Manganese-based nanoparticles for chemodynamic therapy of gastrointestinal cancer

Xiaofeng LIN; Mayang HUANG; Junqian CHEN; Xun ZHOU; Zhuodan ZHONG; Wencong LU; Xianying HUANG; Tianwen LIU

doi:10.12122/j.issn.1673-4254.2023.08.22

. 2023 Aug 20;43(8):1432–1439. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2023.08.22

Show available content in

锰基纳米材料用于胃肠道恶性肿瘤的化学动力治疗

Xiaofeng LIN ¹, Mayang HUANG ¹, Junqian CHEN ¹, Xun ZHOU ¹, Zhuodan ZHONG ¹, Wencong LU ², Xianying HUANG ^3,^*, Tianwen LIU ^1,^*

PMCID: PMC10505582 PMID: 37712282

Abstract

目的

探讨携载葡萄糖氧化酶的富含锰介孔硅纳米(MSN@Mn-GOx)的制备、物化表征及其治疗胃肠道恶性肿瘤的效果。

方法

检测MSN@Mn-GOx的形貌、大小、元素、价态、电位、耗氧能力及类芬顿性能; 采用核磁共振成像(MRI)方法分析MSN@Mn-GOx在T1加权下的成像能力, 构建荷瘤小鼠肠癌模型(n=3), 通过尾静脉注射MSN@Mn-GOx观察注射前后的T1成像能力; 体外试验分为Control组(PBS)、含锰介孔硅(MSN@Mn)组(20 μg/mL MSN@Mn纳米颗粒)及携载葡萄糖氧化酶的富含锰介孔硅(MSN@Mn-GOx)组(20 μg/mL MSN@Mn-GOx纳米颗粒), 按上述分组对胃肠癌细胞进行处理。分别采用细胞增殖-毒性实验(CCK-8)、细胞免疫荧光实验检测MSN@Mn-GOx诱导胃肠癌细胞的活性氧(ROS)生成、细胞增殖及细胞杀伤能力的改变。

结果

MSN@Mn-GOx为带负电荷的100 nm类圆形实心纳米颗粒, 可催化葡萄糖产生大量氧气继而增加H₂O₂浓度。相比于中性H₂O₂溶液, MSN@Mn-GOx在低酸条件(pH=6.0)下可催化生成更多羟自由基(P＜0.05)。MRI成像试验中, MSN@Mn-GOx有浓度依赖性的T1增强成像效果, 在荷瘤小鼠体内观察到, 相比于注射前, 注射MSN@Mn-GOx后的瘤体有T1增强信号(P＜0.01)。细胞免疫荧光实验显示: 相比于Control组, MSN@Mn及MSN@Mn-GOx均可明显诱导胃肠癌细胞ROS产生(P＜0.05)。CCK-8实验显示, 相比于Control组, MSN@Mn及MSN@Mn-GOx对胃肠癌细胞浓度依赖性杀伤效果(P＜0.05)。Edu实验显示, 相比于Control组, MSN@Mn及MSN@Mn-GOx均可抑制胃肠癌细胞的增殖能力(P＜0.05)。

结论

MSN@Mn-GOx具有良好的MRI成像效果、自产H₂O₂能力及类芬顿性能, 可诱导胃肠癌细胞内ROS产生进而产生良好的抗肿瘤效应, 是胃肠道恶性肿瘤治疗的一种潜在新方法。

Keywords: 锰基纳米材料, 纳米颗粒, 胃肠道肿瘤, 化学动力治疗

恶性肿瘤已成为大多数患者死亡的主要原因，其中结直肠癌和胃癌的死亡率居全世界第2和第3位^[1-3]，目前根治性手术切除仍是胃肠道恶性肿瘤患者治愈的唯一机会，据报道约50%的患者术后5年内复发，且中晚期胃肠道恶性肿瘤患者的复发率更高^{[4, 5]}。多项研究证实，对于晚期肿瘤或肿瘤术后复发转移患者，一线、二线化疗为最佳支持治疗，可延长中位生存时间，提高生活质量^[6-9]。针对此类患者而言，2020年美国国立综合癌症网络、欧洲肿瘤协会以及中国卫生部均推荐铂类联合氟尿嘧啶类药物作为一线治疗药物。尽管其研究工作取得了重大的进展，但此类治疗药物选择仍然有限，且毒副作用严重^{[10, 11]}。因此，寻找一种既能提高疗效又能避免传统辅助化疗毒副作用的新治疗方案是突破目前突破胃肠道恶性肿瘤治疗瓶颈的关键。

化学动力治疗（CDT）是利用金属催化剂在肿瘤缺氧微环境下，将细胞内过表达H₂O₂转化为高毒性羟基自由基（· OH），在不需要外界刺激的情况下引起肿瘤细胞严重的氧化损伤^[12]。与其他治疗方式相比，CDT由肿瘤微环境特异性触发，能够有效减少对体内正常组织的损伤^[13]。另外，CDT与化疗联合具有显著的协同作用，一方面可以通过化疗药物增加H₂O₂浓度，使CDT治疗效果增强，另一方面可以减少化疗药物的副作用，因此，CDT与化疗相结合有望成为一种新型、有效的胃肠道恶性肿瘤治疗方案^{[14, 15]}。而作为化学动力试剂的锰基金属纳米材料，如MnO、MnO₂、MnSiO₃、MnS等，适合在肿瘤组织的微酸性（pH 4.5~6.5）环境中催化类芬顿反应，从而重塑肿瘤微环境，诱导肿瘤细胞死亡，因而在肿瘤治疗中极具潜力。一般情况下，被动的锰基纳米药物疗效差、副作用大。因此，需要赋予纳米药物具备主动递送能力及催化属性来促进肿瘤细胞内摄取并提高类芬顿催化效率，进而强化CDT作用。基于此，本研究制备了一种新型的纳米材料，即携载葡萄糖氧化酶的富含锰介孔二氧化硅（MSN@Mn-GOx），探索了其物化表征以及在胃肠癌细胞系中的抗肿瘤效应，以证实该材料是否能够用于胃肠道恶性肿瘤的CDT。

1. 材料和方法

1.1. MSN@Mn-GOx的合成

首先，将2 g十六烷基三甲基氯化铵（CTAC）与0.02 g三乙胺（TEA）混合，加入20 mL ddH₂O，在80 ℃下搅拌20 min进行预热。加入1.5 mL正硅酸乙酯（TEOS）并在80 ℃下搅拌4 h。离心后，分别用乙醇和ddH₂O洗3次。然后将产物溶于20%盐酸，75 ℃洗涤12 h，洗涤3次，除掉CTAC。其次，10 mL得到的纯净MSN溶液加入10 mL MnSO4 · H₂O（8 mg/mL），搅拌20 min，然后将混合物转移至高温反应器中（180 ℃ 12 h），将所得产物ddH₂O洗涤3次，得到MSN@Mn纳米。将GOx（1 mg/mL）添加到MSN@Mn纳米溶液中，室温避光搅拌4 h，得到MSN@Mn-GOx纳米颗粒。

1.2. MSN@Mn-GOx的形态大小

将MSN@Mn-GOx纳米颗粒稀释并滴加到镍网上，使用JEM-2100F透射电子显微镜（日本JEOL）拍摄MSN@Mn-GOx的表面形态。利用动态光散射原理测定MSN@Mn和MSN@Mn-GOx纳米颗粒的粒径和电势。用能源分析EDS分析纳米元素种类。用电感耦合等离子体质谱分析仪ICP分析纳米复合物中锰的含量。用光电子能谱仪XPS分析纳米复合物中锰的价态。

1.3. MSN@Mn-GOx的化学动力效能

采亚甲基蓝（MB）评估MSN@Mn-GOx的化学动力效能，即类芬顿催化能力。MSN@Mn-GOx与不同pH的PBS（pH=6.0和pH=7.5）孵育后，采用分光光度计检测各组溶液在λ=664 nm的吸光度。

1.4. MSN@Mn-GOx的氧气消耗水平

MSN@Mn-GOx与含/不含葡萄糖的含氧溶液中进行孵育，使用溶解氧仪（Thermo）检测不同时间点溶液中的氧含量。

1.5. MSN@Mn-GOx的核磁成像（MRI）能力

雌性裸鼠（4~5周龄）购自南方医科大学实验动物中心。将肠癌细胞（HT-29）以5×10⁶/200 μL的密度注射到雌性裸鼠的右背部，构建荷瘤小鼠肠癌模型。当荷瘤小鼠肿瘤体积超过20 mm×20 mm×20 mm时，在麻醉下将MSN@Mn-GOx纳米颗粒（6 mg/kg）经尾静脉注射到荷瘤小鼠体内。使用7.0 T MAGNETOM Skyra磁共振成像系统（Philips）对不同浓度的MSN@Mn-GOx纳米颗粒溶液（50、100、150、200、250 μg/mL）和注射MSN@Mn-GOx纳米颗粒前后的小鼠进行T1加权序列扫描，获得MRI成像图片。

1.6. 细胞培养

胃肠癌细胞（AGS和HT-29）购自中科院上海细胞库，使用含10%胎牛血清的DMEM培养基、置于37 ℃ 5% CO₂培养箱中进行培养。每24 h更换1次培养基，细胞密度超过70%时，以0.25%胰酶消化进行传代培养。

取对数生长期的胃肠癌细胞进行体外实验，实验分为Control组（PBS）、MSN@Mn组（20 μg/mL MSN@Mn纳米颗粒）和MSN@Mn-GOx组（20 μg/mL MSN@Mn-GOx纳米颗粒）。

1.7. 激光共聚焦实验

胃肠癌细胞（AGS和HT-29）按10 000 /孔接种于共聚焦培养皿，细胞贴壁后分别加入MSN@Mn和MSN@Mn-GOx纳米颗粒（均为20 μg/mL），常规培养24 h后按照检测试剂盒说明书加入DCFH-DA绿色荧光探针，37 ℃避光孵育30 min，加入含DAPI的抗荧光淬灭封片液，激光共聚焦显微镜（Olympus）下观察细胞内的荧光强度。

1.8. CCK-8细胞毒性实验

胃肠癌细胞（AGS和HT-29）按1000/孔接种于96孔板，细胞贴壁后分别加入不同浓度的MSN@Mn和MSN@Mn-GOx纳米颗粒（均为0、2、4、16、25、50 μg/mL）并继续培养24 h，加入10 μL CCK-8试剂，37 ℃孵育2 h，酶标仪设置450 nm波长测定吸光度A_{450 nm}。

1.9. Edu细胞增殖实验

胃肠癌细胞（AGS和HT-29）按10 000 /孔接种于共聚焦培养皿，细胞贴壁后分别加入MSN@Mn和MSN@Mn-GOx纳米颗粒（均为20 μg/mL），常规培养24 h后加入含10 μmol/L EdU染液，继续孵育2 h；EdU标记细胞完成后加入1 mL 4%多聚甲醛室温固定30 min；继续加入0.5% Triton X-100孵育10 min，最后加入DAPI染液，室温避光孵育10 min，激光共聚焦显微镜下观察细胞内的荧光强度。

1.10. 统计学分析

所有数据均采用IBM SPSS 20.0处理。计量资料以均数±标准差表示，两组间数据比较采用t检验，多组间数据比较采用单因素方差分析，组间数据比较采用LSD-t检验。以α=0.05为检验水准，对以上结果均进行双侧检验，P＜0.05为差异具有统计学意义。

2. 结果

2.1. MSN@Mn-GOx的理化特征

透射电镜图显示（图 1A、B），MSN@Mn及MSN@Mn-GOx纳米颗粒均为直径约100 nm的实心圆球。透射电镜下的EDS能谱分析结果显示：MSN@Mn-GOx纳米复以硅（Si）及锰（Mn）元素为主（图 1C）。电感耦合等离子体质谱分析仪ICP分析结果显示：MSN@Mn-GOx中锰的含量约为25%。光电子能谱仪XPS分析结果显示：MSN@Mn-GOx在641.37 eV和653.26 eV处有归属于Mn 2p3/2和Mn 2p1/2的特殊吸收峰，MSN@Mn-GOx纳米复合物大部分为二价态的Mn(Ⅱ)（图 1D）。马尔文粒径仪测定显示，MSN@Mn及MSN@Mn-GOx纳米颗粒的水合平均粒径均约为100 nm（图 1E），平均Zeta电位分别为-32 mV及-35 mV（图 1F）。

2.2. MSN@Mn-GOx的类芬顿催化能力

同样H₂O₂浓度的条件下，不同pH溶液的MSN@Mn-GOx展示出不同的吸光度。相比于pH=7.4的Control组，pH=7.4的溶液中加入MSN@Mn-GOx纳米颗粒后其吸光度明显下降，而加入MSN@Mn-GOx纳米颗粒的pH=6.0溶液，其吸光度进一步下降（P＜0.05，图 2A）。氧消耗实验显示：MSN@Mn-GOx与葡萄糖混合后，培养液中溶解的氧气水平随着时间的延长而降低（图 2B）。

2.3. MSN@Mn-GOx的核磁成像能力

MRI成像结果显示：相比于Control组，MSN@Mn-GOx组可显示出更强的T1加权核磁成像信号值，且随着浓度的升高，其T1信号值越强（图 3A）。活体成像数据可看出：相比于注射MSN@Mn-GOx纳米颗粒前的图片，注射MSN@Mn-GOx纳米颗粒4 h后的裸鼠肿瘤部位有明显的T1增强信号（P＜0.01，图 3B）。

2.4. MSN@Mn-GOx产生ROS的能力

激光共聚焦图片分析显示：相比于Control组，MSN@Mn及MSN@Mn-GOx组能增加胃肠癌细胞内的活性氧（ROS）水平；相比于MSN@Mn组，MSN@Mn-GOx组处理产生的ROS水平明显增加（图 4）。

2.5. MSN@Mn-GOx的肿瘤杀伤能力

CCK-8细胞毒性实验结果显示，不同浓度MSN@Mn及MSN@Mn-GOx纳米颗粒（0、2、4、16、25、50 μg/mL）处理的胃肠癌细胞存活率呈浓度依赖性降低，具有显著的抗增殖作用；与相同浓度的MSN@Mn相比，MSN@Mn-GOx处理的细胞存活率更低下（P＜0.05，图 5）。

EdU实验结果显示，相比于Control组，MSN@Mn及MSN@Mn-GOx组能显著减少胃肠癌细胞内的EdU荧光阳性率；MSN@Mn-GOx组细胞EdU荧光阳性率较MSN@Mn组降低（图 6）。

3. 讨论

胃肠道恶性肿瘤是较常见的消化道恶性肿瘤之一^[3]。目前，进展期胃肠道恶性肿瘤患者的治疗主要以根治性切除联合术后辅助化疗为主。但传统化疗药物容易引发脱发、恶心呕吐、骨髓抑制等全身多系统毒副作用，也易造成化疗耐药，一定程度上限制了该类药物的临床应用。近年来，光动力疗法（PDT）、光热疗法（PTT）、和化学动力疗法（CDT）等新的肿瘤治疗策略正在积极开发和探索。其中，CDT是一种基于芬顿化学原理的有效抗肿瘤策略，因其独特的活性氧（ROS）生成方式而受到广泛关注^{[13, 16]}。各种化学动力试剂金属离子的纳米材料已经被开发，例如Fe²⁺、Cu⁺、Co²⁺、Mn²⁺、Ti³⁺等^[17-19]。本研究以介孔二氧化硅（MSN）为载体，成功制备了含有Mn²⁺的纳米载药复合物MSN@Mn-GOx，该材料充分发挥了MSN载药量高、毒性低的优点，借助Mn²⁺及GOx的偶联，实现了强大的芬顿催化效应；同时，体外细胞实验表明，MSN@Mn-GOx对胃肠癌细胞的增殖特性具有显著抑制作用，展现出高效的抗肿瘤作用。

铁基材料是以往研究最广泛的CDT纳米催化剂^[20]。然而，近年来的研究表明，Mn²⁺介导的类芬顿反应比Fe²⁺介导的芬顿反应具有更高的催化活性，特别是在接近中性的微酸性环境中^[21-23]。因此，锰基纳米材料也被开发用于CDT，例如有研究报道了用于CDT和PDT的H-MnCO₃/Ce6-PEG多功能纳米颗粒，Mn²⁺可在肿瘤微环境弱酸性条件下由MnCO₃快速释放并实现CDT^[24]。有研究开发了一种用于声动力治疗和CDT的Au@MnO纳米颗粒^[25]。在超声辐射和谷胱甘肽作用下，Au@MnO可分解为Mn²⁺和超小Au纳米粒子，超小Au纳米纳米粒子实现声动力治疗，Mn²⁺催化H₂O₂实现CDT。同时，用于CDT的锰基纳米材料还有MnO₂^[26]、MnSiO₃^[27]、MnS^[28]等。除此之外，作为顺磁性物质，Mn²⁺是一种良好的MRI造影剂，具备较高的R1值，这提示本研究制备的MSN@Mn-GOx在体内MRI成像中也将具备良好的成像效果^{[29, 30]}。为验证这一假设，我们在药物处理后麻醉了小鼠并进行了MRI扫描。结果显示：经MSN@Mn-GOx处理后，肿瘤部位出现增强T1加权信号，表明该材料不仅能够能实现肿瘤治疗，而且能够精确定位肿瘤病灶，对制定临床诊治方案具有重要的指导意义。

Mn毒性大，且肿瘤细胞内H₂O₂浓度有限，难以达到满意的抗肿瘤效果。本研究在引入锰基材料的同时加入了天然酶GOx。GOx能够与细胞内的葡萄糖和氧气发生反应，生成大量的H₂O₂和葡萄糖酸，该过程中产生的H₂O₂可用于后续Mn纳米颗粒催化的类芬顿反应，而葡萄糖酸的生成不断增强了肿瘤低pH环境，进一步提高了类芬顿反应催化效率，而这些连续的催化反应产生大量强氧化损伤的· OH，从而引发肿瘤细胞的凋亡和坏死^{[27, 31-33]}。因此，GOx是肿瘤饥饿治疗的理想内源性氧化还原酶。有研究以聚乙二醇修饰的GOx为模板，采用仿生矿化的方法制备铜离子掺杂的磷酸钙纳米颗粒，再负载药物DOX得到PGC@DOX纳米复合材料。该材料在进一步提升GOx的稳定性和安全性的同时，还具备生成H₂O₂及清除GSH的功能，可有效进一步提升Cu²⁺介导的CDT的疗效^[34]。Zhang等^[27]还开发了负载GOx的纳米复合材料，该材料将Mn纳米材料与GOx杂化，实现肿瘤葡萄糖代谢的自放大调控。一方面，锰纳米材料催化H₂O₂生成O₂；形成的O₂能够促进纳米复合物中GOx的葡萄糖消耗能力，有效调控葡萄糖代谢。另一方面，后一反应形成的H₂O₂也有利于Mn纳米材料的催化反应。本研究还证实，MSN@Mn-GOx组较MSN@Mn组细胞ROS生成水平更高，在细胞增殖实验中表现出更强的抗肿瘤作用。因此，MSN@Mn-GOx的成功制备有望做到肿瘤饥饿治疗和CDT的双模式协同治疗。

综上所述，本研究成功制备了纳米复合物MSN@Mn-GOx，并初步验证该材料具有良好的类芬顿催化反应，并能够协同GOx实现肿瘤的饥饿疗法，表现出显著的抗肿瘤作用，可用于磁共振成像和级联反应增强的协同肿瘤治疗，在临床上具有治疗肿瘤的潜力。

Biography

林晓丰，住院医师，E-mail：linxf6565@163.com

Funding Statement

广东省自然科学基金（2020B1515120045，2020A1515110151）

Contributor Information

林晓丰 (Xiaofeng LIN), Email: linxf6565@163.com.

黄显莹 (Xianying HUANG), Email: 147932441@qq.com.

刘添文 (Tianwen LIU), Email: liutianwen100@163.com.

References

1.Chen WQ, Sun KX, Zheng RS, et al. Cancer incidence and mortality in China, 2014. Chung Kuo Yen Cheng Yen Chiu. 2018;30(1):1–12. doi: 10.21147/j.issn.1000-9604.2018.01.01. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
3.Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA A Cancer J Clinicians. 2022;72(1):7–33. doi: 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]
4.Haque E, Esmail A, Muhsen I, et al. Recent trends and advancements in the diagnosis and management of gastric cancer. Cancers (Basel) 2022;14(22):5615–22. doi: 10.3390/cancers14225615. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Eileen M, Morgan E. The Current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: a population-based modelling study. eClinicalMedicine. 2022;47:101404–13. doi: 10.1016/j.eclinm.2022.101404. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Baxter NN, Kennedy EB, Bergsland E, et al. Adjuvant therapy for stage Ⅱ colon cancer: ASCO guideline update. J Clin Oncol. 2022;40(8):892–910. doi: 10.1200/JCO.21.02538. [DOI] [PubMed] [Google Scholar]
7.Kim JK, Marco MR, Roxburgh CSD, et al. Survival after induction chemotherapy and chemoradiation versus chemoradiation and adjuvant chemotherapy for locally advanced rectal cancer. Oncologist. 2022;27(5):380–8. doi: 10.1093/oncolo/oyac025. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Oronsky B, Reid T, Larson C, et al. Locally advanced rectal cancer: the past, present, and future. Semin Oncol. 2020;47(1):85–92. doi: 10.1053/j.seminoncol.2020.02.001. [DOI] [PubMed] [Google Scholar]
9.Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet. 2020;396(10251):635–48. doi: 10.1016/S0140-6736(20)31288-5. [DOI] [PubMed] [Google Scholar]
10.Ilson DH. Advances in the treatment of gastric cancer: 2020-2021. Curr Opin Gastroenterol. 2021;37(6):615–8. doi: 10.1097/MOG.0000000000000776. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Chao R, Xu RH. The drug treatment research of gastrointestinal cancer in China. Eur J Surg Oncol. 2020;46(10):e3–6. doi: 10.1016/j.ejso.2020.06.004. [DOI] [PubMed] [Google Scholar]
12.Qi WT, Tian A. Recent advances in enhanced chemodynamic therapy strategies. Nano Today. 2021;39:101162–9. doi: 10.1016/j.nantod.2021.101162. [DOI] [Google Scholar]
13.Tang Z, Liu Y, He M, et al. Chemodynamic therapy: tumour microenvironment-mediated fenton and fenton-like reactions. Angew Chem Int Ed Engl. 2019;58(4):946–56. doi: 10.1002/anie.201805664. [DOI] [PubMed] [Google Scholar]
14.Jin Q, Yan SQ, Hu H, et al. Enhanced chemodynamic therapy and chemotherapy via delivery of a dual threat ArtePt and iodo-click reaction mediated glutathione consumption. Small Methods. 2021;5(12):e2101047–56. doi: 10.1002/smtd.202101047. [DOI] [PubMed] [Google Scholar]
15.Niu B, Liao K, Zhou Y, et al. Application of glutathione depletion in cancer therapy: enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials. 2021;277:121110–23. doi: 10.1016/j.biomaterials.2021.121110. [DOI] [PubMed] [Google Scholar]
16.Yu ZH, Hu Y, Sun Y, et al. Frontispiece: chemodynamic therapy combined with multifunctional nanomaterials and their applications in tumor treatment. Chem Eur J. 2021;27(56):13953–60. doi: 10.1002/chem.202101514. [DOI] [PubMed] [Google Scholar]
17.Cao CY, Wang XR, Yang N, et al. Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry. Chem Sci. 2022;13(4):863–89. doi: 10.1039/D1SC05482A. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Li X, He M, Zhou QH, et al. Multifunctional mesoporous hollow cobalt sulfide nanoreactors for synergistic chemodynamic/photodynamic/photothermal therapy with enhanced efficacy. ACS Appl Mater Interfaces. 2022;14(45):50601–15. doi: 10.1021/acsami.2c15406. [DOI] [PubMed] [Google Scholar]
19.Wu YZ, Song XR, Xu W, et al. NIR-activated multimodal photothermal/chemodynamic/magnetic resonance imaging nanoplatform for anticancer therapy by Fe(Ⅱ) ions doped MXenes (Fe-Ti3C2) Small. 2021;17(33):2101705–13. doi: 10.1002/smll.202101705. [DOI] [PubMed] [Google Scholar]
20.Zhang L, Forgham H, Shen A, et al. Recent advances in single Fe-based nanoagents for photothermal-chemodynamic cancer therapy. Biosensors. 2022;12(2):86–98. doi: 10.3390/bios12020086. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Lin LS, Song J, Song L, et al. Simultaneous fenton-like Ion delivery and glutathione depletion by MnO(2)-based nanoagent to enhance chemodynamic therapy. Angew Chem Int Ed Engl. 2018;57(18):4902–6. doi: 10.1002/anie.201712027. [DOI] [PubMed] [Google Scholar]
22.Van CM, Pena J. Mn(Ⅱ) Oxidation in fenton and fenton type systems: identification of reaction efficiency and reaction products. Environ Sci Technol. 2017;51(5):2982–91. doi: 10.1021/acs.est.6b05584. [DOI] [PubMed] [Google Scholar]
23.Gao FL, Sun MM, Zhang J, et al. Fenton-like reaction and glutathione depletion by chiral Manganese dioxide nanoparticles for enhanced chemodynamic therapy and chemotherapy. J Colloid Interface Sci. 2022;616:369–78. doi: 10.1016/j.jcis.2022.02.060. [DOI] [PubMed] [Google Scholar]
24.Wang P, Liang C, Zhu JW, et al. Manganese-based nanoplatform As metal ion-enhanced ROS generator for combined chemodynamic/photodynamic therapy. ACS Appl Mater Interfaces. 2019;11(44):41140–7. doi: 10.1021/acsami.9b16617. [DOI] [PubMed] [Google Scholar]
25.Lin XH, Liu SY, Zhang X, et al. An ultrasound activated vesicle of Janus Au-MnO nanoparticles for promoted tumor penetration and sono-chemodynamic therapy of orthotopic liver cancer. Angew Chem Int Ed. 2020;59(4):1682–8. doi: 10.1002/anie.201912768. [DOI] [PubMed] [Google Scholar]
26.Ou JF, Tian H, Wu JY, et al. MnO2-based nanomotors with active Fenton-like Mn2+ delivery for enhanced chemodynamic therapy. ACSAppl Mater Interfaces. 2021;13(32):38050–60. doi: 10.1021/acsami.1c08926. [DOI] [PubMed] [Google Scholar]
27.Zhang JY, Liang C, Wei ZY, et al. TME-triggered MnSiO3@Met@GOx nanosystem for ATP dual-inhibited starvation/chemodynamic synergistic therapy. Biomaterials. 2022;287:121682–8. doi: 10.1016/j.biomaterials.2022.121682. [DOI] [PubMed] [Google Scholar]
28.He T, Qin X, Jiang C, et al. Tumor pH-responsive metastable-phase Manganese sulfide nanotheranostics for traceable hydrogen sulfide gas therapy primed chemodynamic therapy. Theranostics. 2020;10(6):2453–62. doi: 10.7150/thno.42981. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Liu P, PengY, Ding J, et al. Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer. Asian J Pharm Sci. 2022;17(2):177–92. doi: 10.1016/j.ajps.2021.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Tao Q, He G, Ye S, et al. Mn doped Prussian blue nanoparticles for T1/T2 MR imaging, PA imaging and Fenton reaction enhanced mild temperature photothermal therapy of tumor. J Nanobio-technology. 2022;20(1):18–26. doi: 10.1186/s12951-021-01235-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Kou YK, Dai ZC, Cui P, et al. A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy. J Mater Chem B. 2021;9(40):8480–90. doi: 10.1039/D1TB01539G. [DOI] [PubMed] [Google Scholar]
32.Ming J, Zhu TB, Yang WH, et al. Pd@Pt-GOx/HA as a novel enzymatic cascade nanoreactor for high-efficiency starvin-genhanced chemodynamic cancer therapy. ACS Appl Mater Interfaces. 2020;12(46):51249–62. doi: 10.1021/acsami.0c15211. [DOI] [PubMed] [Google Scholar]
33.Wang J, Wang D, Cen M, et al. GOx-assisted synthesis of pillararene based supramolecular polymeric nanoparticles for targeted/synergistic chemo-chemodynamic cancer therapy. J Nanobiotechnology. 2022;20(1):33–40. doi: 10.1186/s12951-021-01237-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Fu LH, Wan YL, Qi C, et al. Nanocatalytic theranostics with glutathione depletion and enhanced reactive oxygen species generation for efficient cancer therapy. Adv Mater. 2021;33(7):e2006892–903. doi: 10.1002/adma.202006892. [DOI] [PubMed] [Google Scholar]

[b1] 1.Chen WQ, Sun KX, Zheng RS, et al. Cancer incidence and mortality in China, 2014. Chung Kuo Yen Cheng Yen Chiu. 2018;30(1):1–12. doi: 10.21147/j.issn.1000-9604.2018.01.01. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b2] 2.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]

[b3] 3.Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA A Cancer J Clinicians. 2022;72(1):7–33. doi: 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]

[b4] 4.Haque E, Esmail A, Muhsen I, et al. Recent trends and advancements in the diagnosis and management of gastric cancer. Cancers (Basel) 2022;14(22):5615–22. doi: 10.3390/cancers14225615. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b5] 5.Eileen M, Morgan E. The Current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: a population-based modelling study. eClinicalMedicine. 2022;47:101404–13. doi: 10.1016/j.eclinm.2022.101404. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b6] 6.Baxter NN, Kennedy EB, Bergsland E, et al. Adjuvant therapy for stage Ⅱ colon cancer: ASCO guideline update. J Clin Oncol. 2022;40(8):892–910. doi: 10.1200/JCO.21.02538. [DOI] [PubMed] [Google Scholar]

[b7] 7.Kim JK, Marco MR, Roxburgh CSD, et al. Survival after induction chemotherapy and chemoradiation versus chemoradiation and adjuvant chemotherapy for locally advanced rectal cancer. Oncologist. 2022;27(5):380–8. doi: 10.1093/oncolo/oyac025. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b8] 8.Oronsky B, Reid T, Larson C, et al. Locally advanced rectal cancer: the past, present, and future. Semin Oncol. 2020;47(1):85–92. doi: 10.1053/j.seminoncol.2020.02.001. [DOI] [PubMed] [Google Scholar]

[b9] 9.Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet. 2020;396(10251):635–48. doi: 10.1016/S0140-6736(20)31288-5. [DOI] [PubMed] [Google Scholar]

[b10] 10.Ilson DH. Advances in the treatment of gastric cancer: 2020-2021. Curr Opin Gastroenterol. 2021;37(6):615–8. doi: 10.1097/MOG.0000000000000776. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b11] 11.Chao R, Xu RH. The drug treatment research of gastrointestinal cancer in China. Eur J Surg Oncol. 2020;46(10):e3–6. doi: 10.1016/j.ejso.2020.06.004. [DOI] [PubMed] [Google Scholar]

[b12] 12.Qi WT, Tian A. Recent advances in enhanced chemodynamic therapy strategies. Nano Today. 2021;39:101162–9. doi: 10.1016/j.nantod.2021.101162. [DOI] [Google Scholar]

[b13] 13.Tang Z, Liu Y, He M, et al. Chemodynamic therapy: tumour microenvironment-mediated fenton and fenton-like reactions. Angew Chem Int Ed Engl. 2019;58(4):946–56. doi: 10.1002/anie.201805664. [DOI] [PubMed] [Google Scholar]

[b14] 14.Jin Q, Yan SQ, Hu H, et al. Enhanced chemodynamic therapy and chemotherapy via delivery of a dual threat ArtePt and iodo-click reaction mediated glutathione consumption. Small Methods. 2021;5(12):e2101047–56. doi: 10.1002/smtd.202101047. [DOI] [PubMed] [Google Scholar]

[b15] 15.Niu B, Liao K, Zhou Y, et al. Application of glutathione depletion in cancer therapy: enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials. 2021;277:121110–23. doi: 10.1016/j.biomaterials.2021.121110. [DOI] [PubMed] [Google Scholar]

[b16] 16.Yu ZH, Hu Y, Sun Y, et al. Frontispiece: chemodynamic therapy combined with multifunctional nanomaterials and their applications in tumor treatment. Chem Eur J. 2021;27(56):13953–60. doi: 10.1002/chem.202101514. [DOI] [PubMed] [Google Scholar]

[b17] 17.Cao CY, Wang XR, Yang N, et al. Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry. Chem Sci. 2022;13(4):863–89. doi: 10.1039/D1SC05482A. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b18] 18.Li X, He M, Zhou QH, et al. Multifunctional mesoporous hollow cobalt sulfide nanoreactors for synergistic chemodynamic/photodynamic/photothermal therapy with enhanced efficacy. ACS Appl Mater Interfaces. 2022;14(45):50601–15. doi: 10.1021/acsami.2c15406. [DOI] [PubMed] [Google Scholar]

[b19] 19.Wu YZ, Song XR, Xu W, et al. NIR-activated multimodal photothermal/chemodynamic/magnetic resonance imaging nanoplatform for anticancer therapy by Fe(Ⅱ) ions doped MXenes (Fe-Ti3C2) Small. 2021;17(33):2101705–13. doi: 10.1002/smll.202101705. [DOI] [PubMed] [Google Scholar]

[b20] 20.Zhang L, Forgham H, Shen A, et al. Recent advances in single Fe-based nanoagents for photothermal-chemodynamic cancer therapy. Biosensors. 2022;12(2):86–98. doi: 10.3390/bios12020086. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b21] 21.Lin LS, Song J, Song L, et al. Simultaneous fenton-like Ion delivery and glutathione depletion by MnO(2)-based nanoagent to enhance chemodynamic therapy. Angew Chem Int Ed Engl. 2018;57(18):4902–6. doi: 10.1002/anie.201712027. [DOI] [PubMed] [Google Scholar]

[b22] 22.Van CM, Pena J. Mn(Ⅱ) Oxidation in fenton and fenton type systems: identification of reaction efficiency and reaction products. Environ Sci Technol. 2017;51(5):2982–91. doi: 10.1021/acs.est.6b05584. [DOI] [PubMed] [Google Scholar]

[b23] 23.Gao FL, Sun MM, Zhang J, et al. Fenton-like reaction and glutathione depletion by chiral Manganese dioxide nanoparticles for enhanced chemodynamic therapy and chemotherapy. J Colloid Interface Sci. 2022;616:369–78. doi: 10.1016/j.jcis.2022.02.060. [DOI] [PubMed] [Google Scholar]

[b24] 24.Wang P, Liang C, Zhu JW, et al. Manganese-based nanoplatform As metal ion-enhanced ROS generator for combined chemodynamic/photodynamic therapy. ACS Appl Mater Interfaces. 2019;11(44):41140–7. doi: 10.1021/acsami.9b16617. [DOI] [PubMed] [Google Scholar]

[b25] 25.Lin XH, Liu SY, Zhang X, et al. An ultrasound activated vesicle of Janus Au-MnO nanoparticles for promoted tumor penetration and sono-chemodynamic therapy of orthotopic liver cancer. Angew Chem Int Ed. 2020;59(4):1682–8. doi: 10.1002/anie.201912768. [DOI] [PubMed] [Google Scholar]

[b26] 26.Ou JF, Tian H, Wu JY, et al. MnO2-based nanomotors with active Fenton-like Mn2+ delivery for enhanced chemodynamic therapy. ACSAppl Mater Interfaces. 2021;13(32):38050–60. doi: 10.1021/acsami.1c08926. [DOI] [PubMed] [Google Scholar]

[b27] 27.Zhang JY, Liang C, Wei ZY, et al. TME-triggered MnSiO3@Met@GOx nanosystem for ATP dual-inhibited starvation/chemodynamic synergistic therapy. Biomaterials. 2022;287:121682–8. doi: 10.1016/j.biomaterials.2022.121682. [DOI] [PubMed] [Google Scholar]

[b28] 28.He T, Qin X, Jiang C, et al. Tumor pH-responsive metastable-phase Manganese sulfide nanotheranostics for traceable hydrogen sulfide gas therapy primed chemodynamic therapy. Theranostics. 2020;10(6):2453–62. doi: 10.7150/thno.42981. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b29] 29.Liu P, PengY, Ding J, et al. Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer. Asian J Pharm Sci. 2022;17(2):177–92. doi: 10.1016/j.ajps.2021.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b30] 30.Tao Q, He G, Ye S, et al. Mn doped Prussian blue nanoparticles for T1/T2 MR imaging, PA imaging and Fenton reaction enhanced mild temperature photothermal therapy of tumor. J Nanobio-technology. 2022;20(1):18–26. doi: 10.1186/s12951-021-01235-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b31] 31.Kou YK, Dai ZC, Cui P, et al. A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy. J Mater Chem B. 2021;9(40):8480–90. doi: 10.1039/D1TB01539G. [DOI] [PubMed] [Google Scholar]

[b32] 32.Ming J, Zhu TB, Yang WH, et al. Pd@Pt-GOx/HA as a novel enzymatic cascade nanoreactor for high-efficiency starvin-genhanced chemodynamic cancer therapy. ACS Appl Mater Interfaces. 2020;12(46):51249–62. doi: 10.1021/acsami.0c15211. [DOI] [PubMed] [Google Scholar]

[b33] 33.Wang J, Wang D, Cen M, et al. GOx-assisted synthesis of pillararene based supramolecular polymeric nanoparticles for targeted/synergistic chemo-chemodynamic cancer therapy. J Nanobiotechnology. 2022;20(1):33–40. doi: 10.1186/s12951-021-01237-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b34] 34.Fu LH, Wan YL, Qi C, et al. Nanocatalytic theranostics with glutathione depletion and enhanced reactive oxygen species generation for efficient cancer therapy. Adv Mater. 2021;33(7):e2006892–903. doi: 10.1002/adma.202006892. [DOI] [PubMed] [Google Scholar]

PERMALINK

锰基纳米材料用于胃肠道恶性肿瘤的化学动力治疗

Manganese-based nanoparticles for chemodynamic therapy of gastrointestinal cancer

Xiaofeng LIN

Mayang HUANG

Junqian CHEN

Xun ZHOU

Zhuodan ZHONG

Wencong LU

Xianying HUANG

Tianwen LIU

Abstract

目的

方法

结果

结论

Abstract

Objective

Methods

Results

Conclusion

1. 材料和方法

1.1. MSN@Mn-GOx的合成

1.2. MSN@Mn-GOx的形态大小

1.3. MSN@Mn-GOx的化学动力效能

1.4. MSN@Mn-GOx的氧气消耗水平

1.5. MSN@Mn-GOx的核磁成像（MRI）能力

1.6. 细胞培养

1.7. 激光共聚焦实验

1.8. CCK-8细胞毒性实验

1.9. Edu细胞增殖实验

1.10. 统计学分析

2. 结果

2.1. MSN@Mn-GOx的理化特征

图 1.

2.2. MSN@Mn-GOx的类芬顿催化能力

图 2.

2.3. MSN@Mn-GOx的核磁成像能力

图 3.

2.4. MSN@Mn-GOx产生ROS的能力

图 4.

2.5. MSN@Mn-GOx的肿瘤杀伤能力

图 5.

图 6.

3. 讨论

Biography

Funding Statement

Contributor Information

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases