纳米技术应用于肿瘤免疫治疗的研究进展
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摘要
近年来,人们对肿瘤生物学和免疫学的基本原理有了更深入的了解,肿瘤的免疫治疗已经取得重大进展,极大促进了一系列新免疫治疗肿瘤药物的发展。肿瘤免疫治疗是指重新启动人体自身免疫系统消除肿瘤细胞。然而,免疫调节化合物系统传递的安全性和有效性问题限制了肿瘤免疫疗法的推广与应用。纳米技术由于其独特的优点,如靶向性好、不良反应少、稳定性好,各种具有不同理化特性的纳米靶向递送体系被开发出来,以刺激免疫系统实现抗肿瘤治疗。本文就近年来纳米技术联合免疫治疗肿瘤的研究进展作一综述。
In recent years, scientists have had a deeper understanding of the basic principles of tumor biology and immunology, and immunotherapy for cancer has made great progresses, greatly promoting the development of a series of new immunotherapy drugs for cancer. Cancer immunotherapy aims at eliminating cancer cells by stimulating and coordinating the immune system. However, the promotion and application of cancer immunotherapy are limited because of the uncertain safety and effectiveness of immune regulatory compound delivery. Due to its unique advantages, such as good targeting, less adverse events, and good stability, various nano-targeted delivery systems with different physical and chemical properties have been developed to stimulate the immune system in anti-tumor therapy. In this review, we summed up the research progresses of nanotechnology combined with immunotherapy for cancer in recent years.
In recent years, scientists have had a deeper understanding of the basic principles of tumor biology and immunology, and immunotherapy for cancer has made great progresses, greatly promoting the development of a series of new immunotherapy drugs for cancer. Cancer immunotherapy aims at eliminating cancer cells by stimulating and coordinating the immune system. However, the promotion and application of cancer immunotherapy are limited because of the uncertain safety and effectiveness of immune regulatory compound delivery. Due to its unique advantages, such as good targeting, less adverse events, and good stability, various nano-targeted delivery systems with different physical and chemical properties have been developed to stimulate the immune system in anti-tumor therapy. In this review, we summed up the research progresses of nanotechnology combined with immunotherapy for cancer in recent years.
引文
[1]LIANG C,XU L,SONG G,LIU Z.Emerging nanomedicine approaches fighting tumor metastasis:animal models,metastasis-targeted drug delivery,phototherapy,and immunotherapy[J].Chem Soc Rev,2016,45:6250-6269.
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[8]GUO Y,WANG D,SONG Q,WU T,ZHUANG X,BAOY,et al.Erythrocyte membrane-enveloped polymeric nanoparticles as nanovaccine for induction of antitumor immunity against melanoma[J].ACS Nano,2015,9:6918-6933.
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[11]TEO P Y,YANG C,WHILDING L M,PARENTE-PEREIRA A C,MAHER J,GEORGE A J,et al.Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine:strategies to enhance T cell killing[J].Adv Healthc Mater,2015,4:1180-1189.
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[13]SEHGAL K,DHODAPKAR K M,DHODAPKAR MV.Targeting human dendritic cells in situ to improve vaccines[J].Immunol Lett,2014,162(1 Pt A):59-67.
[14]ZHUANG X,WU T,ZHAO Y,HU X,BAO Y,GUO Y,et al.Lipid-enveloped zinc phosphate hybrid nanoparticles for codelivery of H-2Kb and H-2Db-restricted antigenic peptides and monophosphoryl lipid A to induce antitumor immunity against melanoma[J].J Control Release,2016,228:26-37.
[15]KUAI R,OCHYL L J,BAHJAT K S,SCHWENDENANA,MOON J J.Designer vaccine nanodiscs for personalized cancer immunotherapy[J].Nat Mater,201716:489-496.
[16]SAHIN U,DERHOVANESSIAN E,MILLER M,KLOKE B P,SOMON P,L?WER M,et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer[J].Nature,2017,547(7662):222-226.
[17]OTT P A,HU Z,KESKIN D B,SHUKLA S A,SUN J,BOZYM D J,et al.An immunogenic personal neoantigen vaccine for patients with melanoma[J].Nature,2017,547(7662):217-221.
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[19]DUAN F,FENG X,YANG X,SUN W,JIN Y,LIU H,et al.A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy[J].Biomaterials,2017,122:23-33.
[20]KANG T,HUANG Y,ZHU Q,CHENG H,PEI Y,FENGJ,et al.Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immunestimulatory modality[J].Biomaterials,2018,164:80-97.
[21]COLZANI B,PANDOLFI L,HOTI A,IOVENE P A,NATALELLO A,AVVAKUMOVA S,et al.Investigation of antitumor activities of trastuzumab delivered by PLGAnanoparticles[J].Int J Nanomedicine,2018,13:957-973.
[22]QIU H,MIN Y,RODGERS Z,ZHANG L,WANGA Z.Nanomedicine approaches to improve cancer immunotherapy[J].Wiley Interdiscip Rev Nanomed Nanobiotechnol,2017,9(5).doi:10.1002/wnan.1456.
[23]KIM A,MIURA Y,ISHII T,MUTAF O F,NISHIYAMAN,CABRAL H,et al.Intracellular delivery of chargeconverted monoclonal antibodies by combinatorial design of block/homo polyion complex micelles[J].Biomacromolecules,2016,17:446-453.
[24]MELERO I,HIRSCHHORN-CYMERMAN D,MORALES-KASTRESANA A,SANMAMED M F,WOLCHOK J D.Agonist antibodies to TNFR molecules that costimulate T and NK cells[J].Clin Cancer Res,2013,19:1044-1053.
[25]CHEN M,OUYANG H,ZHOU S,LI J,YE Y.PLGA-nanoparticle mediated delivery of anti-OX40 monoclonal antibody enhances anti-tumor cytotoxic T cell responses[J].Cell Immunol,2014,287:91-99.
[26]STEELAND S,VANDENBROUCKE R E,LIBERT C.Nanobodies as therapeutics:big opportunities for small antibodies[J].Drug Discov Today,2016,21:1076-1113.
[27]VAN DRIEL P,BOONSTRA M C,SLOOTER M D,HEUKERS R,STAMMES M A,SNOEKS T J A,et al.EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer[J].J Control Release,2016,229:93-105.
[28]YIN H,KANASTY R L,ELTOUKHY A A,VEGAS A J,DORKIN J R,ANDERSON D G.Non-viral vectors for gene-based therapy[J].Nat Rev Genet,2014,15:541-555.
[29]KRANZ L M,DIKEN M,HAAS H,KREITER S,LOQUAI C,REUTER K C,et al.Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy[J].Nature,2016,534(7607):396-401.
[30]LI S Y,LIU Y,XU C F,SHEN S,SUN R,DU X J,et al.Restoring anti-tumor functions of T cells via nanoparticlemediated immune checkpoint modulation[J].J Control Release,2016,231:17-28.
[31]NOY R,POLLARD J W.Tumor-associated macrophages:from mechanisms to therapy[J].Immunity,2014,41:49-61.
[32]QIAN Y,QIAO S,DAI Y,XU G,DAI B,LU L,et al.Molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering RNA to tumor-associated macrophages[J].ACS Nano,2017,11:9536-9549.
[33]ESTRELLA V,CHEN T,LLOYD M,WOJTKOWIAK J,CORNNELL H H,IBRAHIM-HASHIM A,et al.Acidity generated by the tumor microenvironment drives local invasion[J].Cancer Res,2013,73:1524-1535.
[34]DUNN G P,OLD L J,SCHREIBER R D.The immunobiology of cancer immunosurveillance and immunoediting[J].Immunity,2004,21:137-148.
[35]CHEN P,LUO S,WEN Y J,LI Y H,LI J,WANG Y S,et al.Low-dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer[J].Cancer Sci,2014,105:1393-1401.
[36]SONG Q,YIN Y,SHANG L,WU T,ZHANG D,KONGM,et al.Tumor microenvironment responsive nanogel for the combinatorial antitumor effect of chemotherapy and immunotherapy[J].Nano Lett,2017,17:6366-6375
[37]CHIANG C S,LIN Y J,LEE R,LAI Y H,CHENG HW,HSIEH C H,et al.Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy[J].Nat Nanotechnol,2018,13:746-754.
[38]KOSMIDES A K,SIDHOM J W,FRASER A,BESSELLC A,SCHNECK J P.Dual targeting nanoparticle stimulates the immune system to inhibit tumor growth[J].ACS Nano,2017,11:5417-5429.
[39]STEPHAN M T,MOON J J,UM S H,BERSHTEYN A,IRVINE D J.Therapeutic cell engineering with surfaceconjugated synthetic nanoparticles[J].Nat Med,2010,16:1035-1041.
[40]PULE M A,SAVOLDO B,MYERS G D,ROSSIGC,RUSSELL H V,DOTTI G,et al.Virus-specific Tcells engineered to coexpress tumor-specific receptors persistence and antitumor activity in individuals with neuroblastoma[J].Nat Med,2008,14:1264-1270.
[41]PERES E,WOOD G W,POULIK J,BAYNES R,SOOD S,ABIDE M H,et al.High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors[J].Neuropediatrics,2008,39:151-156.
[42]STEPHAN S B,TABER A M,JILEAEVA I,PEGUES E P,SENTMAN C L,STEPHAN M T.Biopolymer implants enhance the efficacy of adoptive T-cell therapy[J].Nat Biotechnol,2015,33:97-101.
[43]SMITH T T,MOFFETT H F,STEPHAN S B,OPELC F,DUMIGAN A G,JIANG X,et al.Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors[J].J Clin Invest,2017127:2176-2191.
[44]SMITH T T,STEPHAN S B,MOFFETT H F,MCKNIGHT L E,JI W,REIMAN D,et al.In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers[J].Nat Nanotechnol,2017,12:813-820.
[45]FRAZIER J L,HAN J E,LIM M,OLIVIA.Immunotherapy combined with chemotherapy in the treatment of tumors[J].Neurosurg Clin N Am,2010,21:187-194.
[46]VAN LIMBERGEN E J,DE RUYSSCHER D K,OLIVOPIMENTEL V,OLIVI A.Combining radiotherapy with immunotherapy:the past,the present and the future[J/OL].Br JRadiol,2017,90(1076):20170157.doi:10.1259/bjr.20170157
[47]KLEINOVINK J W,VAN DRIEL P B,SNOEKS TJ,PROKOPI N,FRANSEN M F,CRUZ L J,et al.Combination of photodynamic therapy and specific immunotherapy efficiently eradicates established tumors[J].Clin Cancer Res,2016,22:1459-1468.
[48]GRABBE S,HAAS H,DIKEN M,KTANZ L M,LANGGUTH P,SAHIN U.Translating nanoparticulatepersonalized cancer vaccines into clinical applications:case study with RNA-lipoplexes for the treatment of melanoma[J].Nanomedicine(Lond),2016,11:2723-2734.
[49]MAHJUB R,JATANA S,LEE S E,QIN Z,PAULI G,SOLEIMANI M,et al.Recent advances in applying nanotechnologies for cancer immunotherapy[J].J Control Release,2018,288:239-263.
[50]WOLFRAM J,ZHU M,YANG Y,SHEN J,GENTILEE,PAOLINO D,et al.Safety of nanoparticles in medicine[J].Curr Drug Targets,2015,16:1671-1681.
[51]SHARMA H S,SHARMA A.Nanoparticles aggravate heat stress induced cognitive deficits,blood-brain barrier disruption,edema formation and brain pathology[J].Prog Brain Res,2007,162:245-273.
[2]KIRKWOOD J M,BUTTERFIELD L H,TARHINIA A,ZAROUR H,KALINSKI P,FERRONE S.Immunotherapy of cancer in 2012[J].CA Cancer J Clin,2012,62:309-335.
[3]KHALIL D N,SMITH E L,BRENTJENS R J,WOLCHOK J D.The future of cancer treatment:immunomodulation,CARs and combination immunotherapy[J/OL].Nat Rev Clin Oncol,2016,13:394.doi:10.1038/nrclinonc.2016.65.
[4]EMENS L A,ASCIERTO P A,DARCY P K,DEMARIAS,EGGERMONT A M M,REDMOND W L,et al.Cancer immunotherapy:opportunities and challenges in the rapidly evolving clinical landscape[J].Eur J Cancer,2017,81:116-129.
[5]SONG W,MUSETTI S N,HUANG L.Nanomaterials for cancer immunotherapy[J].Biomaterials,2017,148:16-30
[6]TOPALIAN S L,HODI F S,BRAHMER J R,GETTINGERS N,SMITH D C,MCDERMOTT D F,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].N Engl J Med,2012,366:2443-2454.
[7]FESNAK A D,JUNE C H,LEVINE B L.Engineered T cells:the promise and challenges of cancer immunotherapy[J].Nat Rev Cancer,2016,16:566-581.
[8]GUO Y,WANG D,SONG Q,WU T,ZHUANG X,BAOY,et al.Erythrocyte membrane-enveloped polymeric nanoparticles as nanovaccine for induction of antitumor immunity against melanoma[J].ACS Nano,2015,9:6918-6933.
[9]SAHA S C,PATEL D,RAHMAN S,SAVVA M.Physicochemical characterization,solubilization,and stabilization of 9-nitrocamptothecin using pluronic block copolymers[J].J Pharm Sci,2013,102:3653-3665.
[10]HAGAN C T T,MEDIK Y B,WANG A Z.Nanotechnology approaches to improving cancer immunotherapy[J].Adv Cancer Res,2018,139:35-56.
[11]TEO P Y,YANG C,WHILDING L M,PARENTE-PEREIRA A C,MAHER J,GEORGE A J,et al.Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine:strategies to enhance T cell killing[J].Adv Healthc Mater,2015,4:1180-1189.
[12]PARK J,WRZESINSKI S H,STERN E,LOOK M,CRISCIONE J,RAGHEB R,et al.Combination delivery of TGF-βinhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy[J].Nat Mater,2012,11:895-905.
[13]SEHGAL K,DHODAPKAR K M,DHODAPKAR MV.Targeting human dendritic cells in situ to improve vaccines[J].Immunol Lett,2014,162(1 Pt A):59-67.
[14]ZHUANG X,WU T,ZHAO Y,HU X,BAO Y,GUO Y,et al.Lipid-enveloped zinc phosphate hybrid nanoparticles for codelivery of H-2Kb and H-2Db-restricted antigenic peptides and monophosphoryl lipid A to induce antitumor immunity against melanoma[J].J Control Release,2016,228:26-37.
[15]KUAI R,OCHYL L J,BAHJAT K S,SCHWENDENANA,MOON J J.Designer vaccine nanodiscs for personalized cancer immunotherapy[J].Nat Mater,201716:489-496.
[16]SAHIN U,DERHOVANESSIAN E,MILLER M,KLOKE B P,SOMON P,L?WER M,et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer[J].Nature,2017,547(7662):222-226.
[17]OTT P A,HU Z,KESKIN D B,SHUKLA S A,SUN J,BOZYM D J,et al.An immunogenic personal neoantigen vaccine for patients with melanoma[J].Nature,2017,547(7662):217-221.
[18]GUPTA R K,SIBER G R.Adjuvants for human vaccines-current status,problems and future prospects[J].Vaccine,1995,13:1263-1276.
[19]DUAN F,FENG X,YANG X,SUN W,JIN Y,LIU H,et al.A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy[J].Biomaterials,2017,122:23-33.
[20]KANG T,HUANG Y,ZHU Q,CHENG H,PEI Y,FENGJ,et al.Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immunestimulatory modality[J].Biomaterials,2018,164:80-97.
[21]COLZANI B,PANDOLFI L,HOTI A,IOVENE P A,NATALELLO A,AVVAKUMOVA S,et al.Investigation of antitumor activities of trastuzumab delivered by PLGAnanoparticles[J].Int J Nanomedicine,2018,13:957-973.
[22]QIU H,MIN Y,RODGERS Z,ZHANG L,WANGA Z.Nanomedicine approaches to improve cancer immunotherapy[J].Wiley Interdiscip Rev Nanomed Nanobiotechnol,2017,9(5).doi:10.1002/wnan.1456.
[23]KIM A,MIURA Y,ISHII T,MUTAF O F,NISHIYAMAN,CABRAL H,et al.Intracellular delivery of chargeconverted monoclonal antibodies by combinatorial design of block/homo polyion complex micelles[J].Biomacromolecules,2016,17:446-453.
[24]MELERO I,HIRSCHHORN-CYMERMAN D,MORALES-KASTRESANA A,SANMAMED M F,WOLCHOK J D.Agonist antibodies to TNFR molecules that costimulate T and NK cells[J].Clin Cancer Res,2013,19:1044-1053.
[25]CHEN M,OUYANG H,ZHOU S,LI J,YE Y.PLGA-nanoparticle mediated delivery of anti-OX40 monoclonal antibody enhances anti-tumor cytotoxic T cell responses[J].Cell Immunol,2014,287:91-99.
[26]STEELAND S,VANDENBROUCKE R E,LIBERT C.Nanobodies as therapeutics:big opportunities for small antibodies[J].Drug Discov Today,2016,21:1076-1113.
[27]VAN DRIEL P,BOONSTRA M C,SLOOTER M D,HEUKERS R,STAMMES M A,SNOEKS T J A,et al.EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer[J].J Control Release,2016,229:93-105.
[28]YIN H,KANASTY R L,ELTOUKHY A A,VEGAS A J,DORKIN J R,ANDERSON D G.Non-viral vectors for gene-based therapy[J].Nat Rev Genet,2014,15:541-555.
[29]KRANZ L M,DIKEN M,HAAS H,KREITER S,LOQUAI C,REUTER K C,et al.Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy[J].Nature,2016,534(7607):396-401.
[30]LI S Y,LIU Y,XU C F,SHEN S,SUN R,DU X J,et al.Restoring anti-tumor functions of T cells via nanoparticlemediated immune checkpoint modulation[J].J Control Release,2016,231:17-28.
[31]NOY R,POLLARD J W.Tumor-associated macrophages:from mechanisms to therapy[J].Immunity,2014,41:49-61.
[32]QIAN Y,QIAO S,DAI Y,XU G,DAI B,LU L,et al.Molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering RNA to tumor-associated macrophages[J].ACS Nano,2017,11:9536-9549.
[33]ESTRELLA V,CHEN T,LLOYD M,WOJTKOWIAK J,CORNNELL H H,IBRAHIM-HASHIM A,et al.Acidity generated by the tumor microenvironment drives local invasion[J].Cancer Res,2013,73:1524-1535.
[34]DUNN G P,OLD L J,SCHREIBER R D.The immunobiology of cancer immunosurveillance and immunoediting[J].Immunity,2004,21:137-148.
[35]CHEN P,LUO S,WEN Y J,LI Y H,LI J,WANG Y S,et al.Low-dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer[J].Cancer Sci,2014,105:1393-1401.
[36]SONG Q,YIN Y,SHANG L,WU T,ZHANG D,KONGM,et al.Tumor microenvironment responsive nanogel for the combinatorial antitumor effect of chemotherapy and immunotherapy[J].Nano Lett,2017,17:6366-6375
[37]CHIANG C S,LIN Y J,LEE R,LAI Y H,CHENG HW,HSIEH C H,et al.Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy[J].Nat Nanotechnol,2018,13:746-754.
[38]KOSMIDES A K,SIDHOM J W,FRASER A,BESSELLC A,SCHNECK J P.Dual targeting nanoparticle stimulates the immune system to inhibit tumor growth[J].ACS Nano,2017,11:5417-5429.
[39]STEPHAN M T,MOON J J,UM S H,BERSHTEYN A,IRVINE D J.Therapeutic cell engineering with surfaceconjugated synthetic nanoparticles[J].Nat Med,2010,16:1035-1041.
[40]PULE M A,SAVOLDO B,MYERS G D,ROSSIGC,RUSSELL H V,DOTTI G,et al.Virus-specific Tcells engineered to coexpress tumor-specific receptors persistence and antitumor activity in individuals with neuroblastoma[J].Nat Med,2008,14:1264-1270.
[41]PERES E,WOOD G W,POULIK J,BAYNES R,SOOD S,ABIDE M H,et al.High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors[J].Neuropediatrics,2008,39:151-156.
[42]STEPHAN S B,TABER A M,JILEAEVA I,PEGUES E P,SENTMAN C L,STEPHAN M T.Biopolymer implants enhance the efficacy of adoptive T-cell therapy[J].Nat Biotechnol,2015,33:97-101.
[43]SMITH T T,MOFFETT H F,STEPHAN S B,OPELC F,DUMIGAN A G,JIANG X,et al.Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors[J].J Clin Invest,2017127:2176-2191.
[44]SMITH T T,STEPHAN S B,MOFFETT H F,MCKNIGHT L E,JI W,REIMAN D,et al.In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers[J].Nat Nanotechnol,2017,12:813-820.
[45]FRAZIER J L,HAN J E,LIM M,OLIVIA.Immunotherapy combined with chemotherapy in the treatment of tumors[J].Neurosurg Clin N Am,2010,21:187-194.
[46]VAN LIMBERGEN E J,DE RUYSSCHER D K,OLIVOPIMENTEL V,OLIVI A.Combining radiotherapy with immunotherapy:the past,the present and the future[J/OL].Br JRadiol,2017,90(1076):20170157.doi:10.1259/bjr.20170157
[47]KLEINOVINK J W,VAN DRIEL P B,SNOEKS TJ,PROKOPI N,FRANSEN M F,CRUZ L J,et al.Combination of photodynamic therapy and specific immunotherapy efficiently eradicates established tumors[J].Clin Cancer Res,2016,22:1459-1468.
[48]GRABBE S,HAAS H,DIKEN M,KTANZ L M,LANGGUTH P,SAHIN U.Translating nanoparticulatepersonalized cancer vaccines into clinical applications:case study with RNA-lipoplexes for the treatment of melanoma[J].Nanomedicine(Lond),2016,11:2723-2734.
[49]MAHJUB R,JATANA S,LEE S E,QIN Z,PAULI G,SOLEIMANI M,et al.Recent advances in applying nanotechnologies for cancer immunotherapy[J].J Control Release,2018,288:239-263.
[50]WOLFRAM J,ZHU M,YANG Y,SHEN J,GENTILEE,PAOLINO D,et al.Safety of nanoparticles in medicine[J].Curr Drug Targets,2015,16:1671-1681.
[51]SHARMA H S,SHARMA A.Nanoparticles aggravate heat stress induced cognitive deficits,blood-brain barrier disruption,edema formation and brain pathology[J].Prog Brain Res,2007,162:245-273.