药学学报

Targeting type	Type of nanostructures	Active drug	Tumor model	Therapeutic efficacy	Ref.
Cancer stem cells	Iron oxide nanoparticle	CTX and siMGMT	Glioblastomas	Enhance the killing effect of drug-resistant GBMs and GSCs as compared to TMZ alone, significantly extend the survival of mice bearing GBM6 orthotopic xenografts	[15]
Micelle	ATRA and CPT	MCF-7 breast cancer	Reduce stemness-related drug resistance, enhance the chemotherapeutic response, suppress the tumor growth and metastasis	[17]
Fibroblasts	Micelle	GEM and CQ	Pancreatic cancer	Suppress tumor fibrosis and down-regulate MMP-2 by inhibiting autophagy, inhibit tumor growth and metastasis, reshape TME and enhance the effect of chemotherapy	[23]
Dendrimer	MCT	4T1 breast cancer	Inhibit the production of exosomes produced by cancer cells, regulate the distribution of T cell subsets in TME, and prevent the progression of fibrosis	[24]
Immune regulation	-	OVA and α-CD40 antibody	B16 melanoma	Better harnessing the immunizing functions of DCs, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity	[28]
Polymer	IRF5 and IKKβ	Ovarian cancer, melanoma, and glioblastoma	Reverse the immunosuppressive microenvironment and transform tumor-associated macrophages into anti-tumor M1 subtypes	[37]
Extracellular matrix	Micelle	EPI and HAase	HepG2 hepatoma carcinoma	Show a better accumulation and deeper tumor penetration in HepG2 tumors, inhibit tumor proliferation with minor side effects	[50]
-	Bintrafusp alfa, NC410 and PD-L1	Colon and breast cancer	Remould the tumor collagen matrix, enhances tumor infiltration and activation of CD8⁺ T cells, realize macrophage repolarization, and achieves high cure rate and long-term tumor specific protection	[51]
Anti-angiogenesis	Silica nanoparticle	PM, CA4 and Apa	MHCC-97H liver cancer	Damage the tumor vascular endothelium to interfere with the interaction between VEGFR-2 and its receptor, thereby inhibiting tumor angiogenesis and expansion	[64]
Polymeric nanoparticle	T4	4T1 breast cancer	Expand in acidic TME, and then release T4 on macrophages and endothelial cells to interact with Tie2 and ANG/Tie2 signaling pathway, thereby inhibiting angiogenesis and tumor cell migration	[66]
Self-assembled VE-DDP-Pro nanoparticle	DDP, cRGD peptide and folate	SKOV3-Luc ovarian cancer	Bind to integrin αvβ3 or α5β1 to reduce MMP-2/VEGF expression and epithelial-mesenchymal transformation, resulting in a self-resistant EDV and VM capacity	[72]
Exosomes	Exosome	aCD47 and aSIRP α	4T1 breast cancer	Repolarize the pro-tumoral M2 to anti-tumoral M1, inhibit tumor growth	[87]
Exosome	ELANE and hiltonol	MDA-MB-231 breast cancer	Promote the activation of cDC1s, improve the tumor-reactive CD8⁺ T cell responses, enhance the immunogenicity of TNBC cells, inhibit tumor growth	[89]
Microbiota	-	SLC strain	HeLa cervical cancer	Lead to a notable reduction of tumor activity	[107]
-	eSLC-CD47nb	A20 B cell lymphoma cancer, 4T1 breast cancer, B16-F10 melanoma	Prevent the metastasis of tumor cells and degenerate the distal uninjected tumors	[108]

Targeting type	Type of nanostructures	Active drug	Tumor model	Therapeutic efficacy	Ref.
Cancer stem cells	Iron oxide nanoparticle	CTX and siMGMT	Glioblastomas	Enhance the killing effect of drug-resistant GBMs and GSCs as compared to TMZ alone, significantly extend the survival of mice bearing GBM6 orthotopic xenografts	[15]
Micelle	ATRA and CPT	MCF-7 breast cancer	Reduce stemness-related drug resistance, enhance the chemotherapeutic response, suppress the tumor growth and metastasis	[17]
Fibroblasts	Micelle	GEM and CQ	Pancreatic cancer	Suppress tumor fibrosis and down-regulate MMP-2 by inhibiting autophagy, inhibit tumor growth and metastasis, reshape TME and enhance the effect of chemotherapy	[23]
Dendrimer	MCT	4T1 breast cancer	Inhibit the production of exosomes produced by cancer cells, regulate the distribution of T cell subsets in TME, and prevent the progression of fibrosis	[24]
Immune regulation	-	OVA and α-CD40 antibody	B16 melanoma	Better harnessing the immunizing functions of DCs, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity	[28]
Polymer	IRF5 and IKKβ	Ovarian cancer, melanoma, and glioblastoma	Reverse the immunosuppressive microenvironment and transform tumor-associated macrophages into anti-tumor M1 subtypes	[37]
Extracellular matrix	Micelle	EPI and HAase	HepG2 hepatoma carcinoma	Show a better accumulation and deeper tumor penetration in HepG2 tumors, inhibit tumor proliferation with minor side effects	[50]
-	Bintrafusp alfa, NC410 and PD-L1	Colon and breast cancer	Remould the tumor collagen matrix, enhances tumor infiltration and activation of CD8⁺ T cells, realize macrophage repolarization, and achieves high cure rate and long-term tumor specific protection	[51]
Anti-angiogenesis	Silica nanoparticle	PM, CA4 and Apa	MHCC-97H liver cancer	Damage the tumor vascular endothelium to interfere with the interaction between VEGFR-2 and its receptor, thereby inhibiting tumor angiogenesis and expansion	[64]
Polymeric nanoparticle	T4	4T1 breast cancer	Expand in acidic TME, and then release T4 on macrophages and endothelial cells to interact with Tie2 and ANG/Tie2 signaling pathway, thereby inhibiting angiogenesis and tumor cell migration	[66]
Self-assembled VE-DDP-Pro nanoparticle	DDP, cRGD peptide and folate	SKOV3-Luc ovarian cancer	Bind to integrin αvβ3 or α5β1 to reduce MMP-2/VEGF expression and epithelial-mesenchymal transformation, resulting in a self-resistant EDV and VM capacity	[72]
Exosomes	Exosome	aCD47 and aSIRP α	4T1 breast cancer	Repolarize the pro-tumoral M2 to anti-tumoral M1, inhibit tumor growth	[87]
Exosome	ELANE and hiltonol	MDA-MB-231 breast cancer	Promote the activation of cDC1s, improve the tumor-reactive CD8⁺ T cell responses, enhance the immunogenicity of TNBC cells, inhibit tumor growth	[89]
Microbiota	-	SLC strain	HeLa cervical cancer	Lead to a notable reduction of tumor activity	[107]
-	eSLC-CD47nb	A20 B cell lymphoma cancer, 4T1 breast cancer, B16-F10 melanoma	Prevent the metastasis of tumor cells and degenerate the distal uninjected tumors	[108]

基于纳米递药系统的肿瘤微环境多靶点调控策略研究进展

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李菁 ¹^,² , 潘婷 ¹^,² , 赵思垚 ¹^,² , 陈晓晴 ¹^,² , 尹昊天 ¹^,² , 吉小烨 ¹^,² , 吴玘璠 ¹^,² , 王伟 ¹^,²^,^*

药学学报 | 专题报道: 基于智能化递药系统的疾病精准治疗研究 2023,58(3): 536-549

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药学学报 | 专题报道: 基于智能化递药系统的疾病精准治疗研究 2023, 58(3): 536-549

基于纳米递药系统的肿瘤微环境多靶点调控策略研究进展

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李菁¹^,², 潘婷¹^,², 赵思垚¹^,², 陈晓晴¹^,², 尹昊天¹^,², 吉小烨¹^,², 吴玘璠¹^,², 王伟¹^,²^,^*

作者信息

1.中国药科大学药学院药剂系, 江苏南京 210098

2.中国药科大学, 天然药物活性组分与药效国家重点实验室, 江苏南京 210098

通讯作者:

*王伟, Tel: 86-25-86185328, E-mail: wangcpu209@cpu.edu.cn

Research progress on multi-target regulation strategies of tumor microenvironment based on nano-drug delivery system

Jing LI¹^,², Ting PAN¹^,², Si-yao ZHAO¹^,², Xiao-qing CHEN¹^,², Hao-tian YIN¹^,², Xiao-ye JI¹^,², Qi-fan WU¹^,², Wei WANG¹^,²^,^*

Affiliations

1. Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China

2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210098, China

出版时间: 2023-03-12 doi: 10.16438/j.0513-4870.2022-0939

文章导航

摘要

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肿瘤微环境(tumor microenvironment, TME) 是由内皮细胞、周细胞、免疫细胞、肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、肿瘤干细胞(cancer stem cells, CSCs) 及细胞外基质(extracellular matrix, ECM) 等成分组成的复杂生物环境。TME与肿瘤细胞间通过大量信号通路相互作用, 参与肿瘤的发展、侵袭和转移进程。因此, TME成为了癌症治疗的潜在靶点, 在肿瘤治疗领域展示出良好的治疗潜力和研究价值。目前, 新型纳米技术被广泛应用于抗肿瘤治疗, 纳米技术介导的药物递送系统正在被研究应用于TME调控从而抑制肿瘤生长。与传统治疗方式相比, 纳米技术介导的药物递送具有许多优点, 包括延长循环时间、提高生物利用度和降低毒性。本文综述了基于TME调控的靶向纳米递药系统研究现状, 包括基于CSCs、CAFs、免疫细胞、ECM、肿瘤血管系统、外泌体、微生物群的调控策略。此外, 本文总结了与传统治疗策略相比TME调控策略的优势及面临的机遇与挑战, 为基于TME调控策略的纳米递药系统应用于肿瘤精准治疗提供了参考和借鉴。

关键词

肿瘤微环境 / 纳米技术 / 调控 / 靶向 / 肿瘤治疗

Abstract

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Tumor microenvironment (TME) is composed of endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), extracellular matrix (ECM) and other components of the complex biological environment. TME interacts with the tumor cells through a large amount of signaling pathways, participates in the process of tumor progression, invasion, and metastasis. Hence, TME has become a potential therapeutic target for cancer treatment, exhibiting excellent therapeutic potential and research value in the field of cancer treatment. Currently, the novel nanotechnology has been widely applied in anticancer therapy, and nanotechnology-mediated drug delivery system is being explored to apply in TME modulation to inhibit tumor progression. Nanotechnology-mediated drug delivery has many advantages over traditional therapeutic modalities, including longer circulation times, improved bioavailability, and reduced toxicity. This review summarized the research of targeted nano-drug delivery based on TME regulation, including regulation strategies based on CSCs, CAFs, immune cells, ECM, tumor vascularization, exosomes, and microbiota. In addition, we summarized the advantages, opportunities, and challenges of TME regulation strategy compared with traditional treatment strategy, which provides a reference for the application of nano-drug delivery system based on TME regulation strategy in tumor precision therapy.

Key words

tumor microenvironment / nanotechnology / regulation / targeting / tumor therapy

引用本文

李菁, 潘婷, 赵思垚, 陈晓晴, 尹昊天, 吉小烨, 吴玘璠, 王伟. 基于纳米递药系统的肿瘤微环境多靶点调控策略研究进展. 药学学报, 2023 , 58 (3) : 536 -549 . DOI: 10.16438/j.0513-4870.2022-0939

Jing LI, Ting PAN, Si-yao ZHAO, Xiao-qing CHEN, Hao-tian YIN, Xiao-ye JI, Qi-fan WU, Wei WANG. Research progress on multi-target regulation strategies of tumor microenvironment based on nano-drug delivery system[J]. Acta Pharmaceutica Sinica, 2023 , 58 (3) : 536 -549 . DOI: 10.16438/j.0513-4870.2022-0939

正文

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肿瘤是由机体局部组织增生, 阻碍机体其他正常细胞功能发挥作用的恶性细胞。早在19世纪, 近代病理学之父Paget就提出了肿瘤生长的“种子-土壤学说”, 该理论指出, 肿瘤细胞的生长需依附于合适的肿瘤微环境(tumor microenvironment, TME)^[1]。TME是指肿瘤细胞存在的周围环境, 包括免疫细胞、肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、脂肪细胞、骨髓源性炎性细胞等除肿瘤细胞外的细胞及非细胞结构的细胞外基质(extracellular matrix, ECM)^[2], 还包括各种细胞分泌的细胞因子、炎性因子、囊泡等, 以及致密的血管和淋巴管网络^[3]。TME中的多种信号因子及大多数成分都有利于肿瘤细胞的生长及转移, 通过ECM导致肿瘤的发展恶化^[4]。

传统肿瘤治疗方式虽可直接杀伤肿瘤细胞, 但往往也多因直接作用于肿瘤细胞而存在许多弊端, 如易使肿瘤细胞产生耐药性、药物渗透率低、复发率高、不良反应大等^[5]。随着人们对TME在肿瘤发生及发展过程中作用的深入探索, 逐渐提出了在肿瘤治疗过程中, 通过靶向调控TME中相关细胞和各种因子水平来实现对恶性肿瘤的控制与治疗^[6]。纳米递药系统通常具有良好的生物相容性与药物稳定性, 一般在10~200 nm, 可于TME中被动积聚, 同时也具有良好的可降解性, 安全性高。此外, 经修饰的纳米递药系统可锚定TME中的不同生物靶点, 进而选择性地控制药物释放, 进行针对性治疗^[7]。如TME中的各种成分会通过相互作用共同构建免疫抑制环境以帮助肿瘤细胞实现免疫逃逸, 可采用纳米技术靶向重塑TME, 实现基于TME抑制途径的特异性阻断, 为有效杀伤肿瘤细胞提供了思路^[8]。

本文综述了基于TME调控的靶向纳米递药系统研究现状, 包括基于肿瘤干细胞(cancer stem cells, CSCs)、CAFs、免疫细胞、ECM、肿瘤血管系统、外泌体、微生物群的调控策略(图 1), 此外, 还总结了与传统治疗策略相比TME调控策略的优势及面临的机遇与挑战。

1 TME靶向策略

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1.1 CSCs靶向纳米递药系统

CSCs是TME中重要的细胞亚群, 具有自我更新、多向分化、耐药性及致瘤性等特征^[9]。CSCs是肿瘤形成及不断生长的根源, 对调节TME有很大作用, 且是导致肿瘤形成、发展、转移、复发和预后不良的关键因素^[10]。虽然传统放疗和化疗对肿瘤有一定治疗作用, 但CSCs具有耐药性, 能通过各种机制避免被杀灭, 包括增强药物转运蛋白的表达、维持缓慢分裂状态和快速修复DNA的能力等, 是肿瘤转移和复发的关键原因^[11]。临床观察表明, 在转移过程中大多数细胞都会死亡, 但仍有少数细胞能存活并渗透到靶器官, 进入潜伏期长期生存, 最终复发^[12]。原发肿瘤内的肿瘤细胞在经过化疗或放疗后, 不能完全被杀灭, 残留的耐药CSCs可能会引起肿瘤复发, 进一步形成继发性肿瘤(图 2)。

纳米技术介导的药物递送系统通过靶向TME的CSCs能有效根除肿瘤, 降低复发和转移的风险。CSCs在化疗期间发展耐药性是癌症治疗中最难克服的障碍, 通过靶向CSCs, 能大幅提高协同抗癌效果, 克服当前疗法下CSCs相关的化疗耐药性, 预防肿瘤复发, 具有可观的临床应用潜力。

胶质母细胞瘤(glioblastoma, GBM) 恶性程度高, 生存率低且预后差^[13]。替莫唑胺(temozolomide, TMZ) 与放射治疗相结合可延长患者生存时间, 但治疗效果受到DNA修复蛋白O⁶-甲基鸟嘌呤-DNA甲基转移酶(O⁶-methylguanine-DNA methyltransferase, MGMT) 的限制, 该蛋白可帮助修复TMZ诱导的DNA损伤, 使肿瘤细胞存活。通过全身施用MGMT抑制剂(O⁶-苄基鸟嘌呤) 来抑制MGMT活性的效果并不好^[14], 所以Wang等^[15]选择了基于小干扰RNA (small interfering RNA, siRNA) 的MGMT抑制剂siMGMT, 制备了一种以氧化铁(Fe₃O₄) 为核心, 涂有壳聚糖-聚乙二醇(polyethylene glycol, PEG)-聚乙烯亚胺(polyethylenimine, PEI) 共聚物的纳米粒, 并负载siMGMT和氯毒素(chlorotoxin, CTX)。与正常脑组织相比, CTX对脑肿瘤细胞表现出特异性靶向, 且CTX还可通过受体介导的胞吞作用提高血脑屏障(blood brain barrier, BBB) 渗透性^[16], 构建的纳米递药系统可成功穿透BBB, 保护siRNA不被核酸酶降解, 且毒性较小。与单独使用TMZ相比, siRNA-CTX和TMZ的联合治疗抑制了MGMT的表达和活性, 使GBM细胞对TMZ敏感, 大大增强了对耐药性GBM和GBM干细胞的杀伤力, 并延长了GBM6原位异种移植小鼠的存活时间。Shen等^[17]开发了一种TME响应性纳米治疗策略, 将分化诱导剂全反式维甲酸(all-trans-retinoic acid, ATRA) 和化疗药物喜树碱(camptothecin, CPT) 负载到同一纳米胶束中, 让ATRA和CPT保持固定的药物比例。ATRA/CPT纳米粒在TME缺氧条件的触发下, 结构上从疏水性的硝基咪唑基团变为亲水性的氨基咪唑基团, 疏水作用减弱, ATRA被加速释放, 诱导了CSC的分化。CSC分化后细胞内活性氧(reactive oxygen species, ROS) 水平上升, 导致与CPT相连的化学键断裂, CPT被释放, 进一步杀伤肿瘤细胞。与单独使用分化诱导剂或化疗药物相比, 分化诱导剂可使肿瘤细胞向正常的成熟方向分化, 且毒性较小, 缺点是对实体瘤的疗效较差。而使用细胞毒性药物的传统单一化疗不仅不能有效杀死耐药的CSC, 还会增加其干性。分化诱导药物和化疗药物的结合大大提高了抗癌效果。这些发现为探索新的纳米治疗手段和克服与CSC相关的化疗耐药性提供了光明的发展前景, 靶向TME内的CSCs将为肿瘤治疗提供更多可能性。

1.2 CAFs靶向纳米递药系统

CAFs是肿瘤间质中含量最丰富的细胞^[18], 参与肿瘤细胞的生成、增殖、侵袭和转移过程^{[19, 20]}。CAFs还可分泌很多生长因子, 包括转化生长因子-β (transforming growth factor-β, TGF-β)、肝细胞生长因子、血管内皮生长因子(vascular endothelial growth factor, VEGF) 等。作为TME的主要组成部分, 抑制CAFs是一种重塑TME, 实现肿瘤治疗的潜在手段。CAF不仅可通过分泌多种细胞因子参与调节免疫反应, 抑制免疫细胞功能, 从而形成免疫抑制性TME, 促进肿瘤生长, CAF还可重塑ECM, 对药物产生屏障作用^[21]。利用CAFs作为治疗靶点, 靶向调控CAFs可增强药物在靶部位的蓄积, 增强药物抗癌效果。CAFs的作用主要是促进肿瘤的发生, 但同时也具有抑制肿瘤的可能性, 但由于缺乏特定的生物标志物, 所以要找到一种专门针对CAF促肿瘤亚型的治疗方法是比较困难的。

联合放射治疗靶向CAFs、调节T细胞和肿瘤相关巨噬细胞已被报道可有效治疗癌症^[22]。Chen等^[23]用6-膦酰基己酸修饰聚-L-赖氨酸, 生成PDGL, 然后装入吉西他滨(gemcitabine, GEM), 制成纳米递药系统PDGL-GEM, 再将其与自噬抑制剂磷酸氯喹(chloroquine phosphate, CQ) 和磷酸钙(calcium phosphate, CAP) 共沉淀后生成PDGL-GEM@CAP/CQ纳米复合物。这种“纳米炸弹”对pH敏感, 在酸性TME中CAP被分解, 释放出CQ和PDGL-GEM, CQ会被周围的CAFs内化, 通过抑制自噬来减少纤维化从而重塑TME, 使化疗药物GEM可深入肿瘤, 增强化疗效果。两种药物通过协同作用, 抑制肿瘤的生长和转移。与单独使用化疗药物GEM或自噬抑制剂CQ相比, PDGL-GEM@CAP/CQ更能抑制成纤维细胞的自噬, 表现出更强的抗肿瘤作用。Son等^[24]在4T1原位肿瘤模型中使用含有马西替坦(micitentan, MCT) 的纳米聚合物胶束, 通过调节CAFs来抑制癌细胞产生外泌体, 并调节T细胞亚群在TME中的分布, 达到阻止纤维化进展的作用。使用含有MCT的纳米粒实现了将MCT被动靶向至具有免疫抑制性的TME, 从而重塑TME, 与免疫检查点疗法联用时, 可显著增强抗肿瘤效果并抑制肿瘤转移。

1.3 免疫调控型纳米递药系统

免疫系统作为人体与生俱来的防线, 其中的特异性免疫具有高度识别能力, 一旦将癌细胞视为“异己”, 即可针对性消杀肿瘤, 避免对于正常组织的伤害。TME中存在大量免疫细胞, 这些细胞与肿瘤的生长与转移密切相关。目前存在一些通过调节细胞免疫来实现肿瘤治疗的手段, 如免疫功能检查点疗法、癌症抗体疗法、单克隆细胞抗体疗法等^[25]。然而, 由于肿瘤组织的低免疫原性和TME中存在大量抑制免疫的因素, 抗肿瘤效应受到极大限制。免疫细胞从对免疫调节的效用上可分为两种: ①免疫反应刺激细胞, 如树突状细胞(dendritic cells, DCs)、细胞毒性T淋巴细胞(cytotoxic T lymphocytes, CTLs)、自然杀伤细胞(natural killer cell, NK)、M1表型巨噬细胞(tumor associated macrophages with M1 phenotype, M1 TAMs) 等; ②免疫抑制细胞, 如骨髓来源的抑制性细胞(myeloid-derived suppressor cells, MDSCs)、M2表型巨噬细胞(tumor associated macrophages with M2 phenotype, M2 TAMs)、调节性T细胞(regulatory T cells, Tregs) 等^[26]。使用纳米技术介导的递药系统增强免疫刺激性细胞的能力, 同时规避免疫抑制性细胞对免疫调节的不利影响是目前肿瘤免疫治疗的主要策略。

1.3.1 免疫反应刺激细胞

DCs被认为是人体内最强大的抗原递送细胞, 未分化成熟前的DCs具有强大的肿瘤抗原识别和吞噬应答能力, 分化成熟后高度表达肿瘤共刺激抗原与附着力因子^[27]。DEC-205受体是一种内吞受体, 在淋巴组织中的DCs上含量丰富。Bonifaz等^[28]设计了一种可有效靶向DCs的纳米递药系统, 将卵清蛋白掺入到DEC-205受体的单克隆抗体中, 同时注射激动剂α-CD40抗体, 使DCs成熟。结果表明, 纳米递药系统可通过靶向内吞受体促进DCs成熟从而表达肿瘤刺激抗原。CTLs由CD8⁺ T淋巴细胞成熟得来, 对肿瘤的免疫治疗发挥重要作用^[29]。由于CTLs上特异性的组织相容性复合体I类(MHC-I) 的限制, 肿瘤细胞可被精确杀死而不影响到其他细胞。另外, CTLs还可分泌穿孔素与细胞毒素更进一步发挥免疫调节作用。除DCs和CTLs外, 还存在一些其他种类的免疫刺激细胞, 在癌症治疗中也发挥重要作用, 如辅助性T细胞(helper T cell, Th)、NK、M1 TAMs等。Th细胞可在其表面表达CD4, 不同类型Th1、Th2、Th17可分泌不同的细胞因子来对免疫调节产生影响^[30]。NK可直接调节细胞毒效应, 在活化后释放穿孔素、颗粒酶等参与抗肿瘤治疗^[31]。M1 TAMs主要存在于实体瘤环境中, 能释放多种因子, 也能进行肿瘤抗原的呈递^[32]。尽管以上免疫刺激细胞可产生许多免疫刺激性反应, 但同时也产生很多问题。比如, 随着肿瘤的发展, NK的能力会逐渐弱化, TAMs的能力也会根据TME的变化而变化等^[33]。

1.3.2 免疫抑制性细胞

Tregs可通过多种途径抑制免疫反应, 产生多种免疫抑制性细胞因子, 削弱肿瘤免疫反应, 明显抑制CD4⁺和CD8⁺ T淋巴细胞的增殖活化, 并削弱NK的细胞毒效应^[34]。此外, Tregs还会下调DCs的核因子κB (nuclear factor kappa-B, NF-κB) 通道以抑制抗原递送过程, 使DCs的活化与免疫反应受到影响^[35]。

与M1 TAMs不同, M2 TAMs在TME中表现出免疫抑制特性, 会增加TME中多种可溶性蛋白分子数量, 也会导致TME中T淋巴细胞失效, 造成免疫抑制性TME, 降低杀伤肿瘤的能力^[36]。因此, 在抗肿瘤的免疫治疗中需降低M2 TAMs数量。TAMs会对TME中分子的改变做出反应, 包括细胞因子、趋化因子、模块识别因子和激素, 具有良好的可塑性。因此, 将具有促进肿瘤生长的M2 TAMs转化为具有杀伤肿瘤能力的M1 TAMs可作为治疗肿瘤的潜在策略。然而, 这种转变是非特异性的, 且会导致全身炎症, 因此Zhang等^[37]便描述了一种不会引起炎症反应且可提供M1偏向转录因子的体外转录的mRNA。在卵巢癌、黑色素瘤和胶质母细胞瘤模型中, 输入含有编码干扰素因子5的mRNA及其激活激酶kappa B抑制因子激酶(inhibitor of kappa B kinase β, IKKβ) 的纳米粒用来逆转TAMs对于肿瘤的支持作用并将其重新转化为具有抗肿瘤效用的表型, 促进肿瘤消退。

1.4 ECM靶向纳米递药系统

ECM是一种存在于细胞周围的三维高分子复杂网络, 可为细胞提供多功能支持^[38], 由胶原蛋白、蛋白聚糖、层黏连蛋白和纤维连接蛋白等成分组成。ECM中蛋白质的多样性也赋予了不同细胞不同的生理属性, 从而调节各种细胞的生理过程^[39]。ECM不仅作为细胞间质存在, 在构成TME中也起到重要作用。Senthebane等^[40]通过搭建三维细胞模型证明了ECM能削弱抗癌药物对肿瘤细胞的细胞周期和增殖的影响, 并会对顺铂(cisplatin, CDDP)、5-氟尿嘧啶和表柔比星(epirubicin, EPI) 产生耐药性。同时, ECM中的胶原蛋白和透明质酸(hyaluronic acid, HA) 等成分可在肿瘤组织附近聚集, 并阻碍药物向肿瘤组织内部渗透^[41]。此外, 当免疫系统积极参与癌症部位受损组织的再生时, 会促进ECM的形成和沉积^[42], 反之, 肿瘤部位的ECM又有助于免疫抑制网络的构建, 在新形成的网络中, 分泌的细胞因子和趋化因子可协助肿瘤细胞逃避免疫系统^[43-45], 这种现象通常被视为免疫反应障碍, 并可阻止药物扩散和肿瘤细胞的细胞坏死^{[46, 47]}。由此可知, 靶向肿瘤微环境ECM中的HA或胶原蛋白是一种肿瘤治疗的有效手段。

1.4.1 降解透明质酸的纳米递药系统

HA是ECM中的重要组分, 是一种带有负电荷的酸性黏多糖, 广泛分布于动物体的关节等部位^[48]。HA在肿瘤组织中过度表达, 形成胶状致密ECM, 可抑制化疗药物积聚, 同时增加肿瘤间质液体压力(interstitial fluid pressures, IFP)^[49]。这将导致递送到肿瘤组织中的化疗药物浓度降低, 无法渗透入致密的肿瘤组织, 阻碍药物向更深层次扩散, 治疗效果大打折扣。因此, HA可作为一个理想的抗癌药物靶点, 通过降解HA来增强化疗药物的渗透, 充分发挥化疗药物的肿瘤杀伤效果。Chen等^[50]设计一种透明质酸酶(hyaluronidase, HAase) 负载EPI的纳米粒, 通过降解ECM中的HA促进载药纳米粒在实体肿瘤组织中的渗透和扩散, 大幅增加EPI渗透深度, 结合纳米递药系统本身具有pH敏感性的特点, 在减小不良反应的同时增强对体内实体瘤生长的抑制。

1.4.2 调节胶原蛋白的纳米递药系统

胶原蛋白是ECM的基本组成成分之一, 是人体组织中发现的28种独特亚型中含量最丰富的蛋白质^[51]。ECM中的胶原蛋白为肿瘤免疫浸润提供了物理屏障, 含有大量胶原蛋白的TME可把肿瘤组织与免疫系统隔开, 使肿瘤组织躲避免疫系统的攻击。含有胶原蛋白的TME也可作为免疫抑制受体的配体, 如白细胞相关免疫球蛋白样受体1 (leukocyte-associated immunoglobulin-like receptor-1, LAIR-1), 此受体广泛表达于免疫细胞表面, 是一种在免疫细胞上广泛表达的免疫检查点。当LAIR-1与胶原样结构域结合后, 会释放免疫抑制信号, 不仅会影响T细胞的正常功能, 还会抑制NK、单核细胞、DCs等免疫细胞的激活和正常功能。此外, 胶原蛋白与TGF-β联合作用可把TME转化为一个免疫抑制性环境^{[52, 53]}。Horn等^[51]报道了靶向抑制LAIR-1并阻断TGF-β与细胞程序性死亡-配体1 (programmed cell death 1 ligand 1, PD-L1) 相结合的疗法, 重塑了肿瘤基质, 增强了肿瘤浸润和CD8⁺ T细胞的活化, 并实现巨噬细胞复极化, 在结肠癌和乳腺癌的小鼠模型中实现了高治愈率和长期肿瘤特异性保护。

1.5 抗血管生成纳米递药系统

血管在肿瘤的发生、发展与转移过程中发挥不可或缺的作用, 为维持肿瘤细胞的正常生命活动提供多种保障, 包括营养供应、代谢废物处理及与其他组织间的交流等^[54]。正常的血管网络由成熟血管均匀分布, 分层组织, 靠促血管生成因子及抗血管生长因子间的动态平衡维持有序的血液供应, 并与体内细胞进行正常的物质交换^[55]。血管形成要经过原血管基底膜酶解、内皮细胞迁移、内皮细胞增殖、新生血管的构建与成熟4个过程, 在正常生理条件下严格受控^[56]。然而, 为满足肿瘤生长需求, 肿瘤血管的生长是连续且失控的^[57], 呈现紊乱、曲折、不成熟等特征, 极大降低了运送营养物质与代谢废物的能力^[58]。促血管生成因子的过度表达导致肿瘤新生血管生成迅速, 生长速度快且呈持续性, 最终使肿瘤血管网络变得杂乱无章。肿瘤血管相比于正常血管具有不成熟性, 细胞间连接松散, 部分毛细血管壁缺乏内皮细胞, 使机体无法正常调控血管活动。肿瘤组织内的血流量仅为正常的1%~10%, 血管结构异常导致TME缺氧、灌注不良和IFP升高^[59]。另外, 肿瘤组织无氧酵解会产生大量H⁺, 使TME呈现低营养、低pH、低氧状态。这些因素一方面会促进肿瘤细胞进一步增殖, 不利于对肿瘤的控制; 另一方面使得抗肿瘤药物向肿瘤组织的输送和渗透受阻, 降低了化疗和放疗的疗效, 甚至产生耐药性和免疫抑制^[60]。值得注意的是, 当肿瘤组织直径大于2 mm时, 就具备了诱导血管形成的能力, 需生成血管以获取其生存和发展的营养^[61]。而肿瘤部位不成熟、不规则、渗漏的血管特征也为肿瘤细胞的增殖和转移提供了重要途径^[62]。因此, 通过抗血管生成来重塑TME是肿瘤靶向治疗中极具潜力的策略之一(图 3)。

新生血管是肿瘤生长和转移的基础, 一般来说, 肿瘤血管的生成受VEGF调节^[63]。因此, VEGF信号系统成为了大多数抗血管生成药物的靶点。Li等^[64]用血小板膜(platelet membrane, PM) 涂层介孔二氧化硅纳米粒(mesoporous silica nanoparticle, MSN) 联合负载了血管破坏剂康普瑞汀A4 (combretastatin A4, CA4) 和抗血管生成药物阿帕替尼(apatinib, Apa), 组装成MSN@PM-C-A纳米递药系统。CA4的优势为快速破坏肿瘤血管内皮, 并诱导继发性血栓形成来阻断对肿瘤的营养供应。而Apa可通过选择性抑制血管内皮生长因子受体-2 (VEGFR-2) 酪氨酸激酶, 来妨碍VEGFR-2与其受体间的相互作用, 抑制肿瘤新生血管生长与扩张。两者的巧妙结合再加上PM对肿瘤血管受损部位的主动靶向能力, 进一步增强纳米粒在肿瘤组织中的积累。在MHCC-97H肝肿瘤模型实验中, MSN@PM-C-A被证实能有效抑制肿瘤部位的血管生成, 显著提高抗肿瘤效率。

化疗后, 肿瘤还可通过重建血管的方式复发, 此过程与在巨噬细胞及内皮细胞中过表达的血管生成素受体, 包含免疫球蛋白和表皮生长因子同源性-2的酪氨酸激酶受体(Tie2) 密切相关^[65]。为防止肿瘤复发, 抑制Tie2活性是关键的。Zhang等^[66]利用一种双响应型两亲性肽修饰疏水肽T4, 组装成抑制Tie2的纳米粒(P-T4)。T4是一种能抑制信号转导、细胞迁移和血管生成的生物活性肽^[67], P-T4在酸性TME中会自发膨胀, 随后在巨噬细胞与内皮细胞表面释放T4与Tie2相互作用, 干扰血管生成素(angiopoietin, ANG)/Tie2信号通路, 从而抑制血管生成和肿瘤细胞迁移。此设计的优势在于, 通过双响应型两亲性肽的装载, 克服了T4溶解度差, 生物利用度低, 循环时间短等缺点^[68], 并减少了网状内皮系统的非特异性吞噬, 进一步延长血液循环^[69], 同时纳入疏水分子二乙基氨基丙酯, 在肿瘤细胞外pH 6.7~7.1时质子化^[70], 对疏水性靶向Tie2的抗肿瘤肽进行了修饰, 在pH 7.4时可自组装成纳米粒。该实验运用了4T1乳腺癌肿瘤细胞模型, 在使用化疗药物Lipo-Dox治疗后肿瘤复发的情况下, P-T4成功抑制了Tie2表达及内皮细胞的迁移与血管形成, 具有良好的抗血管生成活性, 表现出在防止肿瘤复发方面巨大的潜力。除内皮依赖性血管(endothelium-dependent vessel, EDV) 外, 肿瘤血管生成中另一种关键形式是血管生成拟态(vasculogenic mimicry, VM), 是一种不依赖内皮细胞的肿瘤微循环模式, 指肿瘤细胞通过自身变形、基质重塑形成的管道结构^[71]。着眼于与EDV和VM相关的原位恶性转移肿瘤的治疗, Luo等^[72]设计了一种自组装纳米递药系统(VE-CDDP-Pro), 将cRGD-叶酸-肝素纳米粒(VE) 与CDDP螯合, 并通过静电相互作用修饰到鱼精蛋白(protamine, Pro) 纳米粒的表面。在酸性TME下, Pro因带正电荷而易被H⁺吸引^[73], 与VE-CDDP分离, 使其释放到卵巢癌细胞中。释放的VE-CDDP可特异性结合整合素αvβ3或α5β1, 调控AKT/mTOR/MMP-2层黏连蛋白和AKT/mTOR/EMT信号通路, 同时下调基质金属蛋白酶-2 (matrix metalloproteinase-2, MMP-2) 抑制VEGF的表达^[74], 并减少上皮-间充质转化, 触发抗VM和抗EDV。该实验运用了SKOV3-Luc卵巢癌细胞模型。相比于传统的抗EDV药物, VE-CDDP-Pro整合了CDDP对卵巢癌细胞的抗增殖作用和VE纳米粒诱导的抗EDV和VM能力, 并通过Pro改善细胞摄取, 将纳米粒精准递送到肿瘤组织, 显著增加了药物在肿瘤中的积累, 具有良好的肿瘤靶向性、细胞内化能力, 能有效抑制恶性卵巢癌肿瘤细胞的生长和转移。

1.6 外泌体靶向纳米递药系统

肿瘤细胞比正常细胞的代谢更旺盛, 即使在氧气充足条件下, 也主要是靠相对低效的糖酵解形式获取能量, 而不是高效的氧化磷酸化, 所以为了快速增殖, 肿瘤细胞会消耗大量葡萄糖^[75]。因此, 肿瘤细胞的糖代谢重编程能力是其区别于正常细胞的特征之一。肿瘤细胞可通过分泌携带miRNA的细胞外囊泡(extracellular vesicle, EV), 减少糖酵解途径中的关键酶, 即丙酮酸激酶, 抑制转移前TME中非肿瘤细胞葡萄糖的摄取, 有效地将TME内的细胞代谢重新编程^[76]。EV最初被认为是转移细胞代谢废物的载体, 现在被证明能在细胞微环境中发挥多种作用, 因其能携带多种物质, 包括脂质、蛋白质、核酸和代谢废物等, 所运载的货物取决于母细胞的类型^[77]。一般来说, EV包括外泌体和微囊泡, 其组成、大小和产生的机制各不相同, 30~100 nm的直径可涵盖各种细胞产生的外泌体大小的典型范围^[78]。外泌体在细胞间信号传导和调节细胞微环境中发挥着关键作用, 作为细胞释放的天然纳米载体, 其具有天然磷脂双分子层结构、稳定性强且生物相容性较好, 可通过靶向至肿瘤细胞来提高治疗效果, 同时最大限度减少对机体的不良反应, 因此, 外泌体有望成为有效的药物输送载体^[79]。外泌体也被证明可通过受体介导的途径主动靶向至特定细胞, 即在载药外泌体表面设计的配体可将外泌体引导至相应细胞表面过度表达的生物标志物目标位点^{[80, 81]}。

EV已被证明能通过携带各种蛋白质和核酸来参与肿瘤转移过程^[82]。肿瘤细胞在低氧TME中通过肿瘤衍生外泌体(tumor-derived exosomes, TDEs) 介导细胞间通信, 为肿瘤细胞的增殖、侵袭和转移提供了有利条件。TDEs能向肿瘤细胞和基质细胞提供信号, 促进TME内的肿瘤发展。因此, 外泌体被认为是调节TME的关键信号介质, TDEs在抗癌治疗中具有重要意义^[83]。TDEs不仅可作为药物递送的载体, 还可作为治疗的靶点。此外, 由于其携带的各种货物, TDEs也可被用作为癌症诊断和预后的生物标志物^[84]。

免疫细胞衍生的外泌体在免疫调节中发挥重要作用, 如巨噬细胞衍生的EV可激活免疫系统, 促进肿瘤免疫反应^[85]。肿瘤细胞通常会过度表达CD47, 通过与巨噬细胞上表达的信号调节蛋白(signal-regulatory protein alpha, SIRP α) 结合, 抑制巨噬细胞的吞噬作用^[86]。Nie等^[87]开发了一种响应性外泌体纳米生物偶联物, 将二苯并环辛炔(dibenzocyclooctyne, DBCO) 修饰的抗CD47抗体(anti-CD47 antibody, aCD47) 和抗信号调节蛋白α抗体(anti-SIRP α antibody, aSIRP α) 通过pH敏感的苯甲酸亚胺键连接到叠氮化物修饰的M1 TAMs外泌体(M1 macrophage exosomes, M1 Exo) 上(图 4)。通过aCD47的靶向能力, 纳米生物偶联物可在肿瘤细胞中有效积累, 在酸性TME中, 苯甲酸亚胺键被裂解, 释放出两种抗体, 分别与巨噬细胞上的抑制性受体SIRP α和肿瘤细胞上的CD47结合, 从而增强巨噬细胞的吞噬作用。同时, M1 Exo可将M2 TAMs重编程, 让促肿瘤的M2 TAMs重新被诱导为抗肿瘤的M1 TAMs, 这种重编程能力在与抗体偶联后不会受到影响。此协同作用产生了有效抗癌作用, 且不良反应较小。DCs是TME中启动并调节先天性和适应性免疫的核心, 具有呈递肿瘤相关抗原的能力, 因此将抗原和免疫佐剂靶向递送至DCs是开发肿瘤疫苗的重要思路与方法^[88]。Huang等^[89]合成了一种原位DCs疫苗(HELA-Exos), 将免疫原性细胞死亡(immunogenic cell death, ICD) 诱导剂—中性粒细胞弹性蛋白酶(ELANE) 和TLR3激动剂(hiltonol) 加载到α-乳白蛋白(α-LA) 工程化的乳腺癌细胞衍生的外泌体上, 共同用于治疗乳腺癌。HELA-Exos通过激活I型常规DCs, 引发CD8⁺ T细胞反应, 增强了三阴性乳腺癌(triple negative breast cancer, TNBC) 细胞的免疫原性, 在小鼠TNBC模型和乳腺癌患者衍生的肿瘤类器官中表现出强大的抗肿瘤活性。除了乳腺癌, 向肿瘤细胞递送ICD诱导剂和可控佐剂的治疗方法可扩展到各种类型的癌症。

外泌体不仅是癌症治疗药物递送新载体, 也是治疗的新靶点, 许多临床前研究^{[90, 91]}都证明了外泌体在TME中的重要作用。重视开发基于外泌体的抗肿瘤治疗策略是十分必要的。

1.7 微生物群调节型纳米递药系统

正常人体内存在超过100万亿个细菌^[92], 组成了人体微生物群, 其中约97%为结肠内细菌, 约2%~3%为结肠外细菌, 分布于近端肠道、皮肤和肺部等, 约0.1%~1%为古生菌和真核生物^{[93, 94]}。人体微生物系统的组成与癌症风险密切相关^[95]。越来越多的证据表明, 有一类重要的“共谋”微生物会促进致癌作用, 但不足以导致癌症^[96-103]。位于肿瘤部位的微生物群系及其具有生物活性的代谢产物在肿瘤的产生和发展中发挥着许多免疫调节功能, 并可能通过肿瘤间质反馈回路、炎症或功能失调的免疫监视系统促进癌症进展^[104]。例如, Kras基因突变和p53基因缺失无法在无菌或接受过抗生素治疗的小鼠体内导致肺癌产生, 共生肺部微生物群促进γδ T细胞的增殖和激活, 后者通过在局部释放白细胞介素IL-17和IL-23来推动促癌炎症的产生。不同的肿瘤类型具有不同的微生物组成, 微生物的遗传异质性可能可为癌症的诊断和肿瘤的定位提供机会。Nejman等^[105]证明了肿瘤组织内的细菌主要存在于癌细胞和免疫细胞胞内。迄今为止通过修饰的减毒型、营养缺陷型和诱导型的大肠杆菌、双歧杆菌、李斯特氏菌、志贺氏菌、梭状芽孢杆菌、乳球菌、弧菌和沙门氏菌已被设计出来, 并在静脉给药、瘤内给药和口服给药3种途径中显示出了抗肿瘤效果^[106]。Din等^[107]通过实验将非致病性大肠杆菌和沙门氏菌改造为工程菌, 以实验所需周期为间隔向TME中释放趋化因子、溶血素和促凋亡蛋白。Chowdhury等^[108]使用被编程以生长-死亡-再生的细菌种群来循环递送药物, 设计出针对性生产和释放CD47抗体片段的纳米粒, 肿瘤可表达抗体来抑制DC吞噬作用, 同时此过程刺激了CD8⁺ T细胞反应, 进一步阻止肿瘤细胞转移, 还能使远端未注射的肿瘤退化, 具有良好的抗肿瘤效果。

目前对于肿瘤部位微生物群的研究存在争议, 针对肿瘤微生物群的临床观察和临床干预仍存在较大空缺, 且抗生素的使用可能会对诊断或靶向肿瘤部位特异微生物群的治疗造成干扰。同时, 在实验过程中还存在很多关键问题, 如细菌污染、药物毒性、不可重复性等仍是要面对的挑战, 但利用微生物群作为癌症治疗靶点是未来治疗癌症的一个重要方向。

2 总结与展望

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目前的基于TME调控的靶向纳米递药系统主要包括CSCs、CAFs、免疫细胞、ECM、肿瘤血管系统、外泌体、微生物群等(表 1^{[15, 17, 23, 24, 28, 37, 50, 51, 64, 66, 72, 87, 89, 107, 108]})。

CSCs具有耐药性, 可经各种机制避免被传统治疗途径灭杀, 使肿瘤转移、复发、形成继发性肿瘤。纳米技术介导的药物递送系统可提高对CSCs的杀伤力, 有效根除肿瘤, 并降低不良反应。抑制CAFs, 可有效重塑TME, 可通过纳米复合物递送药物, 药物经CAFs内化可有效抑制其纤维化, 或抑制癌细胞产生外泌体, 阻止纤维化进展。肿瘤组织具有低免疫原性, 且TME中存在大量抑制免疫因素, 因此抗肿瘤效应受限。使用纳米技术介导的递药系统可增强免疫刺激性细胞的能力, 规避免疫抑制性细胞对免疫调节的不利影响。靶向TME ECM中的透明质酸或胶原蛋白是一种肿瘤治疗的有效手段, 通过靶向ECM中的透明质酸或胶原蛋白, 可强化药物渗透与扩散, 从而提高肿瘤治疗效果。经传统治疗方式给药后, 肿瘤可通过重建血管的方式复发, 因此可通过抗血管生成的方法重塑TME, 利用纳米递药系统破坏肿瘤血管内皮, 阻断对肿瘤营养供应, 该方法不良反应小, 安全性好。除上述调控策略外, 外泌体作为调节TME的关键信号介质, 可作为癌症治疗药物递送载体及治疗新靶点, 是癌症诊断和预后的良好生物标志物。微生物菌群微生态的失调会增加肿瘤发生的机率, 恢复健康微生物群可作为一种免疫治疗的新形式, 通过纳米递药系统可将药物靶向递送至生物菌群栖息的黏膜层中, 有效抑制生物菌群微生态的失调。

综上所述, 各种靶向调控策略虽较传统治疗方式治疗效果更好, 不良反应更小, 但其针对性更强, 并不能很好地适用于所有的肿瘤治疗及所有的患者, 普适性较差。并且, 大部分治疗策略仍处于研究中, 缺乏完善可行的治疗方案, 操作难度较高, 仍需进一步研究完善。

纳米技术能改善传统给药方式带来的药物在体内分布无选择性的弊端, 提高药物在局部肿瘤组织中的药物浓度, 并有助于提高细胞内化能力, 增强抗肿瘤效果, 抑制肿瘤细胞转移, 有效防止肿瘤复发, 同时减轻药物的不良反应, 提高安全性, 为临床抗肿瘤的治疗提供了新思路^[109]。

然而, 就现阶段纳米技术发展水平而言, 制备高效的纳米递药系统并将其投入临床治疗并获得广泛应用仍要面对多方面挑战。患者体质存在差异, 需提供个性化的治疗方案。而TME是一个机制完整且构造复杂的系统, 对于其中各组分之间的相互作用机制把控还不全面, 这为将不同作用效果的药物分子锚定在单一纳米载体中带来困难。因此, 还需深入探究纳米材料与不同生物体间的相互作用。此外, 纳米递药系统也存在设计复杂、理化性质不稳定、质量控制不理想, 难以实现工业化大生产等问题, 都限制了纳米技术广泛应用于临床肿瘤治疗。但相信随着材料学、生物医学及相关衍生学科的发展, 基于多功能纳米技术的TME靶向及重塑策略有望为抗肿瘤治疗开拓出一个极具光明及应用前景的新型治疗方式。

作者贡献: 李菁负责构思文章框架并进行文章总体整理; 潘婷负责文献汇总及文章撰写; 赵思垚负责信息整理及表格汇总; 陈晓晴负责构思作图及文章撰写; 尹昊天、吉小烨、吴玘璠负责文献调研并参与文章撰写; 王伟负责文章指导、修改及审校。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(31872756)
国家自然科学基金资助项目(32071387)

参考文献

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2023年第58卷第3期

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doi: 10.16438/j.0513-4870.2022-0939

接收时间：2022-07-31
首发时间：2025-11-21
出版时间：2023-03-12

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收稿日期：2022-07-31
修回日期：2022-09-26

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国家自然科学基金资助项目(31872756)

国家自然科学基金资助项目(32071387)

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1.中国药科大学药学院药剂系, 江苏南京 210098

2.中国药科大学, 天然药物活性组分与药效国家重点实验室, 江苏南京 210098

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*王伟, Tel: 86-25-86185328, E-mail: wangcpu209@cpu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Targeting type	Type of nanostructures	Active drug	Tumor model	Therapeutic efficacy	Ref.
Cancer stem cells	Iron oxide nanoparticle	CTX and siMGMT	Glioblastomas	Enhance the killing effect of drug-resistant GBMs and GSCs as compared to TMZ alone, significantly extend the survival of mice bearing GBM6 orthotopic xenografts	[15]
Micelle	ATRA and CPT	MCF-7 breast cancer	Reduce stemness-related drug resistance, enhance the chemotherapeutic response, suppress the tumor growth and metastasis	[17]
Fibroblasts	Micelle	GEM and CQ	Pancreatic cancer	Suppress tumor fibrosis and down-regulate MMP-2 by inhibiting autophagy, inhibit tumor growth and metastasis, reshape TME and enhance the effect of chemotherapy	[23]
Dendrimer	MCT	4T1 breast cancer	Inhibit the production of exosomes produced by cancer cells, regulate the distribution of T cell subsets in TME, and prevent the progression of fibrosis	[24]
Immune regulation	-	OVA and α-CD40 antibody	B16 melanoma	Better harnessing the immunizing functions of DCs, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity	[28]
Polymer	IRF5 and IKKβ	Ovarian cancer, melanoma, and glioblastoma	Reverse the immunosuppressive microenvironment and transform tumor-associated macrophages into anti-tumor M1 subtypes	[37]
Extracellular matrix	Micelle	EPI and HAase	HepG2 hepatoma carcinoma	Show a better accumulation and deeper tumor penetration in HepG2 tumors, inhibit tumor proliferation with minor side effects	[50]
-	Bintrafusp alfa, NC410 and PD-L1	Colon and breast cancer	Remould the tumor collagen matrix, enhances tumor infiltration and activation of CD8⁺ T cells, realize macrophage repolarization, and achieves high cure rate and long-term tumor specific protection	[51]
Anti-angiogenesis	Silica nanoparticle	PM, CA4 and Apa	MHCC-97H liver cancer	Damage the tumor vascular endothelium to interfere with the interaction between VEGFR-2 and its receptor, thereby inhibiting tumor angiogenesis and expansion	[64]
Polymeric nanoparticle	T4	4T1 breast cancer	Expand in acidic TME, and then release T4 on macrophages and endothelial cells to interact with Tie2 and ANG/Tie2 signaling pathway, thereby inhibiting angiogenesis and tumor cell migration	[66]
Self-assembled VE-DDP-Pro nanoparticle	DDP, cRGD peptide and folate	SKOV3-Luc ovarian cancer	Bind to integrin αvβ3 or α5β1 to reduce MMP-2/VEGF expression and epithelial-mesenchymal transformation, resulting in a self-resistant EDV and VM capacity	[72]
Exosomes	Exosome	aCD47 and aSIRP α	4T1 breast cancer	Repolarize the pro-tumoral M2 to anti-tumoral M1, inhibit tumor growth	[87]
Exosome	ELANE and hiltonol	MDA-MB-231 breast cancer	Promote the activation of cDC1s, improve the tumor-reactive CD8⁺ T cell responses, enhance the immunogenicity of TNBC cells, inhibit tumor growth	[89]
Microbiota	-	SLC strain	HeLa cervical cancer	Lead to a notable reduction of tumor activity	[107]
-	eSLC-CD47nb	A20 B cell lymphoma cancer, 4T1 breast cancer, B16-F10 melanoma	Prevent the metastasis of tumor cells and degenerate the distal uninjected tumors	[108]

Targeting type

Type of nanostructures

Active drug

Tumor model

Therapeutic efficacy

Ref.

Cancer stem cells

Iron oxide nanoparticle

CTX and siMGMT

Glioblastomas

Enhance the killing effect of drug-resistant GBMs and GSCs as compared to TMZ alone, significantly extend the survival of mice bearing GBM6 orthotopic xenografts

[15]

Micelle

ATRA and CPT

MCF-7 breast cancer

Reduce stemness-related drug resistance, enhance the chemotherapeutic response, suppress the tumor growth and metastasis

[17]

Fibroblasts

Micelle

GEM and CQ

Pancreatic cancer

Suppress tumor fibrosis and down-regulate MMP-2 by inhibiting autophagy, inhibit tumor growth and metastasis, reshape TME and enhance the effect of chemotherapy

[23]

Dendrimer

MCT

4T1 breast cancer

Inhibit the production of exosomes produced by cancer cells, regulate the distribution of T cell subsets in TME, and prevent the progression of fibrosis

[24]

Immune regulation

OVA and α-CD40 antibody

B16 melanoma

Better harnessing the immunizing functions of DCs, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity

[28]

Polymer

IRF5 and IKKβ

Ovarian cancer, melanoma, and glioblastoma

Reverse the immunosuppressive microenvironment and transform tumor-associated macrophages into anti-tumor M1 subtypes

[37]

Extracellular matrix

Micelle

EPI and HAase

HepG2 hepatoma carcinoma

Show a better accumulation and deeper tumor penetration in HepG2 tumors, inhibit tumor proliferation with minor side effects

[50]

Bintrafusp alfa, NC410 and PD-L1

Colon and breast cancer

Remould the tumor collagen matrix, enhances tumor infiltration and activation of CD8⁺ T cells, realize macrophage repolarization, and achieves high cure rate and long-term tumor specific protection

[51]

Anti-angiogenesis

Silica nanoparticle

PM, CA4 and Apa

MHCC-97H liver cancer

Damage the tumor vascular endothelium to interfere with the interaction between VEGFR-2 and its receptor, thereby inhibiting tumor angiogenesis and expansion

[64]

Polymeric nanoparticle

4T1 breast cancer

Expand in acidic TME, and then release T4 on macrophages and endothelial cells to interact with Tie2 and ANG/Tie2 signaling pathway, thereby inhibiting angiogenesis and tumor cell migration

[66]

Self-assembled VE-DDP-Pro nanoparticle

DDP, cRGD peptide and folate

SKOV3-Luc ovarian cancer

Bind to integrin αvβ3 or α5β1 to reduce MMP-2/VEGF expression and epithelial-mesenchymal transformation, resulting in a self-resistant EDV and VM capacity

[72]

Exosomes

Exosome

aCD47 and aSIRP α

4T1 breast cancer

Repolarize the pro-tumoral M2 to anti-tumoral M1, inhibit tumor growth

[87]

Exosome

ELANE and hiltonol

MDA-MB-231 breast cancer

Promote the activation of cDC1s, improve the tumor-reactive CD8⁺ T cell responses, enhance the immunogenicity of TNBC cells, inhibit tumor growth

[89]