甘露糖修饰的薄壳硅负载硒代胱氨酸的抗肿瘤性能研究

甘露糖修饰的薄壳硅负载硒代胱氨酸的抗肿瘤性能研究[摘要]本研究针对癌症治疗领域对高效低毒抗肿瘤药物的需求，开发了甘露糖修饰的薄壳硅负载硒代胱氨酸的纳米复合体系，旨在增强硒代胱氨酸（SeC）的抗肿瘤性能。首先，研究团队通过实验验证了所合成的薄壳二氧化硅负载硒代胱氨酸纳米材料的物理化学特性，利用透射电子显微镜（TEM）、动态光散射（DLS）及紫外分光光度计等技术手段对材料的形貌、粒径、Zeta电位及药物负载效果进行了全面表征，确认了SeC的成功负载与复合材料的稳定性。接着，采用MTT法评估了该复合体系对宫颈癌HeLa细胞和人结肠腺癌LS174T细胞的增殖抑制效应，结果显示其对肿瘤细胞的抑制效果显著优于单独的SiO2纳米颗粒，并呈浓度依赖性。同时，利用DCFH-DA荧光探针检测细胞内活性氧（ROS）水平，发现甘露糖修饰的SiO2@SeC可显著提升肿瘤细胞内ROS含量，诱导细胞凋亡，揭示了其抗肿瘤机制。本研究创新性地将甘露糖修饰的薄壳硅纳米载体与SeC相结合，充分利用该载体的高负载能力、缓释特性以及甘露糖配体的靶向性优势，为SeC的精准递送提供了新策略，有效解决了SeC水溶性差、稳定性差等临床转化瓶颈问题，为开发新型靶向纳米抗肿瘤药物提供了实验依据与理论支持，推动了纳米技术在癌症治疗领域的应用发展。[关键词]癌症治疗；硒代胱氨酸；抗肿瘤机制；薄壳硅；纳米材料Anti-tumorpropertiesofmannose-modifiedhollowthin-shelledsilicaloadedwithselenocystineAbstract：Tomeetthedemandforhighlyeffectiveandlowtoxicanti-tumordrugsinthefieldofcancertreatment,mannose-modifiedthin-shellsiliconselenocystineloadednanocompositesweredevelopedtoenhancetheanti-tumoractivityofselenocystine(SeC).Firstly,theresearchteamverifiedthephysicalandchemicalpropertiesofthesynthesizedthin-shellsilicaloadedselenocystinenanomaterialsthroughexperiments.Themorphology,particlesize,Zetapotentialanddrugloadingeffectofthematerialswerecomprehensivelycharacterizedbytransmissionelectronmicroscopy(TEM),dynamiclightscattering(DLS)andultravioletspectrophotometer.ThesuccessfulloadingofSeCwasconfirmedwiththestabilityofthecomposite.Then,MTTassaywasusedtoevaluatetheinhibitoryeffectofthecompositesystemontheproliferationofcervicalcancerHeLacellsandhumancolonadenocarcinomaLS174Tcells.TheresultsshowedthattheinhibitoryeffectontumorcellswassignificantlybetterthanthatofSiO2nanoparticlesaloneinaconcentration-dependentmanner.Atthesametime,DCFH-DAfluorescentprobewasusedtodetectthelevelofintracellularreactiveoxygenspecies(ROS),anditwasfoundthatmannose-modifiedSiO2@SeCcouldsignificantlyincreasethecontentofROSintumorcellsandinducecellapoptosis,revealingitsanti-tumormechanism.Thisstudyinnovatesthecombinationofmannose-modifiedthin-shellsiliconnanocapsulesandSeC.Takingfulladvantageofthehighloadingcapacity,sustainedreleasecharacteristicsandthetargetingadvantagesofmannoseligandsofthenanocapsules,thisstudyprovidesanewstrategyfortheprecisedeliveryofSeC,andeffectivelysolvesthebottlenecksofclinicaltransformationsuchaspoorwatersolubilityandpoorstabilityofSeC.Thisstudyprovidesexperimentalbasisandtheoreticalsupportforthedevelopmentofnewtargetednano-anti-tumordrugs,andpromotestheapplicationanddevelopmentofnanotechnologyincancertreatment.Keywords：Cancertreatment;Antitumormechanisms;Selenocystine;Thinshellsilicon;Nanomaterial绪论研究背景国内癌症治疗现状据全球癌症观测站(GLOBOCAN)估计，到2030年，中国癌症患者预计有892,723人，同期死亡人数622,215人，与2022年相比提高了24.2％。肺癌、结肠直肠癌、胃癌、肝癌和食道癌的流行意味着这些癌症是中国标准化年龄死亡率的重要原因。ADDINEN.CITE<EndNote><Cite><Author>Zheng</Author><Year>2022</Year><RecNum>238</RecNum><DisplayText>[1]</DisplayText><record><rec-number>238</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742113406">238</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zheng,Rongshou</author><author>Zhang,Siwei</author><author>Zeng,Hongmei</author><author>Wang,Shaoming</author><author>Sun,Kexin</author><author>Chen,Ru</author><author>Li,Li</author><author>Wei,Wenqiang</author><author>He,Jie</author></authors></contributors><titles><title>CancerincidenceandmortalityinChina,2016</title><secondary-title>JournaloftheNationalCancerCenter</secondary-title></titles><periodical><full-title>JournaloftheNationalCancerCenter</full-title></periodical><pages>1-9</pages><volume>2</volume><number>1</number><keywords><keyword>Cancerregistry</keyword><keyword>Incidence</keyword><keyword>Mortality</keyword><keyword>Statistics</keyword><keyword>China</keyword></keywords><dates><year>2022</year><pub-dates><date>2022/03/01/</date></pub-dates></dates><isbn>2667-0054</isbn><urls><related-urls><url>/science/article/pii/S2667005422000047</url></related-urls></urls><electronic-resource-num>/10.1016/j.jncc.2022.02.002</electronic-resource-num></record></Cite></EndNote>[1]为降低标准化年龄死亡率，近年来国内积极开展对于癌症治疗药物的研究并取得了显著进展，研发和应用逐步从传统化疗、放疗向靶向治疗、免疫治疗及联合治疗方向发展。在靶向治疗方面，国内药企大多采用自主研发和引进国际先进药物的方式，为患者提供了更多精准治疗选择。然而，部分靶向药物研发仍集中在热门靶点，导致同质化竞争较为明显。ADDINEN.CITE<EndNote><Cite><Author>孙雯娟</Author><Year>2022</Year><RecNum>239</RecNum><DisplayText>[2]</DisplayText><record><rec-number>239</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742135099">239</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>孙雯娟</author><author>张波</author></authors></contributors><auth-address>中国医学科学院北京协和医院药剂科;中国医学科学院北京协和医院疑难重症及罕见病国家重点实验室;</auth-address><titles><title>中国新型抗肿瘤药物现状分析及启示</title><secondary-title>协和医学杂志</secondary-title></titles><periodical><full-title>协和医学杂志</full-title></periodical><pages>1036-1044</pages><volume>13</volume><number>06</number><keywords><keyword>新型抗肿瘤药物</keyword><keyword>药品遴选</keyword><keyword>药物可及性</keyword><keyword>中国</keyword></keywords><dates><year>2022</year></dates><isbn>1674-9081</isbn><call-num>11-5882/R</call-num><urls><related-urls><url>/kcms2/article/abstract?v=hW9FdoQEerqrEOjZfVgpCwhj80V_vtZfwSqP5glTeUH9nSSWSfh1DTpN-JuJ_vrFhiDwvuzp5BoQnExHVdOaikuzmFhThQRCMaawu6-cN0Er45WjqRPpwOtiQ5QI0eo2dXWVQt69Ayy4mHivceLkc3kgtKUEbPuBDtFI9_jD5KyzlqoTxRJcaAO25LwgrX1H-bCj9bqzfTE=&uniplatform=NZKPT&language=CHS</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[2]与此同时，免疫治疗药物的研发和应用成为热点，国内已批准多款PD-1和PD-L1抑制剂，CAR-T细胞疗法也取得突破性进展，展现了显著的临床疗效。尽管国内在抗肿瘤药物研发方面取得诸多进展，但仍面临诸多挑战。一方面，部分新型抗肿瘤药物的引进和应用受限，且价格高昂，影响其临床可及性。另一方面，虽然有多种新型抗肿瘤药物投入临床癌症治疗当中，但大多数免疫治疗还没有达到令人满意的抗癌功效，提示我们在药物研发和临床应用方面需进一步努力。在这样的背景下，纳米硒作为一种新兴抗癌药物，逐渐受到关注。硒（Se）是人体代谢中必不可少的微量营养元素，纳米硒在进入人体后会转化为硒半胱氨酸对体内硒蛋白酶进行调控，通过抗氧化、免疫调节以及直接抑制肿瘤细胞增殖等机制发挥抗肿瘤作用。ADDINEN.CITE<EndNote><Cite><Author>Li</Author><Year>2020</Year><RecNum>240</RecNum><DisplayText>[3]</DisplayText><record><rec-number>240</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742138847">240</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Li,Tianyu</author><author>Pan,Shuojiong</author><author>Gao,Shiqian</author><author>Xiang,Wentian</author><author>Sun,Chenxing</author><author>Cao,Wei</author><author>Xu,Huaping</author></authors></contributors><titles><title>Diselenide–PemetrexedAssembliesforCombinedCancerImmuno-,Radio-,andChemotherapies</title><secondary-title>AngewandteChemieInternationalEdition</secondary-title></titles><periodical><full-title>AngewandteChemieInternationalEdition</full-title></periodical><pages>2700-2704</pages><volume>59</volume><number>7</number><dates><year>2020</year></dates><isbn>1433-7851</isbn><urls><related-urls><url>/doi/abs/10.1002/anie.201914453</url></related-urls></urls><electronic-resource-num>/10.1002/anie.201914453</electronic-resource-num></record></Cite></EndNote>[3]此外，纳米硒还具有良好的生物相容性和独特的物理化学性质，可作为抗癌药物与化疗、放疗和免疫治疗相结合，显著提高治疗效果。随着纳米技术的不断发展，纳米硒抗癌药物有望为癌症治疗提供新的思路和策略，进一步推动国内抗肿瘤药物的研发和应用。硒代胱氨酸抗肿瘤性能研究现状硒代胱氨酸抗肿瘤活性及机制硒代胱氨酸（Selenocysteine,SeC）作为一种含硒氨基酸，因其独特的化学结构和潜在的抗癌活性，逐渐成为研究热点。研究表明，SeC在哺乳动物体内参与硒蛋白组成通过多种机制发挥抗肿瘤作用，包括逆转肿瘤耐药性、诱导细胞凋亡、抑制肿瘤细胞增殖以及调节细胞内信号通路等。SeC能够有效逆转肿瘤耐药性，通过抑制耐药相关蛋白的活性，改善多种肿瘤的治疗效果。例如，在非小细胞肺癌中，SeC通过抑制p-Ras、p-ERK、p-PI3K和p-Akt等蛋白的表达，从而逆转TKI的耐药性。此外，硒代胱氨酸还可通过调节多药耐药相关蛋白的表达，在乳腺癌和胰腺癌的治疗中表现出显著的耐药性逆转效果，增强化疗药物的疗效。ADDINEN.CITE<EndNote><Cite><Author>刘露</Author><Year>2023</Year><RecNum>241</RecNum><DisplayText>[4]</DisplayText><record><rec-number>241</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742141388">241</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>刘露</author><author>董健</author><author>张勇</author><author>尹新洁</author></authors></contributors><auth-address>华中科技大学协和江北医院;湖北省荆门市第一人民医院;</auth-address><titles><title>硒代胱氨酸逆转非小细胞肺癌TKI靶向药物耐药体外抗肿瘤的作用机制</title><secondary-title>中国老年学杂志</secondary-title></titles><periodical><full-title>中国老年学杂志</full-title></periodical><pages>445-448</pages><volume>43</volume><number>02</number><keywords><keyword>硒代胱氨酸</keyword><keyword>非小细胞肺癌</keyword><keyword>酪氨酸激酶抑制剂(TKI)靶向药物</keyword><keyword>耐药</keyword><keyword>抗肿瘤机制</keyword></keywords><dates><year>2023</year></dates><isbn>1005-9202</isbn><call-num>22-1241/R</call-num><urls><related-urls><url>/kcms2/article/abstract?v=hW9FdoQEerpN2ngbHVDIqiaPXoVxL12yUHy04KyYWv_uNZ0aCDPUUdD9R5b0nEzxbaatjkbaIklm05kaESn7rX6r6XEZkFQ23HIQRhFvjD2BwdACw4jLpq4fZ4RblS9WBB7iCnOLLYgXxIwZweV74fGUKA9AlVEhc8eHvEZWS8X5ePF6kIoSxxkZoFoxIvqaSZtwZ0trh7Y=&uniplatform=NZKPT&language=CHS</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[4]硒代胱氨酸还能够增强NK92Cell细胞表面NKG2D受体的表达。NKG2D受体能够识别肿瘤细胞表面的应激配体，因此其表达的增加可以使自然杀伤细胞能够更有效地识别和结合肿瘤细胞，从而增强对肿瘤细胞的杀伤能力。同时，硒代胱氨酸通过调控TGF-β/TGF-βRI/Smad2/3信号通路，抑制TGF-β的免疫抑制作用，解除其对自然杀伤细胞功能的抑制，使自然杀伤细胞在肿瘤微环境中能够更好地发挥免疫监视和杀伤作用。最后，硒代胱氨酸还能通过调控硒蛋白的活性，引发DNA损伤响应，从而促进肿瘤细胞表面NKG2DLs的表达，为自然杀伤细胞提供更多的识别和攻击靶点，进一步增强其免疫活性。ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2020</Year><RecNum>6</RecNum><DisplayText>[5]</DisplayText><record><rec-number>6</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1676598373">6</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Chang</author><author>Lai,Haoqiang</author><author>Chen,Tianfeng</author></authors></contributors><titles><title>BoostingNaturalKillerCell-BasedCancerImmunotherapywithSelenocystine/TransformingGrowthFactor-BetaInhibitor-EncapsulatedNanoemulsion</title><secondary-title>ACSNano</secondary-title></titles><periodical><full-title>ACSNano</full-title></periodical><pages>11067-11082</pages><volume>14</volume><number>9</number><dates><year>2020</year><pub-dates><date>2020/09/22</date></pub-dates></dates><publisher>AmericanChemicalSociety</publisher><isbn>1936-0851</isbn><urls><related-urls><url>/10.1021/acsnano.9b10103</url></related-urls></urls><electronic-resource-num>10.1021/acsnano.9b10103</electronic-resource-num></record></Cite></EndNote>[5]图STYLEREF1\s1.SEQ图表\*ARABIC\s11硒代胱氨酸调控硒蛋白表达诱导细胞凋亡途径ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2020</Year><RecNum>6</RecNum><DisplayText>[5]</DisplayText><record><rec-number>6</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1676598373">6</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Chang</author><author>Lai,Haoqiang</author><author>Chen,Tianfeng</author></authors></contributors><titles><title>BoostingNaturalKillerCell-BasedCancerImmunotherapywithSelenocystine/TransformingGrowthFactor-BetaInhibitor-EncapsulatedNanoemulsion</title><secondary-title>ACSNano</secondary-title></titles><periodical><full-title>ACSNano</full-title></periodical><pages>11067-11082</pages><volume>14</volume><number>9</number><dates><year>2020</year><pub-dates><date>2020/09/22</date></pub-dates></dates><publisher>AmericanChemicalSociety</publisher><isbn>1936-0851</isbn><urls><related-urls><url>/10.1021/acsnano.9b10103</url></related-urls></urls><electronic-resource-num>10.1021/acsnano.9b10103</electronic-resource-num></record></Cite></EndNote>[5]Figure1.1Selenocystineregulatesselenoproteinexpressiontoinduceapoptosispathway在硒代胱氨酸自身抗肿瘤机制方面，它能够通过氧化应激损伤诱导肿瘤细胞周期阻滞和细胞凋亡，且这一过程呈现时间和剂量依赖性。其诱导凋亡的机制涉及外在和内在两条途径。外在途径通过激活死亡受体（如Fas和TRAIL受体）触发细胞凋亡，而内在途径则通过调节BCL-2家族蛋白调节线粒体释放凋亡因子（如细胞色素c和AIF），进而激活Caspase非依赖性和p53依赖性细胞凋亡途径。ADDINEN.CITE<EndNote><Cite><Author>王伟</Author><Year>2018</Year><RecNum>242</RecNum><DisplayText>[6]</DisplayText><record><rec-number>242</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742144242">242</key></foreign-keys><ref-typename="Thesis">32</ref-type><contributors><authors><author>王伟</author></authors><tertiary-authors><author>周东生,</author></tertiary-authors></contributors><titles><title>硒代胱氨酸抑制骨肉瘤生长的分子机制研究</title></titles><keywords><keyword>成骨肉瘤</keyword><keyword>硒代胱氨酸</keyword><keyword>细胞凋亡</keyword><keyword>细胞周期阻滞</keyword><keyword>血管生成</keyword><keyword>活性氧</keyword><keyword>DNA损伤</keyword><keyword>线粒体功能障碍</keyword></keywords><dates><year>2018</year></dates><work-type>博士</work-type><urls><related-urls><url>/kcms2/article/abstract?v=hW9FdoQEerqbqkUZUixvi6vRAAo18LIDzLBiYJDzjz8KY2T7jhEjtRONpXTVj6tIqqAjooAkBnyQoe5DyinidrYhk3eV4Ab9AnWGAYnWq7aOPNmUmV_NYsfVAx7b9dmhe2jYWmm9AGv5RJZREw2BQ_goJtM1ys4FLDkF6AK6WTNHtPjkPyEGcsVhlaPjEEzqI2CnQ5i7GVA=&uniplatform=NZKPT&language=CHS</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[6]此外，硒代胱氨酸还可通过调节MAPK和AKT信号通路，诱导ROS介导的DNA损伤和p53磷酸化，进而调节CyclinA等周期相关蛋白的表达从而诱导肿瘤细胞S期阻滞，抑制肿瘤细胞生长。ADDINEN.CITE<EndNote><Cite><Author>王琨</Author><Year>2016</Year><RecNum>153</RecNum><DisplayText>[7]</DisplayText><record><rec-number>153</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1678017628">153</key></foreign-keys><ref-typename="Thesis">32</ref-type><contributors><authors><author>王琨</author></authors><tertiary-authors><author>孙保亮,</author></tertiary-authors></contributors><titles><title>硒代胱氨酸及其衍生物的抗脑胶质瘤机理及神经保护机制研究</title></titles><keywords><keyword>硒代胱氨酸</keyword><keyword>胶质瘤</keyword><keyword>高血糖</keyword><keyword>脑卒中</keyword><keyword>氧化应激</keyword></keywords><dates><year>2016</year></dates><publisher>山东大学</publisher><work-type>博士</work-type><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[7]图STYLEREF1\s1.SEQ图表\*ARABIC\s12SeC诱导的Caspase独立和p53依赖性细胞凋亡途径ADDINEN.CITE<EndNote><Cite><Author>王伟</Author><Year>2018</Year><RecNum>242</RecNum><DisplayText>[6]</DisplayText><record><rec-number>242</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742144242">242</key></foreign-keys><ref-typename="Thesis">32</ref-type><contributors><authors><author>王伟</author></authors><tertiary-authors><author>周东生,</author></tertiary-authors></contributors><titles><title>硒代胱氨酸抑制骨肉瘤生长的分子机制研究</title></titles><keywords><keyword>成骨肉瘤</keyword><keyword>硒代胱氨酸</keyword><keyword>细胞凋亡</keyword><keyword>细胞周期阻滞</keyword><keyword>血管生成</keyword><keyword>活性氧</keyword><keyword>DNA损伤</keyword><keyword>线粒体功能障碍</keyword></keywords><dates><year>2018</year></dates><work-type>博士</work-type><urls><related-urls><url>/kcms2/article/abstract?v=hW9FdoQEerqbqkUZUixvi6vRAAo18LIDzLBiYJDzjz8KY2T7jhEjtRONpXTVj6tIqqAjooAkBnyQoe5DyinidrYhk3eV4Ab9AnWGAYnWq7aOPNmUmV_NYsfVAx7b9dmhe2jYWmm9AGv5RJZREw2BQ_goJtM1ys4FLDkF6AK6WTNHtPjkPyEGcsVhlaPjEEzqI2CnQ5i7GVA=&uniplatform=NZKPT&language=CHS</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[6]Figure1.2Sec-inducedcaspase-independentandp53-dependentapoptoticpathways纳米化硒代胱氨酸抗肿瘤性能研究现状近年来，纳米技术的发展为硒代胱氨酸的抗肿瘤研究带来了新的突破。纳米化硒代胱氨酸不仅显著提高其稳定性和生物利用度，同时还可以减少对正常细胞的毒性。这些特性使得纳米化硒代胱氨酸在癌症治疗中具有广阔的应用前景，因此吸引来国内外很多研究者的研究和讨论，主要集中在硒代胱氨酸的抗肿瘤机制、载体选择以及药物联合治疗等方面。SeC在肿瘤联合治疗中展现出了多维度协同增效的潜力。针对广泛用于临床的顺铂化疗具有耐药性与毒性的问题，SeC通过激活线粒体凋亡通路（如caspase-3/9）及降低线粒体膜电位，显著增强顺铂对宫颈癌HeLa细胞的杀伤效率，并与放疗协同激活p53信号系统，放大DNA损伤效应，实现放射增敏。ADDINEN.CITE<EndNote><Cite><Author>琨</Author><Year>2015</Year><RecNum>160</RecNum><DisplayText>[8,9]</DisplayText><record><rec-number>160</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1678038823">160</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>袁启霞，张毅芳，范丰田，王琨</author></authors></contributors><titles><title>硒代胱氨酸协同增敏顺铂诱导人子宫颈癌HeLa细胞凋亡</title><secondary-title>JournalofPracticaIOncolog</secondary-title></titles><periodical><full-title>JournalofPracticaIOncolog</full-title></periodical><volume>30</volume><dates><year>2015</year></dates><isbn>1001-1692(2015)04-0330-05</isbn><urls></urls></record></Cite><Cite><Author>钱莘、郑沙沙、李国保、解立新</Author><Year>2020</Year><RecNum>161</RecNum><record><rec-number>161</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1678039452">161</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>钱莘、郑沙沙、李国保、解立新</author></authors></contributors><titles><title>硒代胱氨酸对宫颈癌HeLa细胞放射增敏作用体外研究</title><secondary-title>中华肿瘤防治杂志</secondary-title></titles><periodical><full-title>中华肿瘤防治杂志</full-title></periodical><dates><year>2020</year></dates><urls></urls><electronic-resource-num>10.16073/ki.cjcpt.2020.02.04</electronic-resource-num></record></Cite></EndNote>[8,9]SeC在药物联用策略上则通过多靶点干预实现协同增效。例如，SeC与奥拉诺芬（AF）的联合使用能靶向TrxR，从而触发ROS-AKT/ERK-p53双向调控环路，造成DNA损伤与线粒体功能障碍，抑制乳腺癌细胞生长。ADDINEN.CITEADDINEN.CITE.DATA[10]而天然冰片（NB）则通过增强SeC的细胞摄取效率与ROS介导的DNA损伤，促进肝癌细胞凋亡。ADDINEN.CITEADDINEN.CITE.DATA[11]然而，单纯的药物联用仍面临溶解性差与靶向不足等局限，纳米化技术的应用可以有效解决这些问题。例如，乳化法制备的纳米乳液通过共载TGF-β抑制剂与SeC，不仅提升药物稳定性，还通过抑制TGF-β/Smad信号通路增强NK细胞对乳腺癌细胞的免疫识别ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2020</Year><RecNum>65</RecNum><DisplayText>[5]</DisplayText><record><rec-number>65</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1676602546">65</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Chang</author><author>Lai,Haoqiang</author><author>Chen,Tianfeng</author></authors></contributors><titles><title>BoostingNaturalKillerCell-BasedCancerImmunotherapywithSelenocystine/TransformingGrowthFactor-BetaInhibitor-EncapsulatedNanoemulsion</title><secondary-title>ACSNano</secondary-title></titles><periodical><full-title>ACSNano</full-title></periodical><pages>11067-11082</pages><volume>14</volume><number>9</number><dates><year>2020</year><pub-dates><date>2020/09/22</date></pub-dates></dates><publisher>AmericanChemicalSociety</publisher><isbn>1936-0851</isbn><urls><related-urls><url>/10.1021/acsnano.9b10103</url></related-urls></urls><electronic-resource-num>10.1021/acsnano.9b10103</electronic-resource-num></record></Cite></EndNote>[5]。这些研究都表明纳米技术对于增强SeC靶向性、改善药代动力学及整合多机制治疗中的重要作用，为肿瘤联合治疗的临床转化提供了新的方向。在硒代胱氨酸载体选择方面，由于SeC兼具抗氧化和促氧化特性，其亲核性强，稳定性和选择性较差，并且硒代胱氨酸在体内的溶解度较低，这些特点都提醒了研究者们在将其作为抗肿瘤药物时需要关注载体选择的问题，而刚好纳米技术的应用为硒代胱氨酸载体的研究带来了新思路。基于纳米载体的药物递送体系可通过增强肿瘤靶向性及实现药物缓释特性显著提升治疗效果，其作用机制与实体瘤特有的高通透性和EPR效应密切相关。EPR效应在实体瘤中表现得尤为明显，因为在实体瘤中毛细血管丛的结构往往存在异常，相较于正常组织更为疏松，同时该区域的淋巴系统功能失调，导致肿瘤组织的透过性显著增加。ADDINEN.CITE<EndNote><Cite><Author>Alasvand</Author><Year>2017</Year><RecNum>132</RecNum><DisplayText>[12]</DisplayText><record><rec-number>132</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1677937538">132</key></foreign-keys><ref-typename="BookSection">5</ref-type><contributors><authors><author>Alasvand,Neda</author><author>Urbanska,AleksandraM.</author><author>Rahmati,Maryam</author><author>Saeidifar,Maryam</author><author>Gungor-Ozkerim,P.Selcan</author><author>Sefat,Farshid</author><author>Rajadas,Jayakumar</author><author>Mozafari,Masoud</author></authors><secondary-authors><author>Grumezescu,AlexandruMihai</author></secondary-authors></contributors><titles><title>Chapter13-TherapeuticNanoparticlesforTargetedDeliveryofAnticancerDrugs</title><secondary-title>MultifunctionalSystemsforCombinedDelivery,BiosensingandDiagnostics</secondary-title></titles><pages>245-259</pages><keywords><keyword>nanoparticles</keyword><keyword>targeteddrugdelivery</keyword><keyword>cancer</keyword></keywords><dates><year>2017</year><pub-dates><date>2017/01/01/</date></pub-dates></dates><publisher>Elsevier</publisher><isbn>978-0-323-52725-5</isbn><urls><related-urls><url>/science/article/pii/B9780323527255000137</url></related-urls></urls><electronic-resource-num>/10.1016/B978-0-323-52725-5.00013-7</electronic-resource-num></record></Cite></EndNote>[12]这种特殊的病理生理环境使得纳米药物能够更高效和精准地富集在肿瘤组织中，从而增强其治疗效果。为增强SeC的稳定性和靶向性，研究者们广泛探索了多种纳米材料，包括天然多糖、生物可降解聚合物及特殊结构化合物等，以更好地实现硒代胱氨酸的高效递送和靶向治疗。在天然多糖载体方面，壳聚糖（Chitosan,CS）因其良好的生物相容性、生物可降解性和对细胞的靶向能力而受到关注。有研究将硒代胱氨酸封装在壳聚糖/聚磷酸盐纳米颗粒中，发现这种纳米封装形式能够显著提高细胞内硒的水平，并减少硒诱导的DNA损伤反应。此外，壳聚糖的正电性使其能够与肿瘤细胞的负电荷微环境相互作用，从而提高药物的靶向性。ADDINEN.CITE<EndNote><Cite><Author>Zhang</Author><Year>2011</Year><RecNum>244</RecNum><DisplayText>[13]</DisplayText><record><rec-number>244</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742231900">244</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhang,Shu</author><author>Luo,Yangchao</author><author>Zeng,Huawei</author><author>Wang,Qin</author><author>Tian,Fei</author><author>Song,Jiuzhou</author><author>Cheng,Wen-Hsing</author></authors></contributors><titles><title>Encapsulationofseleniuminchitosannanoparticlesimprovesseleniumavailabilityandprotectscellsfromselenium-inducedDNAdamageresponse</title><secondary-title>TheJournalofNutritionalBiochemistry</secondary-title></titles><periodical><full-title>TheJournalofNutritionalBiochemistry</full-title></periodical><pages>1137-1142</pages><volume>22</volume><number>12</number><keywords><keyword>Selenium</keyword><keyword>Chitosan</keyword><keyword>Nanoparticles</keyword><keyword>DNAdamage</keyword><keyword>Cancer</keyword></keywords><dates><year>2011</year><pub-dates><date>2011/12/01/</date></pub-dates></dates><isbn>0955-2863</isbn><urls><related-urls><url>/science/article/pii/S0955286310002421</url></related-urls></urls><electronic-resource-num>/10.1016/j.jnutbio.2010.09.014</electronic-resource-num></record></Cite></EndNote>[13]在生物可降解聚合物方面，研究者们也探索了如PLGA等具有良好的生物相容性和可降解性的材料作为硒代胱氨酸的载体，提高其在体内的稳定性。同时，PLGA纳米颗粒还可以通过表面修饰（如添加靶向配体）进一步增强其靶向能力。ADDINEN.CITE<EndNote><Cite><Author>黄华婷</Author><Year>2022</Year><RecNum>245</RecNum><DisplayText>[14]</DisplayText><record><rec-number>245</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742233084">245</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>黄华婷</author><author>蔡梦如</author><author>付京</author><author>刘晶</author><author>孙铭忆</author><author>游龙泰</author><author>郎晓雪</author><author>胡雪凌</author><author>王开心</author><author>倪健</author><author>董晓旭</author></authors></contributors><auth-address>北京中医药大学中药学院;首都医科大学附属北京中医医院北京市中医药研究所;</auth-address><titles><title>聚乳酸-羟基乙酸共聚物纳米粒载中药抗肿瘤成分的研究进展</title><secondary-title>中草药</secondary-title></titles><periodical><full-title>中草药</full-title></periodical><pages>7295-7306</pages><volume>53</volume><number>22</number><keywords><keyword>聚乳酸-羟基乙酸共聚物</keyword><keyword>中药</keyword><keyword>抗肿瘤</keyword><keyword>制备方法</keyword><keyword>靶向递药</keyword><keyword>免疫佐剂</keyword></keywords><dates><year>2022</year></dates><isbn>0253-2670</isbn><call-num>12-1108/R</call-num><urls><related-urls><url>/kcms2/article/abstract?v=52O9CKbg8L5_g64c3FkBCsScKLXCyBr9DLx8gzg6ru74P8zq94xD0qNAd3R3jjaGUz3tHk-kVuYUHBqjx_DRG8e-iP_VlvqkkYS1K_Yiu3TdAwCjJphlsOfrgzhmT5MxfjWt3YNYVY-wClnUkNzDyVvXaMKtGaVF-Q4UEYzyXysl1I1dlVhFIPyTmCc37Nwm0fk1xseAOyE=&uniplatform=NZKPT&language=CHS</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[14]除了前面提到的两类载体，还有一类具有特殊结构的化合物可以作为载体，以MSNs为例，其具有高比表面积和可调节的孔径，能够有效负载硒代胱氨酸，并通过表面修饰实现肿瘤靶向。在系统性红斑狼疮治疗中，硒代胱氨酸以MSNs为载体不仅提高了药物稳定性，而且由于纳米药物具有的缓释特性还减少了给药频率，提升了药物的安全性和生物相容性。ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2025</Year><RecNum>246</RecNum><DisplayText>[15]</DisplayText><record><rec-number>246</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1742266317">246</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Ting</author><author>Lin,Zhiming</author><author>Zhang,Xi</author><author>Yang,Yu</author><author>Huang,Guanning</author><author>Yu,Yanzi</author><author>Xie,Bin</author><author>He,Lizhen</author><author>Chen,Tianfeng</author></authors></contributors><titles><title>TargetingNanotherapeuticsforHighlyEfficientDiagnosisandTreatmentofSystemicLupusErythematosusthroughRegulationofImmuneResponse</title><secondary-title>SmallScience</secondary-title></titles><periodical><full-title>SmallScience</full-title></periodical><pages>2400521</pages><volume>n/a</volume><number>n/a</number><keywords><keyword>anti-dsDNAantibodies</keyword><keyword>regulationsofimmuneresponse</keyword><keyword>specifictargeting</keyword><keyword>systemiclupuserythematosus</keyword></keywords><dates><year>2025</year><pub-dates><date>2025/01/23</date></pub-dates></dates><publisher>JohnWiley&Sons,Ltd</publisher><urls><related-urls><url>/10.1002/smsc.202400521</url></related-urls></urls><electronic-resource-num>/10.1002/smsc.202400521</electronic-resource-num><access-date>2025/03/17</access-date></record></Cite></EndNote>[15]而本文所研究的硒代胱氨酸也是以甘露糖修饰的薄壳硅纳米材料为载体，通过糖基化靶向增强肿瘤蓄积能力，同时利用表面多孔结构的高负载特性优化SeC释放动力学，为开发高效低毒的联合治疗方案提供理论依据与技术参考。复合材料优势及合成可行性分析我们所研究的甘露糖修饰的薄壳硅负载硒代胱氨酸这种抗肿瘤药物，与传统载体相比，在靶向性、负载能力和生物相容性方面均表现出显著优势，为开发高效低毒的联合治疗方案提供了理论依据与技术参考。首先，甘露糖作为一种靶向配体，能够与巨噬细胞表面的甘露糖受体（CD206）特异性结合。通过受体介导的内吞机制，甘露糖修饰的药物可以精准地被输送到巨噬细胞表面。巨噬细胞在吞噬和分解肿瘤细胞的同时，还能作为抗癌药物的载体，进一步增强对肿瘤细胞的杀伤效率。这种靶向输送机制不仅显著提高了药物在肿瘤部位的蓄积能力，还通过巨噬细胞的免疫功能强化了抗肿瘤效果。ADDINEN.CITE<EndNote><Cite><Author>于尚可</Author><RecNum>247</RecNum><DisplayText>[16]</DisplayText><record><rec-number>247</rec-number><foreign-keys><keyapp="EN"db-id="tvwfzvz54vwf59etfsm5xv05fv9t5xsef9wd"timestamp="1744877170">247</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>于尚可</author><author>李拖平</author><author>杨维巧</author><author>王文娟</author><author>段晓亮</author><author>张智航</author><author>赵汝霞</author></authors></contributors><auth-address>沈阳农业大学食品学院;国家粮食和物资储备局科学研究院;河南工业大学粮油食品学院;天津科技大学食品科学与工程学院;</auth-address><titles><title>糖基化修饰靶向递送药物研究进展</title><secondary-title>中国药学杂志</secondary-title></titles><periodical><full-title>中国药学杂志</full-title></periodical><pages>1-13</pages><keywords><keyword>糖基化</keyword><keyword>靶向递送</keyword><keyword>抗癌药物</keyword><keyword>基因递送</keyword></keywords><dates></dates><isbn>1001-2494</isbn><call-num>11-2162/R</call-num><urls><related-urls><url>/urlid/11.2162.R.20250327.1415.014</url></related-urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[16]而薄壳硅纳米材料的空心结构具有较高的负载能力，能够有效负载硒代胱氨酸，并通过缓释特性延长药物在肿瘤部位的作用时间。硒代胱氨酸作为核心抗肿瘤成分，通过甘露糖修饰的薄壳硅纳米材料作为载体，进一步优化了药物的释放动力学和生物利用度。此外，甘露糖修饰的薄壳硅纳米材料在合成过程中表现出良好的可行性。甘露糖的修饰可以通过物理吸附实现，而薄壳硅的空心结构为药物的高效负载提供了理想的平台，两者可以通过静电吸附进行结合。ADDINEN.CITE<EndNote><Cite><Author>Xu</Author><Year>2024</Year><RecNum>248</Re