2020, Vol. 56
2. 中国药科大学药学院, 江苏 南京 211198
2. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
癌症是由一群形态或功能异常的细胞所形成的恶性肿瘤[1]。肿瘤微环境(tumor microenvironment, TME) 作为肿瘤细胞生存的环境, 由肿瘤细胞周围的免疫细胞、炎症细胞、肿瘤相关成纤维细胞、微血管, 以及各种细胞因子和趋化因子所构成[2]。近年来, 通过对TME研究的不断深入, 已有大量的研究证明肿瘤的发生及发展与TME的特性有着密切的联系[3]。
TME的特点包括弱酸性、低氧、活性氧(reactive oxygen species, ROS) 及还原性物质含量高、免疫抑制性等。如表 1所示, TME与正常细胞生长环境有着很大的区别。弱酸性与乳酸的大量堆积有关, 其有利于肿瘤细胞的迁移及免疫逃逸的发生, 该结论已被Chen和Fischer等[4, 5]所证实。低氧与肿瘤细胞的快速生长及肿瘤血管的异常有关[6]。低氧微环境促使产生缺氧诱导因子-1 (hypoxia inducible factor-1, HIF-1), 从而导致肿瘤细胞产生耐药性, 降低抗肿瘤药物的生物利用度[7]; 缺氧的微环境也会降低细胞对放疗辐射的敏感度, 从而影响放疗疗效[8]。肿瘤细胞内ROS的浓度是正常细胞的100倍, 谷胱甘肽(glutathione, GSH) 的浓度是正常细胞的5~10倍[9]。与正常细胞相比, 肿瘤细胞的氧化还原动态平衡易被打破而呈现氧化应激态, 近而发生凋亡或坏死。微环境的免疫抑制性与TME主动招募调节性T淋巴细胞(regulatory T cells, Tregs)、肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs) 和髓系抑制细胞(myeloid derived suppressor cells, MDSCs) 等免疫抑制细胞的行为有关[10]。招募的MDSCs不仅可诱导产生Tregs, 而且还可联合Tregs共同影响免疫细胞的活性[11]; 此外, M2型TAMs可通过调节白细胞介素-10及白细胞介素-12的含量发挥免疫抑制功能[12]。TME所具有的这些特性为肿瘤的发生及发展提供了便利, 不仅可以促进肿瘤细胞生长与转移, 而且还有利于肿瘤免疫逃逸的发生。
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Table 1 Differences between normal cells and tumor cells in pH, the concentration of oxygen, reactive oxygen species (ROS) and reducing substances and immunosuppression. GSH: Glutathione; VEGF: Vascular endothelial growth; VEGF-R: VEGF receptor |
纳米材料是指在三维空间中至少有一维处于纳米尺寸或由它们作为基本单元构成的小尺寸材料[13]。与传统的抗癌制剂或方法相比, 纳米材料具有以下优点: ①靶向性; ②可作为载体; ③生物安全性高。近年来, 利用纳米材料调节TME已成为肿瘤治疗研究的热点。如图 1所示, 纳米材料如碳酸钙、二氧化锰(manganese dioxide, MnO2)、磷酸钙[calcium phosphate, Ca3(PO4)2] 等可利用自身发生反应消耗氢离子(H+) 从而调节微环境pH值, 还可作为基因的载体抑制乳酸产生而上调pH值; 此外, 载有O2或过氧化氢酶的纳米材料可改善缺氧状况; 载有光敏剂的纳米材料及含有亚铁离子、锰离子、铜离子的纳米材料(发生芬顿或类芬顿反应) 可通过产生ROS而增加胞内ROS的含量; 纳米材料还可作为某些药物或基因的载体调节免疫细胞的活性, 增强机体免疫清除功能。本文主要从调节pH值、氧气含量、活性氧浓度及免疫细胞活性4个方面对肿瘤微环境调节型纳米粒的最新研究进展进行综述(图 1), 提出存在的问题并进行了未来展望。
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Figure 1 The scheme of the mechanism of effect of tumor microenvironmentally modulated nanostructures. PDT: Photodynamic therapy; CDT: Chemodynamic therapy; TAMs: Tumor-associated macrophages; MDSCs: Myeloid derived suppressor cells; APCs: Antigen-presenting cells |
1930年提出的Warburg效应解释了TME呈现弱酸性的原因, 该理论认为肿瘤细胞即使在有氧条件下也会将大量葡萄糖通过糖酵解转变为乳酸, 乳酸的大量堆积进而导致弱酸性微环境的形成[14]。弱酸性的TME有利于肿瘤的侵袭及转移, 因此提高微环境pH值是抑制肿瘤转移的策略之一。虽然目前已发现质子泵抑制剂可通过抑制Ⅴ-型腺苷三磷酸酶调节TME的酸度, 但其作用于机体时具有非选择性及不可控性[15]。相比之下, 纳米材料可通过高渗透长滞留效应或肿瘤靶向分子修饰实现对肿瘤细胞的特异性靶向, 具有良好的生物安全性。如碳酸钙纳米粒(calcium carbonate nanoparticles, nano-CaCO3), Som等[15]将nano-CaCO3注入小鼠体内后, 随着时间的延长, nano-CaCO3选择性积聚在肿瘤部位, 通过消耗肿瘤部位的H+而上调微环境pH值(图 2a)。基于相同的原理, 其他类型的无机纳米材料如Ca3(PO4)2及MnO2均可实现对pH值的调节[16]。
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Figure 2 a: The changes in pH of HT1080 tumor model following treatment with nano-CaCO3. (Adapted from Ref. 15 with permission. Copyright © 2016 The Royal Society of Chemistry); b: The mechanism of effect of cationic lipid nanoparticles. (Adapted from Ref. 18 with permission. Copyright © 2019 American Chemical Society). LDHA: Lactate dehydrogenase A; MCT4: Monocarboxylate transporter 4; siLdha: siRNAs against Ldha; IFN-γ: Interferon γ |
弱酸性的TME会使肿瘤浸润淋巴细胞发生可逆失活, 调节TME的酸度可恢复机体的免疫清除功能[17]。Zhang等[18]利用阳离子脂质纳米粒囊泡包裹小干扰RNA (图 2b), 通过降低乳酸脱氢酶的表达而减少乳酸的产生, 进而改善TME的酸度, 最终使细胞毒性T细胞(CD8+ T细胞) 恢复活性, 抑制肿瘤生长。对免疫缺陷小鼠同样处理后, 肿瘤的生长未受到抑制, 进一步证明通过调节酸性能消除肿瘤的根本原因在于肿瘤浸润淋巴细胞的杀伤活性在中性环境得到恢复。
弱酸性的TME对肿瘤细胞具有一定程度的保护作用, 基于此, 研究人员采用两种方法对其造成破坏: ①利用无机纳米材料直接消耗微环境中的H+; ②调节基因的表达, 减少乳酸的产生, 切断H+的来源。总之, 纳米材料可利用自身消耗H+或者作为基因载体调节乳酸含量而改变TME的pH值, 进而帮助抑制肿瘤生长。
2 提升肿瘤微环境中氧气含量低氧是实体瘤的另一个重要的特征[6], 肿瘤细胞的快速生长导致血液运输的氧气供应不足, 进而导致HIF-1及血管内皮生长因子的高表达, 形成大量的肿瘤血管。这些肿瘤血管分布紊乱, 结构异常, 不但不能解决TME缺氧问题, 而且会通过刺激肿瘤加速生长而进一步恶化肿瘤的缺氧状况, 最终形成恶性循环[19]。
纳米材料可通过携带O2改善缺氧环境而发挥抗肿瘤作用。葡萄糖氧化酶(glucose oxidase, GOX) 可通过降解肿瘤细胞中的葡萄糖而达到“饿死”肿瘤的目的, 但该酶需要在有氧条件下才可发生反应, 所以改善缺氧状况可增强酶活性, 实现对葡萄糖的降解。Zou等[20]利用血红细胞膜包裹全氟正己烷(perfluorohexanes, PFC) 和GOX形成纳米粒-人造自然杀伤细胞(artificial natural killer cells, aNK), 如图 3a所示, 该纳米粒可通过PFC携带O2, 改善缺氧的TME, 增强GOX的催化反应, 通过消耗葡萄糖和生成过氧化氢(hydrogen peroxide, H2O2) 来直接杀伤肿瘤细胞。
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Figure 3 a: The changes of O2 concentrations in phosphate buffered saline (PBS) after treatment of oxygen-presaturated water, artificial natural killer cells (aNK), aNK(O2) and aNK(O2)+glucose. (Adapted from Ref. 20 with permission. Copyright © 2019 Wiley); b: The scheme of the mechanism of effect of HAOP. (Adapted from Ref. 22 with permission. Copyright © 2015 American Chemical Society). c(RGDfK): Tumor targeting ligand; BHQ-3: Black hole quencher-3; MB: Methylene blue; 1O2: Singlet oxygen |
纳米材料除了可以携带O2外, 还可以通过运输过氧化氢酶或利用本身的特性催化瘤内H2O2产生O2来改善缺氧状况。Gu等[21]利用热降解法合成具有MnO2壳的纳米球(C@SMn), H2O2可在其表面MnO2的催化下生成O2, 改善缺氧的TME, 提高治疗效果。除了利用纳米粒本身作为H2O2分解的催化剂外, 还可将过氧化氢酶包裹在纳米粒中, 从而调节TME中O2的含量。Chen等[22]利用过氧化氢酶和光敏剂作为核, 构建了一个核-壳结构的纳米粒(HAOP)。如图 3b所示, 该纳米粒进入肿瘤细胞后, H2O2会渗入纳米粒, 经催化生成O2, 同时造成了纳米粒的裂解, 释放光敏剂, 发挥抗癌疗效。综上所述, 纳米材料可通过携带O2或催化H2O2产生O2, 改善缺氧的TME, 作为辅助手段增强肿瘤治疗的疗效。
3 提高肿瘤微环境中活性氧的含量ROS是一类化学性质活泼并具有较高氧化活性的分子或离子的总称, 主要来源于线粒体, 可分为自由基和非自由基两种类型[23]。细胞中ROS的大量堆积会导致氧化应激的发生, 从而导致细胞发生凋亡或坏死[24]。基于此原理, 能增加胞内ROS含量的光动力学疗法(photodynamic therapy, PDT) 及化学动力学疗法(chemodynamic therapy, CDT) 被广泛应用于肿瘤的治疗。
PDT是一种利用光敏剂在光照条件下将氧气转换为活性氧, 从而杀死肿瘤细胞的一种无创治疗方法, 该方法疗效好、不良反应小[25]。Xu等[26]利用介孔二氧化硅纳米粒负载光敏剂二氢卟吩e6 (chlorin e6, Ce6)、免疫佐剂胞嘧啶鸟嘌呤二核苷酸(CpG) 和肿瘤抗原形成了纳米疫苗-bMSNs (CpG/Ce6)-neoantigen (图 4a)。该纳米粒既可产生大量的单线态氧(singlet oxygen, 1O2), 又可协同免疫疗法抑制肿瘤的生长(图 4b)。Kim等[27]利用多肽p18-4修饰的纳米粒作为Ce6的载体治疗乳腺癌, 由于多肽p18-4的靶向作用导致肿瘤组织中Ce6的含量增加, 激光照射下ROS的含量随之增加, PDT的疗效增强。
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Figure 4 a: The scheme of fabrication of bMSN(CpG/Ce6)-neoantigen and mechanism of bMSN(CpG/Ce6)-neoantigen nanovaccines for cancer immunotherapy; b: The yield of 1O2 after treatment of bMSN, free Ce6 and bMSN(Ce6). (Adapted from Ref. 26 with permission. Copyright © 2019 American Chemical Society). bMSN: Biodegradable mesoporous silica nanoparticles; Ce6: Chlorin e6; CpG ODN: CpG oligodeoxynucleotide; PET: Positron emission tomography; SOSG: Singlet oxygen sensor green |
CDT利用芬顿或类芬顿反应产生的羟基自由基(hydroxyl radical, •OH) 来治疗肿瘤[28]。在芬顿或类芬顿反应中, 通常选用亚铁离子和锰离子作为催化离子。Dong等[29]基于上转换纳米材料合成了一个具有铁酸锌壳的复合纳米材料, 在经紫外线照射后, 发生芬顿反应进而产生•OH。增加H2O2的含量在一定程度上会提升CDT的疗效。Liu等[30]将干扰RNA (RNA interference, RNAi)包裹在无定形氧化铁纳米粒(amorphous iron oxide, AIO)中形成了AIO RNAi纳米粒(图 5a)。该纳米粒裂解后释放的RNAi使单羧酸转运蛋白4 (monocarboxylate transporter 4, MCT4) 基因沉默, 导致酸外排受损, 细胞内酸大量堆积, H2O2含量增多, 通过类芬顿反应增加肿瘤细胞中•OH的含量, 最终导致肿瘤细胞的坏死。
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Figure 5 a: The scheme of the mechanism of effect of AIO RNAi. (Adapted from Ref. 30 with permission. Copyright © 2017 Wiley); b: The scheme of the mechanism of effect of MS@MnO2. (Adapted from Ref. 32 with permission. Copyright © 2018 Wiley). AIO: Amorphous iron oxide; EPR: Enhanced permeability and retention effect; ADS: Antioxidant defense system; GSSG: Glutathione disulfide; MRI: Nuclear magnetic resonance imaging |
肿瘤细胞中高浓度的还原性物质GSH可通过还原ROS导致治疗效果的降低。Hu等[31]根据β-异硫氰酸苯乙酯(phenylethylisothiocyanate, PEITC) 可与GSH反应的特性, 将其与包裹吲哚菁绿(indocyanine green, ICG) 的羟乙基淀粉-油酸共聚物纳米粒相连。最终形成的纳米粒既可消耗肿瘤细胞内GSH, 又可利用ICG作为光敏剂发生光动力学反应, 产生大量1O2, 增强PDT的疗效。此外, Lin等[32]合成了一种具有MnO2覆盖层的介孔二氧化硅纳米粒MS@MnO2 (图 5b)。该纳米粒可利用表面的MnO2覆盖层消耗GSH, 同时生成锰离子, 锰离子可催化类芬顿反应生成•OH, 增强肿瘤的CDT治疗。
综上所述, 纳米材料可通过光动力学反应及芬顿或类芬顿反应产生大量的ROS, 直接杀死肿瘤细胞。此外, 纳米材料还可作为载体降低细胞内GSH浓度、增加底物H2O2的含量, 从而增强PDT和CDT的疗效。
4 调节免疫细胞 4.1 T细胞随着对肿瘤组织及人体免疫系统研究的不断深入, 利用人体自身的免疫系统攻击肿瘤细胞, 从而达到治疗肿瘤目的。这种肿瘤免疫疗法在国内外受到了广泛关注。免疫检查点阻断疗法(immunocheckpoint blocking therapy, ICB) 作为一种新兴的肿瘤免疫疗法, 它不直接作用于肿瘤细胞, 而是通过调节TME, 增强T细胞的活性而间接杀伤肿瘤细胞[33]。目前, 程序性死亡配体1抗体(anti-programmed death protein 1, αPD-L1) 为应用最广泛的免疫检查点抑制剂, 可以结合肿瘤细胞上的程序性死亡配体1 (programmed death protein 1, PD-L1), 保持T细胞杀伤肿瘤细胞的活性[34]。然而, PD-L1不仅在肿瘤细胞上表达, 而且在正常细胞及一些免疫细胞的表面也有表达[35], 故ICB具有一定的不良反应。为了解决这一问题, Zhang等[36]将新型基因编辑技术(clustered regularly interspaced short palindromic repeatsequences, CRISPR) 与ICB相结合(图 6a), 利用4-(羟甲基) 苯基硼酸与质粒DNA (plasmid DNA, pDNA) 结合形成的纳米粒DLNP对弱酸性及高浓度H2O2的TME的双重响应释放pDNA, 敲除肿瘤细胞中PD-L1基因。如图 6b、c所示, 经DLNP治疗后, 小鼠的CD8+ T细胞含量迅速升高, 肿瘤生长受到明显抑制。ICB的疗效与PD-L1在肿瘤细胞表面的表达量及肿瘤细胞周围浸润性淋巴细胞的数量有关[37]。通常将ICB与化疗等其他肿瘤治疗手段相结合, 提高肿瘤浸润性淋巴细胞的数量, 增强ICB的疗效。Wang等[38]将αPD-L1与ICG包裹在基质金属蛋白酶2 (matrix metalloproteinase-2, MMP-2) 响应性纳米粒中, 利用TME中MMP-2过表达的特性释放αPD-L1与ICG, 借助PDT杀死肿瘤细胞, 释放肿瘤抗原, 增加肿瘤的浸润度, 通过联合治疗杀死肿瘤细胞, 消除肿瘤。
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Figure 6 a: The scheme of the mechanism of effect of DLNP; b: The concentrations of CD8+ T cell in the tumors by flow cytometry analysis after treatment of different samples; c: The changes of tumor volume after treatment of different samples. (Adapted from Ref. 36 with permission. Copyright © 2019 American Chemical Society); d: The concentrations of M1 cells and M2 cells after treatment of different samples, F4/80+CD86+ represent M1 macrophages and F4/80+CD206+ represent M2 macrophages. (Adapted from Ref. 43 with permission. Copyright © 2020 Wiley). DLNP: Dual-locking nanoparticles; Cas13a: CRISPR-associated enzyme; PEI: Polyethyleneimine; DOX: Doxorubicin; D-LCA: Low molecular weight heparin-chrysin nanodrug (LCY) with DSPE-PEG-anisamide decoration; GLnano: Gemini-like nanodrugs |
TAMs来源于外周血单核细胞, 是TME中数量最多的免疫细胞[39]。与巨噬细胞相同, 其可分为具有抑瘤作用的M1型和具有促瘤作用的M2型两种[40]。研究证明, M2型TAMs可导致前列腺素E2和血管内皮生长因子的堆积, 刺激内皮细胞的增殖, 进而抑制T细胞的杀伤作用[41]。此外, M2型TAMs还可以通过募集Tregs间接调节血管的分布[42]。总之, M2型TAMs与肿瘤细胞的生长、侵袭、转移及血管的生成有着密不可分的关系。
M2型TAMs具有高度的可塑性, 基于这一特性, Xu等[43]将利用以低分子量肝素为骨架的纳米组合物GLnano装载药物塞来昔布(celecoxib) 和多柔比星(doxorubicin, DOX), 该组合药物注入小鼠体内后, 在TME中MMP-2的作用下, 药物塞来昔布得以释放, M2型极化为M1型, 肿瘤细胞受到抑制(图 6d)。除了药物, microRNA 155也可促进TAMs的M1极化。Zang等[44]利用脂溶性磷酸钙纳米粒作为microRNA 155的载体, 实现对TAMs的激活及重编辑。M2型TAMs的存在与肿瘤治疗的不良预后有关, Tian等[45]构建了由钙盐和二磷酸盐(bisphosphonates, BP) 组成并用32P标记的纳米粒CaBP-PEG。该纳米粒既可通过BP消除M2型TAMs, 又可依靠32P进行放射性同位素治疗, 在消除肿瘤的同时也提升了预后效果。
4.3 髓系抑制细胞MDSCs是髓系细胞在病理条件下异常增殖所产生的一群具有免疫抑制功能的细胞, 与肿瘤发生及免疫逃逸有关[46]。MDSCs可分为两大类亚群: 粒细胞亚群(granulocytic myeloid-derived suppressor cells, G-MDSCs) 和单核细胞亚群(monocytic myeloid-derived suppressor cells, M-MDSCs)。研究证明, G-MDSCs可通过转移前生态位的形成而促进肿瘤转移[47]。Long等[47]合成了苯硼酸(phenylboronic acid, PBA) 修饰、负载DOX及α-半乳糖神经酰胺(α-galactosylceramide, αGC) 的PLT/DOX/αGC纳米粒, 如图 7a所示, 该纳米粒可通过其亲水性部分抑制G-MDSCs的外渗, 阻止G-MDSCs在肺中的早期募集; 其疏水性部分可抑制基质金属蛋白酶-9 (matrix metalloproteinase-9, MMP-9) 的分泌, 在两者共同作用下抑制转移前生态位的形成。有研究显示, MDSCs可通过诱导Treg细胞产生而抑制T细胞的功能, 发挥免疫抑制作用[46]。MDSCs表达的B类清道夫受体1是高密度脂蛋白的高亲和力受体, Plebanek等[48]基于这一原理构建了类高密度脂蛋白纳米粒, 通过与B类清道夫受体1的高亲和力靶向MDSCs, 抑制其活性, 减弱其免疫抑制作用。
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Figure 7 a: The scheme of the mechanism of effect of PLT/DOX/αGC NPs. (Adapted from Ref. 47 with permission. Copyright © 2020 American Chemical Society); b: The scheme of the mechanism of effect of HCP+CpG@NPs-CD80 Ab. (Adapted from Ref. 52 with permission. Copyright © 2019 Wilely). PLT/DOX/αGC NPs: Phenylboronic acid-modified and doxorubicin/α-galactosylceramide-coloaded nanoparticles; HCP+CpG@NPs-CD80 Ab: Nanoparticles loaded with HSP70‐chaperoned polypeptides and oligodeoxynucleotides containing demethylated CpG motifs and modified by antibody against CD80; LMWH: Low molecular weight heparin; TOS: Tocopherol succinate nanoparticle; IL-10: Interleukin-10; LT NP: Low molecular weight heparin-tocopherol succinate nanoparticle; PCL-Hyd-PEG: Poly (ε-caprolactone)-block-poly (ethylene glycol); IL-12: Interleukin-12; TNF-α: Tumor necrosis factor-α; TLR9: Toll-like receptor 9 |
抗原呈递细胞(antigen-presenting cells, APCs) 所具有的抗原呈递功能是机体产生免疫反应的必要条件, APCs的活性及其呈递抗原的量直接影响免疫反应中细胞毒性T淋巴细胞的量[49], 若其活性低或其呈递的抗原的量较少则会降低治疗的效果或出现免疫耐受[50]。在TME中APCs的活化难度增加[51]。为了增加活化的APCs数量, Chang等[52]利用纳米粒携带肿瘤抗原(HSP70-chaperoned polypeptides, HCP) 及佐剂形成HCP+CpG@NPs-CD80 Ab (图 7b), 该纳米粒可特异性靶向APCs, 延长APCs中免疫复合物的存在时间, 激活大量T细胞, 产生强烈的免疫反应。现有的制剂多是通过注射入小鼠体内发挥作用, Liu等[53]通过将磷脂酰丝氨酸包被在干扰素基因刺激受体(stimulator of interferon genes, STING) 激动剂的表面形成脂质体, 可通过吸入方式给药。该纳米脂质体可靶向APCs, 进入细胞后释放STING激动剂, 激活STING信号通路产生I型干扰素, 促进树突状细胞的成熟, 进而刺激机体产生免疫反应。
纳米材料与免疫检查点阻断疗法结合可用于调节T淋巴细胞的活性; 通过携带药物等物质可促进TAMs极化为具有抗肿瘤活性的M1型; 通过靶向MDSCs和APCs可抑制MDSCs的活性, 增强APCs的活性, 导致机体产生强的免疫反应。综上所述, 纳米材料可通过增强免疫杀伤细胞或降低免疫抑制细胞的活性, 从而降低TME的免疫抑制程度, 实现抑制肿瘤生长。
5 总结与展望利用纳米材料可从多个方面实现对TME的调节, 达到理想的抗肿瘤效果。针对TME所呈现的弱酸性特点, 纳米材料可利用自身消耗H+或通过降低乳酸的堆积而上调pH值, 避免出现免疫逃逸。针对TME的缺氧状况, 纳米材料可通过携带O2或催化H2O2产生而增加O2的浓度, 作为辅助手段增强肿瘤治疗的疗效。针对TME中含有高水平ROS及GSH的特点, 纳米材料既可通过PDT及CDT疗法产生大量的ROS直接杀死肿瘤细胞, 又可作为反应物或载体降低细胞内GSH的浓度、增加底物H2O2的含量, 从而增强PDT及CDT的疗效。针对TME呈现的免疫抑制的特点, 纳米材料可与免疫检查点抑制剂结合, 用于调节T淋巴细胞的活性; 纳米材料还可作为载体, 实现对肿瘤相关巨噬细胞的重编程, 促进TAMs的M1极化; 此外, 纳米材料还可靶向MDSCs及APCs, 抑制MDSCs活性, 活化APCs, 降低免疫抑制程度, 增强机体的免疫反应, 从而实现对肿瘤生长的抑制。
相比于其他的治疗手段, 利用纳米技术调控TME相对处于优势地位, 但也存在一些问题: ①肿瘤微环境调节型纳米材料的肿瘤组织渗透性低。低的组织渗透性使纳米材料不能接触到深层肿瘤细胞, 从而降低治疗效果甚至导致治疗失败。目前已证实磁传导可增强纳米材料在实体瘤中的渗透及积聚。此外, 减小纳米材料的尺寸及改变纳米材料的形貌也可提高组织渗透性; ②肿瘤微环境调节型纳米材料生物相容性及负载量有待提高。生物相容性低将会导致两败俱伤的结果, 负载量低将达不到理想的治疗效果甚至会诱导肿瘤出现耐药性。将纳米材料与天然细胞相结合可明显改善材料的生物相容性, 配体修饰及多孔结构可用来提高材料的负载量; ③在对TME的多重调节中, 肿瘤微环境调节型纳米材料应用受限。仅调节TME的某一特性所达到的疗效低且具有局限性, 近年来, 已有多项研究通过改变纳米材料的形貌或表面电荷等负载光敏剂和抗癌药物等, 实现肿瘤联合治疗; ④肿瘤微环境调节型纳米材料的治疗效果受肿瘤微环境异质性的影响。肿瘤异质性呈现“适者生存”原则, 由基因突变或环境因素所导致, 使得肿瘤细胞具有更强的生长能力及侵袭力。肿瘤微环境作为肿瘤异质性产生的原因之一, 其同样具有异质性特点。其异质性与成纤维细胞、脉管系统及免疫细胞有关, 三者相互影响, 呈现动态变化, 进而导致不同部位的肿瘤及瘤内异质性增加, 最终影响肿瘤微环境响应型纳米材料的疗效。因此, 根据肿瘤异质性及肿瘤微环境异质性设计“个性化”纳米材料, 实现“个性化”治疗有望增强肿瘤微环境相应型纳米材料的疗效及应用范围。随着对TME研究的不断深入及纳米技术的不断发展, 这些问题将会得到解决, 越来越多更好的肿瘤微环境调节型纳米材料将会应用于癌症的治疗。
作者贡献: 该文章主要由孙彩霞撰写, 鞠艳敏和戴建君提供重要的指导和意见。
利益冲突: 所有作者声明不存在任何利益冲突。
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