药学学报, 2017, 52(12): 1839-1848
李曼, 杨玉婷, 何勤, 张志荣. 纳米载体在肿瘤免疫治疗中的研究进展[J]. 药学学报, 2017, 52(12): 1839-1848.
LI Man, YANG Yu-ting, HE Qin, ZHANG Zhi-rong. Recent advances of nanocarriers in tumor immunotherapy[J]. Acta Pharmaceutica Sinica, 2017, 52(12): 1839-1848.

李曼, 杨玉婷, 何勤, 张志荣
四川大学华西药学院, 四川 成都 610041
关键词:    纳米载体      靶向递送      免疫治疗      肿瘤      疫苗     
Recent advances of nanocarriers in tumor immunotherapy
LI Man, YANG Yu-ting, HE Qin, ZHANG Zhi-rong
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
In the past 20 years, tumor immunotherapy has made a significant progress in tumor inhibition effects in both laboratory studies and clinical trails. In the immune response to tumor, effective antitumor immunity is induced during the tumor progress; long-term monitoring of the tumor would be achieved through the immune memory, reducing the possibility of tumor recurrence. In the immune treatment strategies, a focus is delivery of therapeutic immune regulators with nanocarriers. It has been demonstrated that due to the special physical and chemical properties, nanocarriers are easily internalized by immune cells, which regulate the immune responses and effectively induce anti-tumor immune cascade to achieve the tumor inhibition effect. In this paper, we will discuss the progress of nanocarrier-mediated antitumor immunotherapy in recent years.
Key words:    nanocarrier    targeted delivery    immunotherapy    tumor    vaccine   
收稿日期: 2017-08-29
DOI: 10.16438/j.0513-4870.2017-0850
基金项目: 国家自然科学基金重大项目(81690260,81690261).
通讯作者: 张志荣,Tel:86-28-85501566,Fax:86-28-85501615,E-mail:zrzzl@vip.sina.com
Email: zrzzl@vip.sina.com
PDF(404KB) Free
李曼  在本刊中的所有文章
杨玉婷  在本刊中的所有文章
何勤  在本刊中的所有文章
张志荣  在本刊中的所有文章

[1] Baronzio G, Parmar G, Shubina I, et al. Update on the challenges and recent advances in cancer immunotherapy[J]. Immunotargets Ther, 2013, 2:39-49.
[2] Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting[J]. Annu Rev Immunol, 2004, 22:329-360.
[3] Goforth R, Salem AK, Zhu X, et al. Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma[J]. Cancer Immunol Immunother, 2009, 58:517-530.
[4] Ahmad F, Mani J, Kumar P, et al. Activation of anti-tumor immune response and reduction of regulatory T cells with Mycobacterium indicus pranii (MIP) therapy in tumor bearing mice[J]. PLoS One, 2011, 6:e25424.
[5] Conniot J, Silva JM, Fernandes JG, et al. Cancer immunotherapy:nanodelivery approaches for immune cell targeting and tracking[J]. Front Chem, 2014, 2:105.
[6] Singh MS, Bhaskar S. Nanocarrier-based immunotherapy in cancer management and research[J]. Immunotargets Ther, 2014, 3:121-134.
[7] Silva JM, Videira M, Gaspar R, et al. Immune system targeting by biodegradable nanoparticles for cancer vaccines[J]. J Control Release, 2013, 168:179-199.
[8] Aslan B, Ozpolat B, Sood AK, et al. Nanotechnology in cancer therapy[J]. J Drug Target, 2013, 21:904-913.
[9] Sharma A, Jain N, Sareen R. Nanocarriers for diagnosis and targeting of breast cancer[J]. BioMed Res Int, 2013, 2013:960821.
[10] Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging[J]. Drug Discov Today, 2003, 8:1112-1120.
[11] Khan DR, Rezler EM, Lauer-Fields J, et al. Effects of drug hydrophobicity on liposomal stability[J]. Chem Bio Drug Des, 2008, 71:3-7.
[12] Frank MM. The reticuloendothelial system and bloodstream clearance[J]. J Lab Clin Med, 1993, 122:487-488.
[13] Krishnamachari Y, Geary SM, Lemke CD, et al. Nanoparticle delivery systems in cancer vaccines[J]. Pharm Res, 2011, 28:215-236.
[14] Ewert K, Evans HM, Ahmad A, et al. Lipoplex structures and their distinct cellular pathways[J]. Adv Genet, 2005, 53:119-155.
[15] van Broekhoven CL, Parish CR, Demangel C, et al. Targeting dendritic cells with antigen-containing liposomes:a highly effective procedure for induction of antitumor immunity and for tumor immunotherapy[J]. Cancer Res, 2004, 64:4357-4365.
[16] Zhang MM, Yang YT, Yu QW, et al. Preliminary study on immune mechanisms of pH-sensitive transmembrane peptide modified liposome loaded with α -galactosylceramides[J]. Acta Pharm Sin (药学学报), 2017, 56:634-640.
[17] U'Ren L, Kedl R, Dow S. Vaccination with liposome-DNA complexes elicits enhanced antitumor immunity[J]. Cancer Gene Ther, 2006, 13:1033-1044.
[18] Yoshikawa T, Okada N, Oda A, et al. Nanoparticles built by self-assembly of amphiphilic gamma-PGA can deliver antigens to antigen-presenting cells with high efficiency:a new tumor-vaccine carrier for eliciting effector T cells[J]. Vaccine, 2008, 26:1303-1313.
[19] Chan KWY, Bulte JWM, Mcmahon MT. Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes:physicochemical properties and imaging applications[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2013, 6:111-124.
[20] Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue[J]. Adv Drug Deliver Rev, 2003, 55:329-347.
[21] Albertsson AC. Degradable Aliphatic Polyesters[M]. Berlin:Springer, 2002.
[22] Singh R, Lillard JW Jr. Nanoparticle-based targeted drug delivery[J]. Exp Mol Pathol, 2009, 86:215-223.
[23] Gelperina S, Kisich K, Iseman MD, et al. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis[J]. Am J Resp Crit Care, 2005, 172:1487-1490.
[24] Prokop A, Davidson JM. Nanovehicular intracellular delivery systems[J]. J Pharm Sci, 2008, 97:3518-3590.
[25] Danhier F, Ansorena E, Silva JM, et al. PLGA-based nanoparticles:an overview of biomedical applications[J]. J Control Release, 2012, 161:505-522.
[26] Chen M, Ouyang H, Zhou S, et al. PLGA-nanoparticle mediated delivery of anti-OX40 monoclonal antibody enhances anti-tumor cytotoxic T cell responses[J]. Cell Immunol, 2014, 287:91-99.
[27] Johansen P, Estevez F, Zurbriggen R, et al. Towards clinical testing of a single-administration tetanus vaccine based on PLA/PLGA microspheres[J]. Vaccine, 2000, 19:1047-1054.
[28] Zhang Z, Tongchusak S, Mizukami Y, et al. Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery[J]. Biomaterials, 2011, 32:3666-3678.
[29] Roy A, Singh MS, Upadhyay P, et al. Nanoparticle mediated co-delivery of paclitaxel and a TLR-4 agonist results in tumor regression and enhanced immune response in the tumor microenvironment of a mouse model[J]. Int J Pharm, 2013, 445:171-180.
[30] Schlosser E, Mueller M, Fischer S, et al. TLR ligands and antigen need to be coencapsulated into the same biodegradable microsphere for the generation of potent cytotoxic T lymphocyte responses[J]. Vaccine, 2008, 26:1626-1637.
[31] Cruz LJ, Tacken PJ, Fokkink R, et al. Targeted PLGA nano-but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro[J]. J Control Release, 2010, 144:118-126.
[32] Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems[J]. J Control Release, 2001, 73:137-172.
[33] Jhaveri AM, Torchilin VP. Multifunctional polymeric micelles for delivery of drugs and siRNA[J]. Front Pharmacol, 2014, 5:77.
[34] Keller S, Wilson JT, Patilea GI, et al. Neutral polymer micelle carriers with pH-responsive, endosome-releasing activity modulate antigen trafficking to enhance CD8+ T cell responses[J]. J Control Release, 2014, 191:24-33.
[35] Wilson JT, Keller S, Manganiello MJ, et al. pH-Responsive nanoparticle vaccines for dual-delivery of antigens and immunostimulatory oligonucleotides[J]. ACS Nano, 2013, 7:3912-3925.
[36] Lee CC, Mackay JA, Fréchet JM, et al. Designing dendrimers for biological applications[J]. Nat Biotechnol, 2005, 23:1517-1526.
[37] Yang W, Cheng AY, Xu TW, et al. Targeting cancer cells with biotin-dendrimer conjugates[J]. Eur J Med Chem, 2009, 44:862-868.
[38] Nanjwade BK, Bechra HM, Derkar GK, et al. Dendrimers:emerging polymers for drug-delivery systems[J]. Eur J Pharm Sci, 2009, 38:185-196.
[39] Gilewski TA, Ragupathi G, Dickler M, et al. Immunization of high-risk breast cancer patients with clustered sTn-KLH conjugate plus the immunologic adjuvant QS-21[J]. Clin Cancer Res, 2007, 13:2977-2985.
[40] Slovin SF, Ragupathi G, Musselli C, et al. Fully synthetic carbohydrate-based vaccines in biochemically relapsed prostate cancer:clinical trial results with α-N -acetylgalactosamine-O -serine/threonine conjugate vaccine[J]. J Clin Oncol, 2003, 21:4292-4298.
[41] Krug LM, Ragupathi G, Hood C, et al. Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin[J]. Clin Cancer Res, 2004, 10:6094-6100.
[42] Weiner LM, Murray JC, Shuptrine CW. Antibody-based immunotherapy of cancer[J]. Cell, 2012, 148:1081-1084.
[43] Mahalingam D, Curiel TJ. Antibodies as cancer immunotherapy[M]//Curiel T, ed. Cancer Immunotherapy. New York:Springer, 2013:335-376.
[44] Bachmann MF, Jennings GT. Vaccine delivery:a matter of size, geometry, kinetics and molecular patterns[J]. Nat Rev Immunol, 2010, 10:787-796.
[45] Xiang SD, Scholzen A, Minigo G, et al. Pathogen recognition and development of particulate vaccines:does size matter?[J]. Methods, 2006, 40:1-9.
[46] Manolova V, Flace A, Bauer M, et al. Nanoparticles target distinct dendritic cell populations according to their size[J]. Eur J Immunol, 2008, 38:1404-1413.
[47] Foged C, Brodin B, Frokjaer S, et al. Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model[J]. Int J Pharm, 2005, 298:315-322.
[48] Fifis T, Gamvrellis A, Crimeen-Irwin B, et al. Size-dependent immunogenicity:therapeutic and protective properties of nano-vaccines against tumors[J]. J Immunol, 2004, 173:3148-3154.
[49] Goldinger SM, Dummer R, Baumgaertner P, et al. Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8+ T-cell responses in melanoma patients[J]. Eur J Immunol, 2012, 42:3049-3061.
[50] Gratton SEA, Ropp PA, Pohlhaus PD, et al. The effect of particle design on cellular internalization pathways[J]. Proc Natl Acad Sci U S A, 2008, 105:11613-11618.
[51] Yue ZG, Wei W, Lv PP, et al. Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles[J]. Biomacromolecules, 2011, 12:2440-2446.
[52] Thiele L, Merkle HP, Walter E. Phagocytosis and phagosomal fate of surface-modified microparticles in dendritic cells and macrophages[J]. Pharm Res, 2003, 20:221-228.
[53] Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature:the key role of tumor-selective macromolecular drug targeting[J]. Adv Enzyme Regul, 2001, 41:189-207.
[54] Gao H, Xiong Y, Zhang S, et al. RGD and interleukin-13 peptide functionalized nanoparticles for enhanced glioblastoma cells and neovasculature dual targeting delivery and elevated tumor penetration[J]. Mol Pharm, 2014, 11:1042-1052.
[55] Cheng J, Teply BA, Sherifi I, et al. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery[J]. Biomaterials, 2007, 28:869-876.
[56] Stephan MT, Moon JJ, Um SH, et al. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles[J]. Nat Med, 2010, 16:1035-1041.
[57] Carrillo-Conde B, Song EH, Chavez-Santoscoy A, et al. Mannose-functionalized "pathogen-like" polyanhydride nanoparticles target C-type lectin receptors on dendritic cells[J]. Mol Pharm, 2011, 8:1877-1886.
[58] Lu Y, Kawakami S, Yamashita F, et al. Development of an antigen-presenting cell-targeted DNA vaccine against melanoma by mannosylated liposomes[J]. Biomaterials, 2007, 28:3255-3262.
[59] Vonderheide RH, Bajor DL, Winograd R, et al. CD40 immunotherapy for pancreatic cancer[J]. Cancer Immunol Immun, 2013, 62:949-954.
[60] Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response[J]. Biochem J, 2009, 420:1-16.
[61] Shen L, Higuchi T, Tubbe I, et al. A trifunctional dextran-based nanovaccine targets and activates murine dendritic cells, and induces potent cellular and humoral immune responses in vivo[J]. PLoS One, 2013, 8:e80904.
[62] Wesch D, Peters C, Oberg HH, et al. Modulation of γδ T cell responses by TLR ligands[J]. Cell Mol Life Sci, 2011, 68:2357-2370.
[63] Unger WW, Van KY. ‘Dressed for success’ C-type lectin receptors for the delivery of glyco-vaccines to dendritic cells[J]. Curr Opin Immunol, 2011, 23:131-137.
[64] van Kooyk Y. C-type lectins on dendritic cells:key modulators for the induction of immune responses[J]. Biochem Soc Trans, 2008, 36:1478-1481.
[65] Ali OA, Verbeke C, Johnson C, et al. Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants[J]. Cancer Res, 2014, 74:1670-1681.
[66] Ali OA, Huebsch N, Cao L, et al. Infection-mimicking materials to program dendritic cells in situ[J]. Nat Materials, 2009, 8:151-158.
[67] Moon JJ, Huang B, Irvine DJ. Engineering nano-and microparticles to tune immunity[J]. Adv Mater, 2012, 24:3724-3746.
[68] Little SR. Reorienting our view of particle-based adjuvants for subunit vaccines[J]. Proc Natl Acad Sci U S A, 2012, 109:999-1000.
[69] Hong S, Ackerman AL, Virginia C, et al. Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles[J]. Immunology, 2006, 117:78-88.
[70] Harding CV, Song R. Phagocytic processing of exogenous particulate antigens by macrophages for presentation by class I MHC molecules[J]. J Immunol, 1994, 153:4925-4933.
[71] Waeckerlemen Y, Allmen EU, Gander B, et al. Encapsulation of proteins and peptides into biodegradable poly(D, L -lactide-co-glycolide) microspheres prolongs and enhances antigen presentation by human dendritic cells[J]. Vaccine, 2006, 24:1847-1857.
1.胥海婷, 吴亿晗, 石金凤, 李佳鑫, 章津铭, 傅超美.基于纳米共载策略的光热治疗联合化疗抗肿瘤研究进展[J]. 药学学报, 2020,55(8): 1774-1783
2.王相宜, 张锦, 李燕, 贺玖明.肿瘤代谢调控与肿瘤免疫治疗以及代谢分析方法研究进展[J]. 药学学报, 2020,55(9): 2080-2091
3.邵荣光.基于单克隆抗体的肿瘤免疫治疗[J]. 药学学报, 2020,55(6): 1110-1118
4.张盈盈, 陈丽青, 刘璇, 辛欣, 孟令玮, 金明姬, 高钟镐, 黄伟.外泌体作为药物递送载体的研究进展[J]. 药学学报, 2019,54(6): 1010-1016
5.叶鑫宇, 梅林.基于黑磷量子点的光热效应在树突状细胞激活中的作用[J]. 药学学报, 2019,54(7): 1297-1302
6.金晶, 季鸣, 陈晓光.蛋白翻译后修饰与肿瘤免疫治疗[J]. 药学学报, 2019,54(10): 1711-1717
7.吕英琪, 陈曜星, 卫晨萱, 江淦, 高小玲.胶质母细胞瘤的免疫治疗研究进展[J]. 药学学报, 2019,54(10): 1792-1801
8.候博, 王当歌, 高晶, 王晖, 李亚平, 于海军.微环境激活型纳米递药系统用于肿瘤免疫治疗的研究进展[J]. 药学学报, 2019,54(10): 1802-1809
9.赵星, 顾杨卓, 宋相容.mRNA致敏的树突状细胞用于肿瘤免疫治疗的研究进展[J]. 药学学报, 2019,54(10): 1818-1823
10.王明晋, 伏蓉, 姜慧敏, 金晶, 陈晓光.STING激动剂细胞筛选模型的建立和应用[J]. 药学学报, 2019,54(10): 1875-1880
11.杜婷婷, 来芳芳, 陈晓光.吲哚胺2,3-双加氧酶1在肿瘤免疫治疗中的研究进展[J]. 药学学报, 2018,53(8): 1271-1278
12.张心苑, 崔国楠, 徐柏玲.吲哚胺2,3-双加氧酶IDO1抑制剂的研究进展[J]. 药学学报, 2018,53(11): 1784-1796
13.贾学丽, 张佳, 赵婷, 杜青, 曹德英, 向柏, 耿革霞, 齐宪荣.低pH插入肽研究概况[J]. 药学学报, 2018,53(3): 375-382
14.张梦梦, 杨玉婷, 余倩雯, 何勤.pH敏感穿膜肽修饰的载α-半乳糖神经酰胺的脂质体免疫作用机制的初步研究[J]. 药学学报, 2017,52(4): 634-640
15.樊敦, 余敬谋, 黄皓, 金一.环境响应性递释系统在基因与药物共传递应用中的研究进展[J]. 药学学报, 2017,52(5): 713-721
16.张苗苗, 贾东方, 刁勇.嵌合抗原受体T细胞肿瘤免疫治疗的风险与对策[J]. 药学学报, 2016,51(7): 1032-1038
17.张利, 魏刚, 陆伟跃.可活化细胞穿膜肽在肿瘤治疗领域的应用[J]. 药学学报, 2014,49(12): 1639-1643
18.陈伟光, 王士斌.纳米载体共载基因与化疗药物用于癌症治疗的研究进展[J]. 药学学报, 2013,48(7): 1091-1098
19.霍常鑫 叶新山.肿瘤糖疫苗的研究进展[J]. 药学学报, 2012,47(3): 261-270
20.狄维;王林;彭涛;王升启.基于肿瘤相关糖抗原的抗肿瘤疫苗研究进展[J]. 药学学报, 2005,40(7): 591-599