铁蛋白纳米颗粒应用于生物医疗领域的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2015.10.010

摘要/Abstract

摘要： 在漫长的进化过程中, 生物系统中出现了多种多样的纳米粒子。其中铁蛋白纳米粒子广泛存在于所有生物体内, 是参与生命活动的重要功能蛋白。近年来, 铁蛋白自组装纳米粒子特殊的理化性质使其在生物医学领域应用中呈现出巨大的优势和应用前景。铁蛋白纳米笼的应用主要包括微量血清铁蛋白的临床检查、作为营养物质补充机体铁需求、纳米生物材料平台和纳米材料的生物呈递等。综述了铁蛋白纳米粒子在疾病诊断与治疗以及药物呈递与疫苗开发上的应用, 并对铁蛋白纳米粒子在生物医学领域的应用前景进行展望。

关键词: 铁蛋白, 纳米技术, 生物医药

Abstract: Biological systems have generated wide varieties of nanoparticles during the process of long evolution. As one of naturally occurring nanoparticles, ferritin widely exists in all organisms, and is a key functional protein in life activities. Recently, the specific physicochemical properties of self-assembling ferritin nanoparticles allow it possessing the enormous advantages and application prospect in biomedical field. Current applications of ferritin nanocages include clinical measurements of trace amounts released into serum, nutritional sources of concentrated iron, nano biomaterial templates, and biological delivery of nanomaterials. This review presents an overview of ferritin nanoparticles in the diseases diagnose and treatment, delivery of medicines and development of vaccine, and outlines the potential prospects of applying ferritin nanoparticles on biomedicine.

Key words: ferritin, nanoparticles, biomedicine

李志鹏,刘庆友,石德顺,. 铁蛋白纳米颗粒应用于生物医疗领域的研究进展[J]. 生物技术通报, 2015, 31(10): 38-47.

Li Zhipeng, Liu Qingyou, Shi Deshun. Research Progress on Application of Ferritin Nanoparticles in the Field of Biomedicine[J]. Biotechnology Bulletin, 2015, 31(10): 38-47.

参考文献

[1]Lippert PC, Zachos JC. A biogenic origin for anomalous fine-grained magnetic material at the Paleocene-Eocene boundary at Wilson Lake, New Jersey[J]. Paleoceanography, 2007, 22（4）. DOI：10.1029/2007PA001471.
[2] Stanley S. Biological nanoparticles and their influence on organisms[J]. Curr Opin Biotechnol, 2014, 28C：69-74.
[3]Theil EC, Behera RK, Tosha T. Ferritins for Chemistry and for Life[J]. Coord Chem Rev, 2013, 257（2）：579-586.
[4]Theil EC. Ferritin protein nanocages-the story[J]. Nanotechnol Percept, 2012, 8（1）：7-16.
[5] Laufberger V. Sur la cristallisation de la ferritine[J]. Bull Soc Chim Biol, 1937, 19：1575-1582.
[6]Gerrity RG, Thomas K, Rosenthal J, et al. Accumulation of ferritin in the aortic intima of hyperlipemic swine[C]. New York：Journal of Cell Biology, 1981：A417.
[7]Worwood M, Aherne W, Dawkins S, et al. The characteristics of ferritin from human tissues, serum and blood cells[J]. Clin Sci Mol Med, 1975, 48：441-451.
[8]Hampton JC. An electron microscope study of the source and distribution of ferritin in hepatic parenchymal cells of the newborn rabbit[J]. Blood, 1960, 15：480-490.
[9]Proudhon D, Briat JF, Lescure AM. Iron induction of ferritin synthesis in soybean cell suspensions[J]. Plant Physiol, 1989, 90（2）：586-590.
[10]David CN, Easterbrook K. Ferritin in the fungus Phycomyces[J]. J Cell Biol, 1971, 48（1）：15-28.
[11]Andrews SC, Harrison PM, Guest JR. Cloning, sequencing, and mapping of the bacterioferritin gene（bfr）of Escherichia coli K-12[J]. J Bacteriol, 1989, 171（7）：3940-3947.
[12]Towe KM. Structural distinction between ferritin and iron-dextran（imferon）. An electron diffraction comparison[J]. J Biol Chem, 1981, 256（18）：9377-9378.
[13]Harrison PM, Fischbach FA, Hoy TG, et al. Ferric oxyhydroxide core of ferritin[J]. Nature, 1967, 216（5121）：1188-1190.
[14]Theil EC. Ferritin protein nanocages use ion channels, catalytic sites, and nucleation channels to manage iron/oxygen chemistry[J]. Curr Opin Chem Biol, 2011, 15（2）：304-311.
[15]Schwartz JK, Liu XS, Tosha T, et al. Spectroscopic definition of the ferroxidase site in M ferritin：comparison of binuclear substrate vs cofactor active sites[J]. J Am Chem Soc, 2008, 130（29）：9441-9450.
[16]Barnés CM, Theil EC, Raymond KN. Iron uptake in ferritin is blocked by binding of[Cr（TREN）（H₂O）（OH）]²⁺, a slow dissociating model for[Fe（H₂O）6]²⁺[J]. Proceedings of the National Academy of Sciences, 2002, 99（8）：5195-5200.
[17]Harrison PM, Arosio P. The ferritins：molecular properties, iron storage function and cellular regulation[J]. Biochim Biophys Acta, 1996, 1275（3）：161-203.
[18]Torti FM, Torti SV. Regulation of ferritin genes and protein[J]. Blood, 2002, 99（10）：3505-3516.
[19]Lawson DM, Artymiuk PJ, Yewdall SJ, et al. Solving the structure of human H ferritin by genetically engineering intermolecular crystal contacts[J]. Nature, 1991, 349（6309）：541-544.
[20]Cozzi A, Corsi B, Levi S, et al. Overexpression of wild type and mutated human ferritin H-chain in HeLa cells：in vivo role of ferritin ferroxidase activity[J]. J Biol Chem, 2000, 275（33）：25122-25129.
[21] Levi S, Yewdall SJ, Harrison PM, et al. Evidence that H- and L-chains have co-operative roles in the iron-uptake mechanism of human ferritin[J]. Biochemistry J, 1992（288）：591-596.
[22]Meyron-Holtz EG, Moshe-Belizowski S, Cohen LA. A possible role for secreted ferritin in tissue iron distribution[J]. J Neural Transm, 2011, 118（3）：337-347.
[23]Arosio P, Ingrassia R, Cavadini P. Ferritins：a family of molecules for iron storage, antioxidation and more[J]. Biochim Biophys Acta, 2009, 1790（7）：589-599.
[24]Beck JR, Meier FA, French EE, et al. Serum-ferritin[J]. Lancet, 1979, 1（8125）：1080.
[25]Blake DR, Bacon PA, Eastham EJ, et al. Synovial fluid ferritin in rheumatoid arthritis[J]. Br Med J, 1980, 281（6242）：715-716.
[26]Sindic CJ, Collet-Cassart D, Cambiaso CL, et al. The clinical relevance of ferritin concentration in the cerebrospinal fluid[J]. J Neurol Neurosurg Psychiatry, 1981, 44（4）：329-333.
[27]Santambrogio P, Pinto P, Levi S, et al. Effects of modifications near the 2-, 3- and 4-fold symmetry axes on human ferritin renaturation[J]. Biochem J, 1997, 322（Pt 2）：461-468.
[28]Stefanini S, Cavallo S, Wang CQ, et al. Thermal stability of horse spleen apoferritin and human recombinant H apoferritin[J]. Arch Biochem Biophys, 1996, 325（1）：58-64.
[29]Kang S, Oltrogge LM, Broomell CC, et al. Controlled assembly of bifunctional chimeric protein cages and composition analysis using noncovalent mass spectrometry[J]. J Am Chem Soc, 2008, 130（49）：16527-16529.
[30]Uchida M, Kang S, Reichhardt C, et al. The ferritin superfamily：Supramolecular templates for materials synthesis[J]. Biochim Biophys Acta, 2010, 1800（8）：834-845.
[31]Lin X, Xie J, Niu G, et al. Chimeric ferritin nanocages for multiple function loading and multimodal imaging[J]. Nano Lett, 2011, 11（2）：814-819.
[32] Heywood BR. Synthesis of inorganic nanophase materials in supramolecular protein cages[J]. Nature, 1991, 349（6311）：684-687.
[33] Mann S, Archibald DD, Didymus JM, et al. Crystallization at inorganic-organic interfaces：biominerals and biomimetic synthesis[J]. Science, 1993, 261（5126）：1286-1292.
[34] Uchida M, Flenniken ML, Allen M, et al. Targeting of cancer cells with ferrimagnetic ferritin cage nanoparticles[J]. J Am Chem Soc, 2006, 128（51）：16626-16633.
[35] Andrews NC. Forging a field：the golden age of iron biology[J]. Blood, 2008, 112（2）：219-230.
[36] Cadenas E. Biochemistry of oxygen toxicity[J]. Annu Rev Biochem, 1989, 58：79-110.
[37] Alkhateeb AA, Connor JR. Nuclear ferritin：A new role for ferritin in cell biology[J]. Biochim Biophys Acta, 2010, 1800（8）：793-797.
[38] Levi S, Arosio P. Mitochondrial ferritin[J]. Int J Biochem Cell Biol, 2004, 36（10）：1887-1889.
[39] Knovich MA, Storey JA, Coffman LG, et al. Ferritin for the clinician[J]. Blood Rev, 2009, 23（3）：95-104.
[40] Jezequel P, Campion L, Spyratos F, et al. Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors：A multicentric 2004 national PHRC study[J]. Int J Cancer, 2012, 131（2）：426-437.
[41] Volpino P, Cangemi V, Caputo V, et al. Clinical usefulness of serum ferritin measurements in lung cancer patients[J]. J Nucl Med Allied Sci, 1984, 28（1）：27-30.
[42] Gray CP, Arosio P, Hersey P. Association of increased levels of heavy-chain ferritin with increased CD4⁺ CD25⁺ regulatory T-cell levels in patients with melanoma[J]. Clin Cancer Res, 2003, 9（7）：2551-2559.
[43]Fantechi E, Innocenti C, Zanardelli M, et al. A smart platform for hyperthermia application in cancer treatment：cobalt-doped ferrite nanoparticles mineralized in human ferritin cages[J]. ACS Nano, 2014, 8（5）：4705-4719.
[44]Almeida SM, Cunha S, Yamada E, et al. Quantification of cerebrospinal fluid ferritin as a biomarker for CNS malignant infiltration[J]. Arq Neuropsiquiatr, 2008, 66（3B）：720-724.
[45]Szymendera JJ, Kozlowicz-Gudzinska I, Madej G, et al. Clinical usefulness of serum ferritin measurements in patients with testicular germ cell tumors[J]. Oncology, 1985, 42（4）：253-258.
[46]Zhang XZ, Su AL, Hu MQ, et al. Elevated serum ferritin levels in patients with hematologic malignancies[J]. Asian Pac J Cancer Prev, 2014, 15（15）：6099-6101.
[47]Matzner Y, Konijn AM, Hershko C. Serum ferritin in hematologic malignancies[J]. Am J Hematol, 1980, 9（1）：13-22.
[48]Wang W, Knovich MA, Coffman LG, et al. Serum ferritin：Past, present and future[J]. Biochim Biophys Acta, 2010, 1800（8）：760-769.
[49]Daniels TR, Delgado T, Helguera G, et al. The transferrin receptor part II：targeted delivery of therapeutic agents into cancer cells[J]. Clin Immunol, 2006, 121（2）：159-176.
[50]Reissmann KR, Dietrich MR. On the presence of ferritin in the peripheral blood of patients with hepatocellular disease[J]. J Clin Invest, 1956, 35（6）：588-595.
[51]Daniels TR, Bernabeu E, Rodriguez JA, et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer[J]. Biochim Biophys Acta, 2012, 1820（3）：291-317.
[52]Chen H, Yeh J, Wang L, et al. Reducing non-specific binding and uptake of nanoparticles and improving cell targeting with an antifouling peo-b-p gamma amps copolymer coating[J]. Biomaterials, 2010, 20（31）：5397-5407.
[53] Doshi N, Mitragotri S. Designer biomaterials for nanomedicine[J]. Advanced Functional Materials, 2009, 19（24）：3843-3854.
[54] Fan K, Cao C, Pan Y, et al. Magnetoferritin nanoparticles for targeting and visualizing tumour tissues[J]. Nat Nanotechnol, 2012, 7（7）：459-464.
[55]Gao L, Zhuang J, Nie L, et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles[J]. Nat Nanotechnol, 2007, 2（9）：577-583.
[56]O'Leary TJ. Standardization in immunohistochemistry[J]. Appl Immunohistochem Mol Morphol, 2001, 9（1）：3-8.
[57]Fan K, Cao C, Pan Y, et al. Magnetoferritin nanoparticles for targeting and visualizing tumour tissues[J]. Nat Nanotechnol, 2012, 7（7）：459-464.
[58]Uchida M, Terashima M, Cunningham CH, et al. A human ferritin iron oxide nano-composite magnetic resonance contrast agent[J]. Magn Reson Med, 2008, 60（5）：1073-1081.
[59]Dreher MR, Liu W, Michelich CR, et al. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers[J]. J Natl Cancer Inst, 2006, 98（5）：335-344.
[60]Lee LA, Wang Q. Adaptations of nanoscale viruses and other protein cages for medical applications[J]. Nanomedicine, 2006, 2（3）：137-149.
[61]Gilad AA, Winnard PJ, van Zijl PC, et al. Developing MR reporter genes：promises and pitfalls[J]. NMR Biomed, 2007, 20（3）：275-290.
[62]Cohen B, Ziv K, Plaks V, et al. Ferritin nanoparticles as magnetic resonance reporter gene[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2009, 1（2）：181-188.
[63]Li X, Qiu L, Zhu P, et al. Epidermal growth factor-ferritin H-chain protein nanoparticles for tumor active targeting[J]. Small, 2012, 8（16）：2505-2514.
[64]Kang HJ, Kang YJ, Lee YM, et al. Developing an antibody-binding protein cage as a molecular recognition drug modular nanoplatform[J]. Biomaterials, 2012, 33（21）：5423-5430.
[65]Lin X, Xie J, Zhu L, et al. Hybrid ferritin nanoparticles as activatable probes for tumor imaging[J]. Angew Chem Int Ed Engl, 2011, 50（7）：1569-1572.
[66]Ji T, Zhao Y, Wang J, et al. Tumor fibroblast specific activation of a hybrid ferritin nanocage-based optical probe for tumor microenvironment imaging[J]. Small, 2013, 9（14）：2427-2431.
[67]Li K, Zhang ZP, Luo M, et al. Multifunctional ferritin cage nanostructures for fluorescence and MR imaging of tumor cells[J]. Nanoscale, 2012, 4（1）：188-193.
[68]Aime S, Frullano L, Geninatti CS. Compartmentalization of a gadolinium complex in the apoferritin cavity：a route to obtain high relaxivity contrast agents for magnetic resonance imaging[J]. Angew Chem Int Ed Engl, 2002, 41（6）：1017-1019.
[69] Geninatti CS, Bussolati B, Tei L, et al. Magnetic resonance visualization of tumor angiogenesis by targeting neural cell adhesion molecules with the highly sensitive gadolinium-loaded apoferritin probe[J]. Cancer Res, 2006, 66（18）：9196-9201.
[70] Huang P, Rong P, Jin A, et al. Dye-loaded ferritin nanocages for multimodal imaging and photothermal therapy[J]. Adv Mater, 2014, 26（37）：6401-6408.
[71]Terashima M, Uchida M, Kosuge H, et al. Human ferritin cages for imaging vascular macrophages[J]. Biomaterials, 2011, 32（5）：1430-1437.
[72] Kitagawa T, Kosuge H, Uchida M, et al. RGD-conjugated human ferritin nanoparticles for imaging vascular inflammation and angiogenesis in experimental carotid and aortic disease[J]. Mol Imaging Biol, 2012, 14（3）：315-324.
[73] Naumova AV, Reinecke H, Yarnykh V, et al. Ferritin overexpression for noninvasive magnetic resonance imaging-based tracking of stem cells transplanted into the heart[J]. Mol Imaging, 2010, 9（4）：201-210.
[74]Sun C, Yang H, Yuan Y, et al. Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging[J]. J Am Chem Soc, 2011, 133（22）：8617-8624.
[75] Li M, Mann S. DNA-directed assembly of multifunctional nanoparticle networks using metallic and bioinorganic building blocks[J]. J Mater Chem, 2004, 14（14）：2260-2263.
[76] Liu G, Wu H, Wang J, et al. Apoferritin-templated synthesis of metal phosphate nanoparticle labels for electrochemical immunoassay[J]. Small, 2006, 2（10）：1139-1143.
[77] Zhao J, Liu M, Zhang Y, et al. Apoferritin protein nanoparticles dually labeled with aptamer and horseradish peroxidase as a sensing probe for thrombin detection[J]. Anal Chim Acta, 2013, 759：53-60.
[78]Lee SH, Lee H, Park JS, et al. A novel approach to ultrasensitive diagnosis using supramolecular protein nanoparticles[J]. FASEB J, 2007, 21（7）：1324-1334.
[79]Lee EJ, Ahn KY, Lee JH, et al. A novel bioassay platform using ferritin-based nanoprobe hydrogel[J]. Adv Mater, 2012, 24（35）：4739-4744, 4730.
[80]Liang M, Fan K, Zhou M, et al. H-ferritin-nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection[J]. Proc Natl Acad Sci USA, 2014, 111（41）：14900-14905.
[81] Li CQ, Soistman E, Carter DC. Ferritin nanoparticle technology. A new platform for antigen presentation and vaccine development[J]. Industrial Biotechnology, 2006, 2（2）：143-147.
[82]Kanekiyo M, Wei CJ, Yassine H M, et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies[J]. Nature, 2013, 499（7456）：102-106.
[83]Han J, Kang YJ, Shin C, et al. Ferritin protein cage nanoparticles as versatile antigen delivery nanoplatforms for dendritic cell（DC）-based vaccine development[J]. Nanomedicine：Nanotechnology, Biology and Medicine, 2014, 10（3）：561-569.