Research progress of pH-responsive drug delivery systems in cancer immunotherapy
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摘要:
肿瘤免疫疗法是激活宿主自身免疫系统对抗肿瘤的治疗方式，已广泛应用于临床，然而存在响应率低、免疫相关不良事件等缺陷。有别于传统的化学治疗，免疫治疗的靶标表现出更为广泛的空间异质性，分布在不同细胞类型及二级细胞器中，药物分子易产生脱靶与在靶毒性，极大地影响了治疗的有效性与安全性。由于代谢水平的改变，肿瘤微环境较正常组织显微酸性，而细胞内吞途径伴随着质子的进一步泵入，因此pH可以作为理想的选择性刺激条件，以实现“门控”式的药物精准递释。近年来，pH响应型材料在肿瘤免疫治疗中被广泛研究，如高分子聚合物、生物大分子、脂质纳米粒、生物膜、无机纳米粒、金属-有机框架等。本文从不同的载体类型出发，综述了pH响应型肿瘤免疫治疗的研究策略，为新一代靶向制剂研发提供参考。
Abstract:Cancer immunotherapy, which is an attractive strategy harnessing the host's own immune system to remove tumor cells, has been widely used in clinical practice, yet with low response rate and immune-related adverse events. Unlike traditional chemotherapy, the targets of immunotherapy exhibit high spatial heterogeneity and are distributed in different cell types or secondary organelles, resulting in off-target and on-target toxicity, which greatly reduces the efficacy and safety of treatment. Due to the altered metabolic level, tumor tissues often display a lower pH than normal tissues. In addition, the endocytosis pathway is accompanied by continuous pumping of protons. Therefore, the variation of environmental pH values could serve as an ideal stimulus for precise drug delivery and release. In recent years, pH-responsive materials (e.g., polymers, biomacromolecules, lipid nanoparticles, biofilm, inorganic nanoparticles, and metal-organic frameworks) have been widely investigated in the field of cancer immunotherapy. This paper summarizes recent strategies of pH-responsive drug delivery systems based on different types of carriers, aiming to provide some reference for the design of next generation of tumor-targeting formulations in cancer immunotherapy.
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Keywords:
- tumor /
- immunotherapy /
- drug delivery system /
- pH-responsive /
- targeted delivery
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表 1 pH响应型药物递送系统的类型及其优缺点
载体类型 优势 缺点 代表性设计 响应原理 高分子聚合物 易于合成、改性灵活 降解困难、免疫原性 PAMAM[9]、PDPA[10] 叔胺质子化 生物大分子 生物相容性高 稳定性低、成本高 壳聚糖外壳[11]
牛血清白蛋白外壳[12]
DNA四面体[13]羟基/氨基质子化
溶酶体降解
酰胺键断裂脂质体/脂质纳米粒 生物相容性高 载药量低 DOPE脂质体[14]
β葡聚糖脂质体[15]
PEI脂质纳米粒[16]磷酸乙醇胺质子化
羟基质子化
叔胺质子化生物膜 同源靶向性、可逃避免疫
系统的清除生物安全性尚不明确、
异质性细胞膜[17]
外泌体[18]酸响应涨破
苯甲酸亚胺键断裂无机材料 高稳定性、载药量高 不易代谢与清除 MSN包裹聚合物外壳[19] MnO2[20]、CaCO3[21] 叔胺质子化
酸响应化学分解金属-有机框架 结构灵活可调、具有免疫活性 生物安全性尚不明确 ZIF-8[22]、MOF-5[23]、铁基MOF[24]、
锰基MOF[25]有机配体质子化 无载体递送系统 载药量高 药物易泄漏和降解 多肽/抗体-药物偶联物[26]
光敏剂-药物偶联物[27]
佐剂-抗原自组装[28]腙键断裂
腙键断裂
非共价结合减弱
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[1] Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion[J]. Nat Rev Cancer, 2021, 21(5): 298-312. doi: 10.1038/s41568-021-00339-z
[2] Sharma P, Goswami S, Raychaudhuri D, et al. Immune checkpoint therapy-current perspectives and future directions[J]. Cell, 2023, 186(8): 1652-1669. doi: 10.1016/j.cell.2023.03.006
[3] Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors[J]. Nat Rev Dis Primers, 2020, 6(1): 38. doi: 10.1038/s41572-020-0160-6
[4] Xiao Y, Zhang T, Ma XB, et al. Microenvironment-responsive prodrug-induced pyroptosis boosts cancer immunotherapy[J]. Adv Sci, 2021, 8(24): e2101840. doi: 10.1002/advs.202101840
[5] Wang YL, Khan A, Liu YX, et al. Chitosan oligosaccharide-based dual pH responsive nano-micelles for targeted delivery of hydrophobic drugs[J]. Carbohydr Polym, 2019, 223: 115061. doi: 10.1016/j.carbpol.2019.115061
[6] Jiang DD, Gao T, Liang S, et al. Lymph node delivery strategy enables the activation of cytotoxic T lymphocytes and natural killer cells to augment cancer immunotherapy[J]. ACS Appl Mater Interfaces, 2021, 13(19): 22213-22224. doi: 10.1021/acsami.1c03709
[7] Cappellesso F, Orban MP, Shirgaonkar N, et al. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer[J]. Nat Cancer, 2022, 3(12): 1464-1483. doi: 10.1038/s43018-022-00470-2
[8] Luo L, Xu FS, Peng HL, et al. Stimuli-responsive polymeric prodrug-based nanomedicine delivering nifuroxazide and doxorubicin against primary breast cancer and pulmonary metastasis[J]. J Control Release, 2020, 318: 124-135. doi: 10.1016/j.jconrel.2019.12.017
[9] Xia CY, Yin S, Xu SS, et al. Low molecular weight heparin-coated and dendrimer-based core-shell nanoplatform with enhanced immune activation and multiple anti-metastatic effects for melanoma treatment[J]. Theranostics, 2019, 9(2): 337-354. doi: 10.7150/thno.29026
[10] Su T, Cheng FR, Qi JL, et al. Responsive multivesicular polymeric nanovaccines that codeliver STING agonists and neoantigens for combination tumor immunotherapy[J]. Adv Sci, 2022, 9(23): e2201895. doi: 10.1002/advs.202201895
[11] Guo K, Liu YX, Ding M, et al. Enhanced drug release from a pH-responsive nanocarrier can augment colon cancer treatment by blocking PD-L1 checkpoint and consuming tumor glucose[J]. Mater Des, 2022, 219: 110824. doi: 10.1016/j.matdes.2022.110824
[12] Li C, Wang X, Song H, et al. Current multifunctional albumin-based nanoplatforms for cancer multi-mode therapy[J]. Asian J Pharm Sci, 2020, 15(1): 1-12. doi: 10.1016/j.ajps.2018.12.006
[13] Fan Q, Li ZH, Yin J, et al. Inhalable pH-responsive DNA tetrahedron nanoplatform for boosting anti-tumor immune responses against metastatic lung cancer[J]. Biomaterials, 2023, 301: 122283. doi: 10.1016/j.biomaterials.2023.122283
[14] Li XY, Luo Y, Huang ZJ, et al. Multifunctional liposomes remodeling tumor immune microenvironment for tumor chemoimmunotherapy[J]. Small Methods, 2023, 7(5): e2201327. doi: 10.1002/smtd.202201327
[15] Yuba, Kado Y, Kasho N, et al. Cationic lipid potentiated the adjuvanticity of polysaccharide derivative-modified liposome vaccines[J]. J Control Release, 2023, 362: 767-776. doi: 10.1016/j.jconrel.2022.10.016
[16] Yang GX, Zhou D, Dai Y, et al. Construction of PEI-EGFR-PD-L1-siRNA dual functional nano-vaccine and therapeutic efficacy evaluation for lung cancer[J]. Thorac Cancer, 2022, 13(21): 2941-2950. doi: 10.1111/1759-7714.14618
[17] Gong CN, Yu XY, Zhang W, et al. Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles[J]. J Nanobiotechnology, 2021, 19(1): 58. doi: 10.1186/s12951-021-00805-8
[18] Zhang XQ, Wei ZH, Yong TY, et al. Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy[J]. Nat Commun, 2023, 14(1): 5653. doi: 10.1038/s41467-023-41438-9
[19] Zheng YD, Zhang ZZ, Liu Q, et al. Multifunctional nanomodulators regulate multiple pathways to enhance antitumor immunity[J]. ACS Appl Bio Mater, 2020, 3(7): 4635-4642. doi: 10.1021/acsabm.0c00513
[20] Yang GB, Xu LG, Chao Y, et al. Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses[J]. Nat Commun, 2017, 8(1): 902. doi: 10.1038/s41467-017-01050-0
[21] Li YH, Gong SH, Pan W, et al. A tumor acidity activatable and Ca2+-assisted immuno-nanoagent enhances breast cancer therapy and suppresses cancer recurrence[J]. Chem Sci, 2020, 11(28): 7429-7437. doi: 10.1039/D0SC00293C
[22] Zhang HJ, Chen W, Gong K, et al. Nanoscale zeolitic imidazolate framework-8 as efficient vehicles for enhanced delivery of CpG oligodeoxynucleotides[J]. ACS Appl Mater Interfaces, 2017, 9(37): 31519-31525. doi: 10.1021/acsami.7b09583
[23] Dai Z, Wang QY, Tang J, et al. Immune-regulating bimetallic metal-organic framework nanoparticles designed for cancer immunotherapy[J]. Biomaterials, 2022, 280: 121261. doi: 10.1016/j.biomaterials.2021.121261
[24] Xu R, Yang J, Qian Y, et al. Ferroptosis/pyroptosis dual-inductive combinational anti-cancer therapy achieved by transferrin decorated nanoMOF[J]. Nanoscale Horiz, 2021, 6(4): 348-356. doi: 10.1039/D0NH00674B
[25] Xu MM, Chang YC, Zhu GH, et al. Transforming cold tumors into hot ones with a metal-organic framework-based biomimetic nanosystem for enhanced immunotherapy[J]. ACS Appl Mater Interfaces, 2023, 15(14): 17470-17484. doi: 10.1021/acsami.2c21005
[26] Lin F, Chen L, Zhang H, et al. Bioorthogonal prodrug-antibody conjugates for on-target and on-demand chemotherapy[J]. CCS Chem, 2019, 1(2): 226-236. doi: 10.31635/ccschem.019.20180038
[27] Jin C, Wang Y, Li YF, et al. Doxorubicin-near infrared dye conjugate induces immunogenic cell death to enhance cancer immunotherapy[J]. Int J Pharm, 2021, 607: 121027. doi: 10.1016/j.ijpharm.2021.121027
[28] Zeng T, Zang WJ, Xiao H, et al. Carrier-free nanovaccine: an innovative strategy for ultrahigh melanoma neoantigen loading[J]. ACS Nano, 2023, 17(18): 18114-18127. doi: 10.1021/acsnano.3c04887
[29] Mao LZ, Ma PQ, Luo X, et al. Stimuli-responsive polymeric nanovaccines toward next-generation immunotherapy[J]. ACS Nano, 2023, 17(11): 9826-9849. doi: 10.1021/acsnano.3c02273
[30] Banstola A, Poudel K, Kim JO, et al. Recent progress in stimuli-responsive nanosystems for inducing immunogenic cell death[J]. J Control Release, 2021, 337: 505-520. doi: 10.1016/j.jconrel.2021.07.038
[31] Tang MM, Chen BL, Xia HM, et al. pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy[J]. Nat Commun, 2023, 14(1): 5888. doi: 10.1038/s41467-023-41592-0
[32] Carson CS, Becker KW, Garland KM, et al. A nanovaccine for enhancing cellular immunity via cytosolic co-delivery of antigen and polyIC RNA[J]. J Control Release, 2022, 345: 354-370. doi: 10.1016/j.jconrel.2022.03.020
[33] Cen D, Ge QW, Xie CK, et al. ZnS@BSA nanoclusters potentiate efficacy of cancer immunotherapy[J]. Adv Mater, 2021, 33(49): e2104037. doi: 10.1002/adma.202104037
[34] Gumala A, Sutriyo S. Active targeting gold nanoparticle for chemotherapy drug delivery: a review[J]. Pharm Sci-Iran, 2022, 28(3): 342-354.
[35] Kundu M, Chatterjee S, Ghosh N, et al. Tumor targeted delivery of umbelliferone via a smart mesoporous silica nanoparticles controlled-release drug delivery system for increased anticancer efficiency[J]. Mater Sci Eng C Mater Biol Appl, 2020, 116: 111239. doi: 10.1016/j.msec.2020.111239
[36] Zhu WW, Dong ZL, Fu TT, et al. Modulation of hypoxia in solid tumor microenvironment with MnO2 nanoparticles to enhance photodynamic therapy[J]. Adv Funct Materials, 2016, 26(30): 5490-5498. doi: 10.1002/adfm.201600676
[37] Poostforooshan J, Belbekhouche S, Shaban M, et al. Aerosol-assisted synthesis of tailor-made hollow mesoporous silica microspheres for controlled release of antibacterial and anticancer agents[J]. ACS Appl Mater Interfaces, 2020, 12(6): 6885-6898. doi: 10.1021/acsami.9b20510
[38] Özsoy M, Atiroğlu V, Guney Eskiler G, et al. A protein-sulfosalicylic acid/boswellic acids @metal-organic framework nanocomposite as anticancer drug delivery system[J]. Colloids Surf B Biointerfaces, 2021, 204: 111788. doi: 10.1016/j.colsurfb.2021.111788
[39] Gao P, Chen YY, Pan W, et al. Antitumor agents based on metal-organic frameworks[J]. Angew Chem Int Ed Engl, 2021, 60(31): 16763-16776. doi: 10.1002/anie.202102574
[40] Nong WQ, Wu J, Ghiladi RA, et al. The structural appeal of metal–organic frameworks in antimicrobial applications[J]. Coord Chem Rev, 2021, 442: 214007. doi: 10.1016/j.ccr.2021.214007
[41] Hou DY, Cheng DB, Zhang NY, et al. In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy[J]. Nat Commun, 2024, 15(1): 454.
[42] Zheng YC, Sun LQ, Guo JM, et al. The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy[J]. Cancer Commun, 2023, 43(10): 1071-1096. doi: 10.1002/cac2.12487
[43] Bargh JD, Isidro-Llobet A, Parker JS, et al. Cleavable linkers in antibody-drug conjugates[J]. Chem Soc Rev, 2019, 48(16): 4361-4374. doi: 10.1039/C8CS00676H
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