骨架。角蛋白分子内的二硫键、氢键和离子键增加了其结构的稳定性和强度[35]。根据硫含量的不同,角蛋白可分为硬角蛋白和软角蛋白。具有较高硫含量(5%,质量分数)的硬角蛋白,由短晶纤维嵌入高交联的弹性体基质组成[36]。软角蛋白,具有低硫含量(1%,质量分数),由松散的细胞质丝束组成,是上皮组织中的细胞骨架元素。

      角蛋白基生物材料在生物医用领域得到广泛的研究和应用。例如,在伤口修复领域,角蛋白敷料在慢性伤口如糖尿病伤口中进行了治疗测试,取得了良好的治疗效果[37];利用角蛋白水凝胶和纱布绷带包裹的混合物成功治疗了隐性营养不良性大疱性表皮松解症患者[38]。在肿瘤治疗中,放疗会对皮肤产生一定的影响,例如微弱或暗沉的红斑、干性脱屑或急性放射性皮炎。在一项临床研究中使用角蛋白基敷料减弱放疗对乳腺癌患者皮肤的副作用(表3)。虽然目前角蛋白基材料应用于临床的产品较少,但是已经开展了广泛的临床前研究。例如,角蛋白基生物材料可以显著提高骨间充质干细胞的附着和增殖,使骨密度增加,可达到天然骨的水平,同时减少异位骨的生长[39-41]。角蛋白基敷料具有伤口敷料所需的许多关键特性,包括吸收伤口渗出物的成胶能力、良好的吸水率、最佳的水蒸气透过率、低毒性和生物可降解性等。角蛋白衍生物还可以与蛋白水解伤口环境相互作用,以促进伤口愈合[42-44]。此外,角蛋白具有丰富的二硫键,在药物递送中可显著改善其黏膜黏附性,保护敏感的药物并增加生物利用度[45]。此外,在炎症和癌组织中过表达的胰蛋白酶可以将角蛋白分解为无毒的多肽或者氨基酸。因此,角蛋白可以作为药物载体实现药物可控释放用于肿瘤治疗[46, 47]

      NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and completion dateClinical trial identifier
      1Keratin dressingsVaricose ulcer14330 months, September 2019NCT02896725
      2Topical keratinBreast carcinoma255 months, November 2018NCT03374995
      Data sources:https://clinicaltrials.gov/

      表 3  已经完成人体临床试验的角蛋白基产品

      Table 3.  Keratin-based products completed for human clinical trials

    • 白蛋白是一种心形蛋白质,包含3个同源域,每个域还包括2个单独的子域。根据来源的不同,可以分为人血清白蛋白(HSA)、牛血清白蛋白(BSA)等。BSA和HSA是具有76%序列同源性的同源蛋白,主要成分的区别在于BSA分子中有一个色氨酸残基。人体中,白蛋白约占血清总蛋白的60%,在生理上具有两个重要作用[48]:(1)调节血浆的渗透压;(2)结合和运输金属离子、小分子、疏水物质(如脂肪酸等),维持物质的正常转运。

      白蛋白可以作为一种优良载体来装载药物、金属离子或其他有机或无机物质等[49]。由于具有较好的生物相容性和免疫原性,因此可作为载体用于癌症成像和治疗。目前,HSA基载体已在临床上应用于癌症、艾滋病以及慢性病的治疗(表4)。2005年,FDA批准了白蛋白结合型紫杉醇药物Abraxane用于临床治疗多种癌症。除此之外,还开发了白蛋白结合雷帕霉素和哌替啶来治疗骨髓瘤[50]。INNO-206是多柔比星 (DNA 拓扑异构酶 II 抑制剂) 的白蛋白结合前药,在2017年通过了3期临床试验[51]。同时,基于白蛋白纳米药物可以通过光热疗法(PTT)[52, 53]、光动力疗法(PDT)[54]和声动力疗法(SDT)[55]等不同方式来治疗肿瘤。此外,还可以设计具有“all-in-one”特点的纳米材料,借助成像功能介导肿瘤治疗[56, 57],实现三模态成像荧光成像(FL)、光声成像(PA)、核磁共振成像(MRI)和PDT功能。

      NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and
      completion date
      Clinical trial identifier
      1sEphB4-HSAKaposi sarcoma6518 months, June 2022NCT03993106
      2Pembrolizumab + sEphB4-HSAMetastatic urothelial carcinoma3860 months, December 2025NCT04486781
      3Succinylated human serum albuminHIV infections612 months, June 2006NCT00128063
      4Human albuminGastric cancer anastomotic leak1 04948 months, December 2019NCT04490668
      5Interferonbeta-1a HSA-free biosimilarMultiple sclerosis241 month, August 2015NCT02517788
      6HSA-GCSFChemotherapy-induced neutropenia21620 months, April 2016 NCT02465801
      7Human serum AL bumin/Interferon alpha2aChronic hepatitis B3212 months, November 2014NCT01997944
      8 rHSA-GCSFChemotherapy-induced neutropenia8022 months, April 2019NCT02925741
      Data sources:https://clinicaltrials.gov/

      表 4  已经完成人体临床试验的人血清白蛋白基产品

      Table 4.  HSA-based products completed for human clinical trials

    • 转铁蛋白(Tf)是一种碳水化合物质量分数约为6%的糖蛋白。一个Tf分子由两个相似的结构域组成,每个结构域都含有一个铁结合位点,这与它在体内的重要功能相对应,即将铁离子转运到器官和组织以维持正常的铁代谢[58]

      基于Tf基材料,目前已经完成了先天性无转铁蛋白血症、缺铁性贫血等疾病,以及酒精滥用检测等的临床研究。例如,在临床上治疗缺铁性贫血,对比其他不同类型的铁离子,Tf具有较好的疗效。此外,Tf也应用于慢性肾病、慢性骨髓增生等疾病的治疗(表5)。随着肿瘤在体内的快速生长,导致其对铁有更高的需求,因此转铁蛋白受体(TFRs)在许多肿瘤中过度表达,甚至是正常细胞中的100倍以上[59]。这使得Tf基载体具有肿瘤靶向能力,有利于开发其在肿瘤药物靶向递送中的应用。虽然Tf有诸多优点,但是目前还没有基于Tf的纳米药物处于临床试验阶段或获得FDA批准。基于Tf的纳米药物TransMID (Tf通过赖氨酸交联剂和硫酯与高效白喉毒素CRM-107结合制备而成)曾进行了治疗多形性胶质母细胞瘤的临床研究,该纳米药物成功通过了I和II期临床试验。但是,由于预计会产生阴性结果,最终撤回了III期临床试验。到目前为止,大多数与Tf相关的研究都利用Tf作为靶向基团[60, 61],修饰到其他类型的纳米载体表面,如脂质体[62]、碳点[63]、SiO2[64]、PLGA[65]、聚L-赖氨酸[66]、Au纳米粒子[67]等。基于Tf的肿瘤治疗纳米药物研究相对较少,这大概是因为与HSA和BSA相比,Tf要昂贵得多,没有核壳结构,不利于物质负载。然而,由于其固有的靶向能力和协调金属离子或药物的潜力,寻找新的基于Tf的纳米平台用于有效的肿瘤治疗仍然具有重要意义。

      NoIntervention/TreatmentCondition/DiseaseNumber of
      participants
      Study period and
      completion date
      Clinical trial
      identifier
      1Transferrin saturation coefficientIron-deficiency1364 months, September 2019 NCT04139265
      2 Carbohydrate deficient transferrinAlcohol abuse1946 months, October 2016NCT02822911
      3Iron acetyl-transferaseIron deficiency anemia5832 months, October 2010NCT00802139
      4Ferritinand transferrin saturationAnemia40836 months, September 2017NCT02276690
      5Ferrous sulphateIron-deficiency anemia349 months, March 2016NCT02498886
      6Ferric citrateChronic kidney disease6030 months, March 2019NCT02888171
      7Heme-iron polypeptideAnemia8011 months, November 2012NCT01733979
      8Monoclonal antibody A27.15Chronic myeloproliferative disorders2736 months, February 2001NCT00003082
      Data sources:https://clinicaltrials.gov/

      表 5  已经完成人体临床试验的转铁蛋白基产品

      Table 5.  Transferrin-based products completed for human clinical trials

    • 血红蛋白是被研究最多的一类呼吸蛋白,它是高等生物体内负责运载氧气(O2)的一种蛋白质,分别含有2条α肽链、β肽链,以及一个环状血红素。每一个血红素,能结合一个分子O2 (1 g血红蛋白能结合1.39 mL O2)并被血液运输[68]。为解决传统输血的问题,如交叉配血、严重的血液短缺和病毒交叉感染,被称为血液替代品的人工氧气载体已经进行了广泛的研究。到目前为止,主要有两种类型的氧气载体:完全合成氧载体(包括全氟化物和血红素杂化物)和基于血红蛋白的氧载体(HBOCs)。在这些氧载体中,HBOCs由于其独特的输氧能力受到极大关注[69],而目前Hb主要临床研究和主要应用也集中在氧气载体方面(表6)。

      NoIntervention/TreatmentCondition/DiseaseNumber of
      participants
      Study period and
      completion date
      Clinical trial
      identifier
      1HBOC-201Coronary occlusion512 months, April 2008 NCT00479895
      2HBOC-201Angina pectoris4544 months, July 2007 NCT00317512
      3HBOC-201Wounds and injuries5352 months, December 2008 NCT00301483
      4HBOC-201Anemia5080 months, July 2020NCT01881503
      5Hemoglobin glutamer 250 - bovinePeripheral vascular disease1624 months, June 2008NCT00300040
      Data sources:https://clinicaltrials.gov/

      表 6  已经完成人体临床试验的血红蛋白基产品

      Table 6.  Hemoglobin-based products completed for human clinical trials

      近年来研究发现,当微生物侵入人体时,红细胞内的Hb会释放出活性氧,活性氧能迅速杀死入侵的致病微生物。并且,病原体越强,Hb产生的活性氧就越多[70, 71]。此外,Hb在与细菌共培养时能够被微生物蛋白酶直接激活产生更多的活性氧,从而能有效抑制金黄色葡萄球菌和铜绿假单胞菌等细菌,具有杀灭致病细菌的作用[72]。另外,以Hb为基础的供氧治疗越来越多地与放疗、化疗、光动力治疗和免疫治疗等治疗手段相结合,并取得了良好疗效,为肿瘤治疗提供了新的治疗手段。例如,通过将Hb与光敏剂结合用于肿瘤的光动力疗法,Hb可通过供氧增强光动力治疗效果[73-76]。总之,随着Hb的抗菌免疫能力、类过氧化物酶活性以及靶向能力等多种功能的不断发现,Hb不再单纯作为载氧蛋白,其多重生物学功能越来越引起研究者的兴趣。对Hb的深入研究,将有助于拓展对Hb更多功能性的开发与应用,也可为开发新抗菌和药物载体提供新思路。

    • 玉米中的主要贮藏蛋白玉米醇溶蛋白(Zein)是一种富含多巴胺的蛋白质,含有疏水氨基酸、脯氨酸和谷氨酰胺,除易于电纺外,还具有良好的生物相容性和生物可降解性等特点。它由非极性疏水、极性中性氨基酸残基组成,其两亲性使其能够自组装形成微观结构,并通过范德华力相互作用和分子内氢键来获得化学结构的稳定性,可以应用在食品和药品中。在临床研究中,主要考察玉米醇溶蛋白作为食品在回肠中的消化率以及生物利用度 (表7)。玉米醇溶蛋白凭借较好的生物相容性、生物可降解性,已被广泛应用于其他生物医学领域中,例如组织工程、纳米药物递送体系等[77]。通过静电纺丝将玉米醇溶蛋白与柠檬酸、阿拉伯胶等物质制备成纺丝纤维膜,体外试验表明,静电纺丝纤维膜具有改善细胞附着,促进细胞增殖的作用,可作为伤口敷料[78, 79]。此外,玉米醇溶蛋白纤维支架还具备优异的促进骨修复的能力[80, 81]。玉米醇溶蛋白是优良的载体材料,可负载抗肿瘤药物用于肿瘤治疗。例如,在Zein表面修饰靶向分子用于肿瘤的靶向治疗,提高疗效[82, 83];Kaushik等[84]制备了玉米醇溶蛋白果胶交联负载阿霉素且具有pH响应性的水凝胶,该水凝胶对宫颈癌细胞系表现出优异的细胞毒性。

      NoIntervention/TreatmentCondition/DiseaseNumber of participantsStudy period and completion dateClinical trial identifier
      1 ZeinAmino acid2833 months, July 2020 NCT03279211
      2 ZeinBiological availability108 months, January 2019 NCT04207372
      3Milk protein-carbohydrate-soy proteinHypertension35260 months, April 2008 NCT00107744
      4Soy protein dietMetabolic syndrome X154 months, December 2012NCT01694056
      5Soy protein + IsoflavonesGestational diabetes4033 months, September 2016 NCT02806739
      6Soy proteinHypercholesterolemia6036 months, June 2012NCT00945737
      7Soy proteinOsteoporosis20336 months, January 2004NCT00661856
      8Seaweed and soy proteinBreast cancer336 months, March 1999NCT01204957
      9GlutenCeliac disease169 months, May 2019NCT03409796
      10GlutenGluten sensitivity10862 months, April 2016NCT01485341
      11GlutenCeliac disease6012 months, October 2018NCT03288831
      12AN-PEPGluten digestion129 months, May 2012NCT01335503
      Data sources:https://clinicaltrials.gov/

      表 7  已经完成人体临床试验的植物蛋白基产品

      Table 7.  Plant protein-based products completed for human clinical trials

    • 大豆蛋白是从大豆中分离出来的球形蛋白,具有长期储存稳定性。大豆蛋白中包含极性、非极性和带电荷的氨基酸残基,包括赖氨酸、酪氨酸、亮氨酸、苯丙氨酸、天冬氨酸和谷氨酸,可以与各种生物活性分子和药物相互作用,最常见的相互作用是疏水相互作用、氢键和范德华力作用。大豆蛋白已被广泛用于黏合剂、涂料、水凝胶和乳化剂的制备。由于它的生物相容性和与细胞外基质天然成分的生物化学相似性,因此在生物医学领域应用前景广阔。大豆蛋白含有几种与健康相关的营养因子,如生物活性肽、大豆异黄酮等;此外,大豆蛋白质中各种必需氨基酸的构成比例适宜,因此具有较高的生物学价值。目前临床上在治疗肥胖和血脂等方面,大豆蛋白被证明可以改善血脂循环并减轻体重 (表7)。同时,在相关研究中,大豆蛋白基生物材料能够诱导新组织形成,减少宿主组织的炎症反应,促进伤口愈合[85, 86]。基于大豆蛋白的纤维毡表现出良好的抗菌活性,并且具有良好的生物相容性,可以作为敷料应用于伤口修复[87, 88]。在药物递送领域中,大豆蛋白基载体可以接枝靶向分子使其具有靶向功能,提高细胞内吞量[89]。此外,大豆蛋白可以制备成热敏性水凝胶用于控制药物释放系统[90],还能促进新骨形成,可以应用到骨组织工程中[91, 92]

    • 小麦是世界上重要的作物之一,是蛋白质、硫胺素、核黄素和钾的宝贵来源,此外也能提供膳食纤维、烟酸、铁、锌、维生素B6、镁、磷、铜、硒和锰成分等。小麦谷蛋白(WG)由于二硫交联分子中存在2%(质量分数)半胱氨酸,具有良好的水稳定性,因此小麦谷蛋白通过不同的形式,如薄膜、纤维和水凝胶,被用于控释应用和组织工程。目前,小麦谷蛋白纳米粒已被用作维生素E、乙酸芳樟酯和氯化苄的转运体,并且已经完成了考察小麦谷蛋白对患有肠易激综合征人群影响的临床试验 (表7)。此外,小麦醇溶蛋白薄膜也应用于药物释放,例如制作软胶囊;另一方面,小麦醇溶蛋白更多地被用于组织工程应用。与PLA膜相比,小麦谷蛋白薄膜具有良好的水稳定性,能够更好地支持成骨细胞的附着和增殖[11]。Xu等[93]用小麦谷蛋白电纺成3D纤维支架,模拟软组织的天然细胞外基质,与市售3D非纤维支架相比,小麦谷蛋白基3D纤维支架表现出更好的支持间充质干细胞的增殖和成脂分化。

    • 蛋白质是生命活动的特定执行者,由于其结构的不同,决定了它们在生命活动中所扮演的角色不同,如血红蛋白在体内运输氧气,起着氧载体的作用;人转铁蛋白维持正常的铁代谢并且具有特异性靶向转铁蛋白受体等作用。目前合成的生物聚合物在医学领域发挥着巨大作用,但是也面临着诸多问题,如生物相容性、不可降解或者降解产物对机体有害以及潜在的免疫原性等问题。天然来源的聚合物蛋白质具有良好的生物相容性、生物可降解性以及独特的物理化学特性,相比合成的聚合物具有较大的优势,因此在生物医学领域如药物递送、组织工程、伤口修复以及生物电子学等方面得到了广泛研究与利用。本文总结了常见动物来源的蛋白丝素蛋白、角蛋白、白蛋白、人转铁蛋白、血红蛋白,以及植物来源的玉米醇溶蛋白、大豆蛋白、小麦谷蛋白在生物医学领域的临床应用以及潜在临床应用。

      近几十年来蛋白质基材料在生物医学领域发展迅速,经过较长时间的研究,尽管已经取得了很大的进步,但是还存在如下亟待解决的问题:(1)蛋白质材料易受到环境影响而丧失生物学活性,如果需要利用蛋白质特有的生物学功能,这一方面问题必须解决,但如果蛋白质仅作为载体就不用过多考虑;(2)蛋白质基纳米材料需要精确控制尺寸和形貌,目前需要迫切解决的是无定形结构和尺寸分布广的问题;(3)目前蛋白质基生物材料研究广泛,但应用到临床以及后续临床转化上市的产品却很少,即使已经上市的蛋白质基药物如白蛋白结合型紫杉醇Abraxane,在使用时仍然存在着白细胞下降、骨髓抑制等副作用,因此还需不断改进药物,将毒副作用降低到最小。蛋白质基生物材料在生物医学领域的应用及发展需要多学科合作,充分发挥优势,为人类的健康发展提供帮助。

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