肿瘤微环境响应型多柔比星前药的研究进展

来源期刊：广州医药 | 1189-1200 发布时间：2025-09-20 收稿时间：2025/11/3 14:39:22 阅读量：38

作者：: 王悦,

马文静,

侯金松,

吴豪,

关键词：: 肿瘤微环境多柔比星前药肿瘤治疗谷胱甘肽活性氧; tumor microenvironment doxorubicin prodrug tumor therapy glutathione reactive oxygen species

DOI：: 10. 20223 / j. cnki. 1000-8535. 2025. 09. 005

收稿时间：: 2024-08-06
修订日期：
接收日期：
引用总数：: 0

与正常组织细胞微环境相比,肿瘤微环境具有一定的异质性,包括偏酸性、氧化还原状态失衡、存在高浓度活性氧以及酶过量表达等。根据以上肿瘤微环境特点,可设计出一系列通过各种特殊微环境响应型连接臂相连的小分子或聚合物前药纳米粒。其中,多柔比星阿霉素作为一类最常见的广谱抗肿瘤药物在治疗肿瘤的过程中发挥重要作用。文章探讨了在肿瘤微环境特异性的生理状态下针对不同微环境所设计的多柔比星前药及其释放特性等,归纳总结了肿瘤微环境响应型多柔比星前药的研究进展。

肿瘤严重威胁着人类的健康。目前，化学治疗（化疗）是治疗肿瘤的主要手段，尤其是针对不能通过手术治疗并伴随转移扩散的肿瘤，然而其存在较强的不良反应和毒性风险^［1］。随着纳米技术在药物递送系统中的广泛应用，化疗药物的安全性问题得到了一定的改善。但是，构建高效低毒的纳米药物递药系统仍然是目前科研人员着力于解决的难题。前药是一类药理活性较低或无药理活性的药物衍生物，给药后可在体内转化生成活性药物发挥治疗作用^［2］。相比于正常组织，肿瘤部位代谢和增殖异常会造成较为复杂且异质性较高的特殊微环境情况，包括微酸性、高活性氧（reactive oxygen species，ROS）浓度、高还原性、乏氧性以及酶过量表达等^［3］。许多学者根据肿瘤部位异常的微环境特征设计出微环境敏感型纳米前药，在治疗肿瘤方面表现出较为理想的疗效提升潜力。

多柔比星（doxorubicin，DOX）是现阶段临床使用较广泛的一类抗肿瘤药物，具有高效的抗癌活性，然而因其存在毒副作用大、生物利用度低以及水溶性差等问题，严重限制了其临床应用^［4］。为了克服上述问题，部分学者根据肿瘤组织和肿瘤细胞内部的微环境特征，对DOX进行分子设计及前药制备^［5］。例如针对肿瘤微环境的偏酸性、高浓度谷胱甘肽（glutathione，GSH）以及高浓度ROS^［6］，可以分别通过腙键、二硫键和硼酸酯键等将DOX与亲水性外壳进行化学偶联生成两亲性前药，从而提高DOX在肿瘤周围的释放，这在一定程度上减少了对正常组织的伤害，提高了DOX的潜在治疗效果。在设计小分子或聚合物前药的过程中，针对肿瘤微环境选择适宜的连接臂直接关系到药物效果，并且也是较为值得关注的问题。本文总结了基于各种肿瘤微环境制备的DOX前药，概述其微环境敏感机制，以期为DOX微环境响应型前药的设计和应用提供借鉴和依据。

1 单响应性多柔比星前药

1.1 酸（pH）响应性多柔比星前药

肿瘤组织周围异常的血管结构以及肿瘤细胞的过度增殖，使得肿瘤细胞通常处于乏氧状态，导致其代谢途径发生变化。与正常组织以有氧代谢的途径相比，肿瘤组织通常依赖无氧糖降解的方式进行代谢，此过程中产生的乳酸和二氧化碳共同导致了肿瘤部位的偏酸性微环境（pH范围为6.2~6.8）。利用这种特殊的微酸环境，研究人员构建了一系列pH敏感响应性多柔比星前药纳米递药系统。pH响应也是在众多肿瘤微环境响应中运用最广泛的一类智能响应。见图1。

图 1 基于 pH 敏感的 DOX 前药的制备及释药机制

1.1.1 通过亚氨键连接的多柔比星前药 Dong等^［7］制备了DOX衍生物DOX-hyd-N3，并将其连接到喜树碱前药CPT-ss-poly（BYP-co-EEP）的侧链上形成具有亚氨键结构的DOX前药，前药初始粒径约为90 nm，将其放入pH为5.0的磷酸盐缓冲液（phosphate buffered saline，PBS）内，2 h后粒径增长至570 nm，此外，研究人员还考察该前药在不同pH条件下的药物释放效果。结果显示，在pH为5.0的条件中，DOX在100 h内的释放率约为61%，而在pH为7.4的条件中，DOX的释放率仅为17%。Xiong等^［8］通过以叔丁基羰基肼为载体，以亚氨键将DOX与维生素E琥珀酸共价键合，制备了具有pH敏感的DOX前药TOS-H-DOX，然后通过透析法来考察药物的释放。结果显示，72 h内在pH为5.0、6.4和7.4的条件下，TOS-H-DOX分别释放约90%、30%和10%。并且不具有pH敏感的TOS-A-DOX在pH为5.0、6.4、7.4的条件下释药量均不超过30%。见表1。

表1 以亚胺键连接的酸敏感DOX前药及其体外释放特征

药物	前药名称	敏感键	考察时间	考察指标
DOX	P-DOX[9]	亚氨键	70 h	pH 7.4 20% vs pH 6.0 60% vs pH 5.0 75%
	PLL(CB/DOX)-b-PMPC[10]	亚氨键	4 h	pH 7.4 90 nm vs pH 6.5 130 nm vs pH 5.8 210 nm
	mPEG-b-DOX[11]	亚氨键	50 h	pH 7.4 35% vs pH 5.0 50%

1.1.2 通过腙键连接的多柔比星前药 Zhang等^［12］成功设计并合成了RGD环肽（cRGD）修饰的右旋糖酐-g-多柔比星（cRGD-DEX-DOX）前药。该前药可与二肼苯达嗪（dihydralazine，HDZ）在水溶液中自组装形成粒径为130 nm、均一且稳定性良好的多柔比星前药纳米粒体系cRGD-Dex-DOX/HDZ 纳米颗粒（nanoparticles，NPs），并分别在pH为7.4、6.0和5.0条件下研究了cRGD-Dex-DOX/HDZ NPs中DOX和HDZ的体外累积释放情况，结果表明，在pH为7.4条件下，72 h后DOX和HDZ仅分别释放了总量的34.7%和34.4%，当pH降至6.0时，DOX和HDZ的释放百分比分别增至59.5%和64.2%，当pH进一步降低至5.0时，72 h后DOX和HDZ的释放百分比可分别达到91.6%和88.7%。Yao等^［13］首先合成了与半胱氨酸-天冬氨酸蛋白酶-3（caspase-3）响应肽偶联的聚集诱导发光原（AIEgen）光敏剂，然后利用固相多肽合成法合成了AIEgen标记的多肽AIEgen-GDEVDG-CREKA（AIE – Pep），并合成了DOX的6 -马来酰亚胺基己酰腙衍生物（Mal-DOX），最后通过巯基-马来酰亚胺反应将Mal-DOX连接到AIE-Pep上，得到具有腙键结构的DOX前药AIE-Pep-DOX（APD）。体外释放实验结果表明，在pH为7.4条件下，APD在10 h内DOX的释放量维持在5 %以下，而在pH 6.5和pH 6.0条件下，10 h后的释药量分别超过60 %和90 %。见表2。

表2 以腙键连接的酸敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
HCCP-BM-DOX[14]	腙键	56 h	pH7.4 15.8% vs pH5.0 28.5%
DOXDT[15]	腙键	90 h	pH7.4 10% vs pH6.8 20% vs pH5.0 70%
mPPDPP-hyd-DOX[16]	腙键	50 h	pH7.4 10% vs pH6.5 20% vs pH5.0 60%
DOX-PhMV-PEG[17]	腙键	192 h	pH7.4 10% vs pH6.4 40% vs pH5.2 80%
DOX-hyd-TS[18]	腙键	50 h	pH7.4 20% vs pH6.8 40% vs pH5.0 85%

1.1.3 以马来酸二甲酯键连接的多柔比星前药 Li等^［19］将顺丁烯二酸酐（maleic anhydride，MAH）与DOX反应合成了D-DOXMAH，然后连接聚合物聚乙二醇（polyethylene glycol，PEG）形成了DOX前药D-DOXMAH-S-PEG，通过体外药物释放实验发现，当该DOX前药在pH为7.4条件下时，35 h内DOX的释药量仅为5%，但是该DOX前药在pH为5.0条件下时，35 h内DOX的释药量可达到40%。Ma等^［20］利用聚醚F127（Polyether F12）嫁接壳聚糖（chitosan，CS）合成了聚合物F127-CS，然后在侧链上连接DOX衍生物CA-DOX，形成了DOX前药F127-CS-DOX，分别将F127-CS-DOX置于pH为7.4和5.0的条件中，48 h后，在pH为7.4条件下DOX的释药量约为55%，在pH为5.0条件下DOX的释药量达到75%。

1.2 活性氧响应性多柔比星前药

ROS是细胞代谢过程中产生的一类具有高反应性的氧中间产物，生物体内的ROS主要包括过氧化氢（H₂O₂）、单线态氧（¹ O₂）、超氧自由基（•O₂ ^-）等，在机体内信号传导和代谢过程中发挥重要作用^［21］。H₂O₂是最典型的ROS，研究表明，正常生理环境下胞外H₂O₂浓度在0.5~7 μmol/L范围内，而在病理条件下H₂O₂浓度约为1.0 mmol/L^［22］。正常生理和病理状态下H₂O₂浓度差为研究者设计活性氧敏感型前药提供了依据。目前，用于制备ROS敏感性DOX前药的连接臂有硫缩酮、芳基硼酸等。见图2。

图 2 基于 ROS 敏感的 DOX 前药的制备及释药机制

1.2.1 以硫缩酮键为连接臂的多柔比星前药 Wang等^［23］采用聚合物载体，通过ROS敏感的侧基硫缩酮键（thioketal bond，TK）实现了DOX的负载，通过将巯基缩酮键接枝到聚碳酸酯（polycarbonate，PEG-PBC）的悬垂羟基上从而合成了PEG-PBC-TK，然后将DOX接枝到侧链后，形成PEG-PBC-TKDOX胶束，该纳米载体在肿瘤部位高ROS环境下，硫缩酮键响应断裂，从而释放出负载药物DOX。通过体外药物释放实验发现，50 h后当该前药胶束在0 mmol/L H₂O₂环境下时，DOX的释药量不超过20%；当该前药胶束在10 mmol/LH₂O₂条件下时，释药量约为40%；当环境条件变为20 mmol/L H₂O₂时，该前药胶束的释放量可达70%左右。Pan等^［24］通过聚合物聚乙二醇PEG和TK以及2-巯基托噻咪唑（2-propylthioimidazole，MTL）合成了药物载体mPEG-TK，然后将DOX·HCl嫁接于该药物载体上，形成具有ROS响应的DOX前药PEG-TK-DOX，通过体外释放实验发现，24 h后前药纳米粒在37 ℃、不含H₂O₂条件下，只有微量DOX被释放出来，但在37 ℃、100 μmol/L H₂O₂条件下，DOX的释放量可达到45.5%。见表3。

表3 ROS敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
mPEG-TK-DOX[25]	硫缩酮键	12 h	PBS 9 h 30 nm vs PBS+ROS 9 h 956 nm
PEG-TK-DOX[26]	硫缩酮键	48 h	PBS 250 nm vs PBS+ROS 1500 nm
MAN-TK-DOX[27]	硫缩酮键	80 h	1μmol/L H2O2 16.8% vs 100μmol/L H2O2 45%
DOX-TK-OXY[28]	硫缩酮键	144 h	PBS 12% vs PBS+H2O2 76.8%
P-TK-DOX[29]	硫缩酮键	12 h	PBS 10% vs PBS+H2O2 76.5%

1.2.2 通过芳基硼酸材料制备的多柔比星前药 Li等^［30］首先通过4-（羟甲基）苯硼酸吡啶丙酮和对硝基苯甲酰氯反应，然后将其与DOX反应获得具有ROS敏感的DOX前药BDOX，体外释药实验结果显示，50 h内，在含有1 μmol/L H₂O₂条件下，DOX的释放量不足30%，在含有10 μmol/L H₂O₂条件下，DOX的释放量在60%左右，而在含有100 μmol/L H₂O₂条件下，DOX的释放量接近90%。

1.3 谷胱甘肽响应性多柔比星前药

GSH是一类由谷氨酸、半胱氨酸以及甘氨酸所组成的三肽，是人和其他动物体内含量最多的一类低分子硫醇物质^［31］。人体细胞内的还原型GSH和氧化型GSH呈现动态平衡状态并构成胞内最常见的氧化还原对。然而肿瘤细胞的乏氧环境，导致胞内还原型GSH的含量与正常组织相比较高^［32］，使得肿瘤微环境具有更高的还原性。在此基础上，研究人员发现二硫键（-S-S-）在普通生理环境中可以稳定地存在，在高浓度还原型GSH的存在下容易断裂，二硫键被还原，从而实现药物释放^［33］。现阶段DOX上的氨基与含有二硫键的羧基化合物进行偶联制备DOX前药，是实现GSH敏感型DOX快速释放的主要途径，并且沈阳药科大学何仲贵等^［34］首次提出了三硫键偶联DOX制备DOX前药，为GSH微环境敏感型前药带来新的突破。见图3。

图 3 基于 GSH 敏感的 DOX 前药的制备及释药机制

1.3.1 以二硫键为连接臂的多柔比星前药根据宫宇等^［35］的报道，他们通过开环聚合、酰胺化等化学反应，以DPA为载体，将合成的PEG-b-PLL和DOX偶联，制备了以二硫键连接的还原响应型DOX大分子前药（PEG-b-PLL-ss-DOX），通过在不同GSH条件下进行对比实验发现，非还原响应性纳米载药胶束在不同GSH条件下粒径无明显变化，但还原响应性纳米载药胶束在不同GSH条件下粒径发生了明显改变，且随着介质中GSH的浓度不断增大，所释放的DOX的量也随之增大。见表4。

表4 GSH敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
PEG-PCL-SS-DOX[36]	二硫键	70 h	0 mmol/L DTT 70% vs 50 mmol/L DTT 90%
PP-SS-DOX[37]	二硫键	100 h	PBS 80% vs PBS+DTT 100%
DOX-SS-H[38]	二硫键	25 h	0 mmol/L DTT 0% vs 50 mmol/L DTT 38%
DOX-SS-FOL[39]	二硫键	3 h	PBS 0% vs PBS+GSH 100%
DOX-SS-PTX[40]	二硫键	120 h	PBS 40% vs PBS+GSH 90%

1.3.2 以三硫键为连接臂的多柔比星前药研究发现，在体内抗肿瘤效果方面，三硫键桥接DOX形成的前药自组装纳米粒较二硫键而言具有更好的效果^［41］。Yang等^［34］以3，3′-三硫代二丙酸（3，3′-trithiodipropionic）为连接物，通过氨基将两个DOX分子共轭连接，合成了DOX均二聚体前药DOX-SSS-DOX（DSSSD），体外药物释放实验结果表明，210 h内，DDSSSD前药纳米粒在含有0.1 mmol/L GSH环境下时，释药量为15%左右；在含有0.5 mmol/L GSH环境下时，释药量可达60%；在含有1 mmol/L GSH环境下时，释药量达到了80%。

1.4 酶敏感型多柔比星前药

蛋白酶是人体内用于水解蛋白质的一种重要物质，其中组织蛋白酶B是木瓜蛋白酶类半胱氨酸蛋白酶家族的重要成员，并且在肿瘤部位呈现高表达状态^［42］。组织蛋白酶B可以水解多种氨基酸多肽^［43］。研究人员利用多肽和DOX以及适宜载体制备得到DOX前药。此类前药在正常组织中可以稳定存在，当药物到达肿瘤部位时，肿瘤微环境的组织蛋白酶B可以水解氨基酸连接臂导致DOX在肿瘤部位快速释放，达到杀死肿瘤细胞的目的^［44］。见图4。

图 4 基于酶敏感的 DOX 前药的制备及释药机制

Liu等^［45］通过4-（对碘苯基）丁酸连接子与DOX相连开发了一种新型多柔比星前药IPBA-DOX，该前药能够独立且强烈地与血液中的白蛋白（human serum albumin，HSA）结合。药代动力学研究结果表明，与游离DOX相比，IPBA-DOX的AUC增加了约7倍，且IPBA - DOX的半衰期（17.5 h）比DOX（3.2 h）更长，清除率［3.44L/（h-kg）］比DOX减少至原来的1/7。IPBA - DOX可以在体内高亲和力地与HSA结合，并延长其体循环时间，从而潜在地提高药物的化疗效果。雷帅权^［46］首先通过反应合成了多肽，然后用合成的TPGS3350-COOH连接多肽的氨基，得到了TPGS3350-Pep，最后将其尾端的羧基与DOX的氨基反应得到了DOX前药TPGS3350-Pep-DOX，通过体外药物释放实验发现，该前药胶束在前15 h的释放中，在有基质金属蛋白酶-9（MMP-9）酶存在下累计释放DOX约为29.45%，在没有MMP-9存在条件下，DOX的累计释放量约为17.68%。

2 多重响应性多柔比星前药

鉴于抗肿瘤药物在递送过程中的复杂性以及肿瘤微环境的异质性，在一个纳米递药系统中引入两个甚至多个微环境响应性位点可以将药物的治疗效果最大化^［47］。近年来，许多研究者利用pH/GSH、pH/ROS、pH/酶共同响应制备DOX前药，结果发现与单响应型前药相比，双响应型前药具有双重/多重刺激响应性，因而具有更好的肿瘤靶向性，能够减少药物在正常组织中的非特异性释放，从而降低其毒副作用，在药物释放、抗肿瘤效果等方面展现出更加显著的效果，为DOX的纳米前药制备提供了新的借鉴。见图5。

图 5 多重敏感的 DOX 前药的制备及释药机制

2.1 pH/GSH双响应性多柔比星前药

Zhu等^［48］首先将酰胺化DOX与二硫代二乙酸（-ss-）反应生成中间体DOX-ss，然后将DOX-ss和卷曲霉素（Cm）进一步酰胺化得到靶向前药DOX-ss-Cm，分别在pH为7.4、6.5、5.5以及改变所含GSH量的条件下，对DOX-ss-Cm释药量进行考察，发现在pH为7.4含5 mmol/L GSH时，DOX的释药量不足40%，但在pH为5.5含5 mmol/L GSH时，DOX的释药量接近70%，验证了该DOX前药具有pH敏感性。此外，研究人员通过改变释药环境中的GSH含量发现，当pH稳定在5.5时，含有5 mmol/L GSH时释药量在70%左右，含有10 mmol/L GSH时释药量在80%左右，进一步表明，该DOX-ss-Cm也具有良好的GSH响应性。见表5。

表5 pH/GSH敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
NTZ-DCMMs[49]	二硫键	24h	pH7.4 7.2% vs pH7.4+10 mmol/L GSH 63.4%
BP(DM-D)(PP)n-DOX[50]	亚氨键、二硫键	50h	pH7.4 0% vs pH5.0 45% vs pH5.0+10 mmol/L GSH 55%
DOX-S-DHA@TEPP-46 Lips[51]	单硫键	72h	pH7.4 30% vs pH7.4+1 mmol/L GSH 58% vs pH7.4+10 mmol/L GSH 75%

2.2 pH/ROS双响应性多柔比星前药

Hu等^［52］通过α-酰胺化反应将两个DOX分子与二硒代二乙酸（DSeDAA）分子偶联，设计得到一种二硒键桥联的pH/ROS双响应性多柔比星二聚体前药D-DOXSeSe，药物释放实验结果表明，在pH 5.0+0.1 mmol/L H₂O₂或pH 5.0+0.5 mmol/L H₂O₂条件下，D-DOXSeSe 48 h内没有明显药物释放，96 h药物释放量仍较低，在pH 5.0+10 mmol/L H₂O₂条件下，96 h后药物释放量达32%。Wang等^［53］通过将ROS产生剂β-拉帕醌（Lap）与DOX前药（BDOX）包载于pH敏感的纳米胶束中，开发了一种pH、ROS双响应性前药PPHI@B/L，为了考察该前药的pH敏感性，分别在pH为7.4、6.8、4.5条件下进行释放实验，结果表明，在pH为7.4时Lap和BDOX的释放率最低，在pH为6.8时释放速率略有增加，在pH为4.5时，药物释放急剧增加，48 h内BDOX和Lap的释放率分别达到81.3%和90.9%。同时为了考察PPHI@B/L对ROS的敏感性，在不同H₂O₂浓度下对BDOX的转化率进行了考察，结果显示，在100 μmol/L H₂O₂条件下，超过99%的BDOX在4 h得到转化，当H₂O₂浓度达到1 mmol/L时，BDOX在0.5 h左右完全转化为DOX，但当H₂O₂浓度为1 μmol/L时，BDOX转化率仅为7.73%，而在没有H₂O₂存在条件下，几乎没有BDOX转化。见表6。

表6 pH/ROS敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
SPP-DOX/Ce6[54]	酰胺键、硫酮缩醛键	72 h	pH7.4+NIR 71.4% vs pH6.5+NIR 75%
DPQ-DOX NPs[55]	酚硼酸酯键	72 h	pH7.4 20% vs pH6.5 37% vs pH7.4+1 mmol/L H2O2 80% vs pH6.5+1 m mol/L H2O2 95%
DT-NP[56]	苯基硼酸酯键、3,3- 二甲基丁酸丙酯键	24 h	pH7.4 7% vs pH6.8 30% vs pH 5.0 48% 0 mmol/L H2O2 6% vs 100 μmol/L H2O2 15% vs 10 mmol/L H2O2 45%

2.3 pH/酶双响应性多柔比星前药

Ren等^［57］通过合成的两亲性化合物HA-Ce6偶连DOX形成了pH、酶双响应性DOX前药HA-Ce6（DOX），体外药物释放实验结果表明，该DOX前药在pH为7.4条件下时，12 h内DOX的释放量不足30%；但当该DOX前药在pH为5.4条件下时，12 h内DOX的释放量为40%；不仅如此，当该前药胶束在pH为7.4且含有透明质酸酶的条件下时，DOX的释放量为38%左右；当前药胶束在pH为5.4且透明质酸酶同时存在时，DOX的释放量可达60%。见表7。

表7 pH/酶敏感DOX前药及其体外释放特征

前药名称	敏感键	考察时间	考察指标
CDs-C9-AANL-DOX[58]	咪唑基团、肽键	24 h	pH7.4 2% vs pH5.0 2.5% vs pH5.0+蛋白酶 17%
pOEGMA-DOX[59]	腙键、肽键	60 h	pH7.4 9% vs pH7.4 +蛋白酶 22% vs pH5.4 70% vs pH5.4 +蛋白酶 75%
CLM[60]	腙键、肽键	48 h	pH7.4 7% vs pH7.4 +蛋白酶 10% vs pH5.4 36 h 100% vs pH5.4 +蛋白酶 24 h 100%

3 研究限制及解决措施

尽管肿瘤微环境响应型DOX前药在设计方面取得了重大进展，且大量体内外试验均证实此类前药具有巨大的优势，但距离其真正走入临床还需克服诸多障碍和困难^［61］。肿瘤的异质性和微环境的复杂性导致前药的激活和药物释放效率难以预测和控制；前药在体内的生物利用度可能受限，影响其疗效；血液循环中，前药可能因物理化学稳定性不足而提前释放药物导致疗效降低和潜在的不良反应；一些前药载体可能引起患者的免疫反应，或在非靶组织中蓄积导致毒性；纳米药物的规模化生产和质量控制具有挑战性，需要精确的物理化学表征和质量保证等^［62-63］，以上因素共同作用，增加了肿瘤微环境响应型DOX前药从实验室走入临床应用的挑战和难度。此外，临床转化的实际困难还涉及临床试验的低成功率、患者筛选不足导致治疗效果因人而异以及缺乏明确的指导原则和标准等^［64］。

为克服以上挑战，可采取的解决措施包括优化药物设计以提高DOX前药的稳定性和靶向性、开发出新的生物标记物以预测药物的分布和疗效、改进药物载体以提高包载效率和肿瘤靶向性、实施个性化医疗策略、加强临床试验设计、提高生产质量、促进跨学科合作以及与监管机构合作完善监管框架等^［63-65］。这些综合性措施旨在进一步提高DOX前药的临床转化率，以确保其在肿瘤治疗中的安全性和有效性。

4 总结与展望

本文探讨了在肿瘤微环境特异性的生理状态下针对不同微环境所设计的多柔比星前药的粒径及药物释放变化。无论是小分子类前药还是聚合物前药，DOX的释放和纳米前药的粒径均有所变化，并且在体内外实验中展现出优于原药的活性以及更低的毒副作用^［66］。但是现阶段距离临床应用仍存在一定距离，相信随着研究的不断深入和技术的持续革新，研究者们将开发出更为智能、高效和先进的纳米递药系统^［67］。期待这些纳米递药系统早日进入临床应用，为癌症患者提供更安全、更有效的治疗方案。

1、%E2%80%83%20CHEN%E2%80%83X%EF%BC%8CCUBILLOS-RUIZ%E2%80%83J%E2%80%83R%EF%BC%8EEndoplasmic%E2%80%83%0Areticulum%E2%80%83%20st%20ress%E2%80%83%20signals%E2%80%83%20in%E2%80%83%20the%E2%80%83%20tumou%20r%E2%80%83%20and%E2%80%83%20its%E2%80%83%0Amicroenvironment%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENat%E2%80%83Rev%E2%80%83Cancer%EF%BC%8C2021%EF%BC%8C21%0A%EF%BC%882%EF%BC%89%EF%BC%9A71-88%EF%BC%8E

2、LI%E2%80%83C%EF%BC%8CPENET%E2%80%83M%E2%80%83F%EF%BC%8CWINNARD%E2%80%83P%E2%80%83Jr%EF%BC%8Cet%E2%80%83al%EF%BC%8EImage-guided%E2%80%83enzyme%2Fprodrug%E2%80%83cancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EClin%E2%80%83%0ACancer%E2%80%83Res%EF%BC%8C2008%EF%BC%8C14%EF%BC%882%EF%BC%89%EF%BC%9A515-522%EF%BC%8E

3、张赟，王小凡．肿瘤微环境调控癌症发生发展的研究概述［J］．中国科学：生命科学，2022，52（9）：1377-1390．

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5、ZHENG%E2%80%83K%EF%BC%8CLI%E2%80%83R%EF%BC%8CZHOU%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EDual%E2%80%83actions%E2%80%83of%E2%80%83%0Aalbumin%E2%80%83%20packaging%E2%80%83and%E2%80%83tumor%E2%80%83targeting%E2%80%83enhance%E2%80%83the%E2%80%83%0Aantitumor%E2%80%83%20efficacy%E2%80%83%20and%E2%80%83%20reduce%E2%80%83the%E2%80%83%20cardiotoxicity%E2%80%83%20of%E2%80%83%0Adoxorubicin%E2%80%83in%E2%80%83vivo%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Nanomedicine%EF%BC%8C2015%0A%EF%BC%8810%EF%BC%89%EF%BC%9A5327-5342%EF%BC%8E

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8、XIONG%E2%80%83S%E2%80%83J%EF%BC%8CWANG%E2%80%83Z%EF%BC%8CLIU%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83pH-sensitive%E2%80%83%0Aprodrug%E2%80%83strategy%E2%80%83to%E2%80%83co-deliver%E2%80%83DOX%E2%80%83and%E2%80%83TOS%E2%80%83in%E2%80%83TPGS%E2%80%83%0Ananomicelles%E2%80%83for%E2%80%83tumor%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EColloids%E2%80%83Surf%E2%80%83B%E2%80%83%0ABiointerfaces%EF%BC%8C2019%EF%BC%88173%EF%BC%89%EF%BC%9A346-355%EF%BC%8E

9、KALVA%E2%80%83N%EF%BC%8CUTHAMAN%E2%80%83S%EF%BC%8CAUGUSTINE%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0APhoto-%E2%80%83%20and%E2%80%83%20pH-responsive%E2%80%83%20polycarbonate%E2%80%83%20block%E2%80%83%0Acopolymer%E2%80%83prodrug%E2%80%83nanomicelles%E2%80%83for%E2%80%83controlled%E2%80%83%20release%E2%80%83%0Aof%E2%80%83doxorubicin%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMacromol%E2%80%83Biosci%EF%BC%8C2020%EF%BC%8C20%0A%EF%BC%888%EF%BC%89%EF%BC%9Ae2000118%EF%BC%8E

10、MA%E2%80%83B%EF%BC%8CZHANG%E2%80%83W%EF%BC%8CWANG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EpH-sensitive%E2%80%83%0Adoxorubicin-conjugated%E2%80%83prodrug%E2%80%83micelles%E2%80%83with%E2%80%83charge-conversion%E2%80%83for%E2%80%83cancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Biomater%EF%BC%8C%0A2018%EF%BC%8870%EF%BC%89%EF%BC%9A186-196%EF%BC%8E

11、ZHAO%E2%80%83D%E2%80%83P%EF%BC%8CLIU%E2%80%83N%EF%BC%8CSHI%E2%80%83K%E2%80%83M%EF%BC%8Cet%E2%80%83al%EF%BC%8EPreparation%E2%80%83%0Aof%E2%80%83%20a%E2%80%83multifunctional%E2%80%83%20verapamil-loaded%E2%80%83%20nano-carrier%E2%80%83%0Abased%E2%80%83on%E2%80%83a%E2%80%83self-assembling%E2%80%83PEGylated%E2%80%83prodrug%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AColloids%E2%80%83Surf%E2%80%83B%E2%80%83Biointerfaces%EF%BC%8C2015%EF%BC%88135%EF%BC%89%EF%BC%9A682-%0A688%EF%BC%8E

12、ZHANG%E2%80%83L%E2%80%83X%EF%BC%8CHUANG%E2%80%83J%E2%80%83X%EF%BC%8CBURATTO%E2%80%83D%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83%0ApH-responsive%E2%80%83nanoparticle%E2%80%83delivery%E2%80%83system%E2%80%83containing%E2%80%83%0Adihydralazine%E2%80%83%20and%E2%80%83%20doxorubicin-based%E2%80%83%20prodrug%E2%80%83for%E2%80%83%0Aenhancing%E2%80%83antitumor%E2%80%83efficacy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAggregate%EF%BC%8C%0A2024%EF%BC%8C5%EF%BC%881%EF%BC%89%EF%BC%9Ae434%EF%BC%8E

13、YAO%E2%80%83D%E2%80%83F%EF%BC%8CWANG%E2%80%83Y%E2%80%83S%EF%BC%8CBIAN%E2%80%83K%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83self-cascaded%E2%80%83%20unimolecular%E2%80%83%20prodrug%E2%80%83for%E2%80%83%20pH-responsive%E2%80%83chemotherapy%E2%80%83and%E2%80%83tumor-detained%E2%80%83photodynamic-immunotherapy%E2%80%83of%E2%80%83triple-negative%E2%80%83breast%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ABiomaterials%EF%BC%8C2023%EF%BC%88292%EF%BC%89%EF%BC%9A121920%EF%BC%8E

14、%E2%80%83%20ZHOU%E2%80%83N%EF%BC%8CZHANG%E2%80%83N%EF%BC%8CZHI%E2%80%83Z%EF%BC%8Cet%E2%80%83al%EF%BC%8EOne-pot%E2%80%83%0Asynthesis%E2%80%83of%E2%80%83acid-degradable%E2%80%83polyphosphazene%E2%80%83prodrugs%E2%80%83%0Afor%E2%80%83efficient%E2%80%83tumor%E2%80%83chemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Mater%E2%80%83Chem%E2%80%83%0AB%EF%BC%8C2020%EF%BC%8C8%EF%BC%8846%EF%BC%89%EF%BC%9A10540-10548%EF%BC%8E

15、%E2%80%83%20ZHANG%E2%80%83X%EF%BC%8CZHANG%E2%80%83T%EF%BC%8CMA%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EThe%E2%80%83%20design%E2%80%83%0Aand%E2%80%83%20synthesis%E2%80%83of%E2%80%83%20dextran-doxorubicin%E2%80%83%20prodrug-based%E2%80%83%0ApH-sensitive%E2%80%83%20drug%E2%80%83%20delivery%E2%80%83%20system%E2%80%83for%E2%80%83improving%E2%80%83%0Achemotherapy%E2%80%83efficacy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAsian%E2%80%83J%E2%80%83Pharm%E2%80%83Sci%EF%BC%8C%0A2020%EF%BC%8C15%EF%BC%885%EF%BC%89%EF%BC%9A605-616%EF%BC%8E

16、LIAO%E2%80%83J%E2%80%83H%EF%BC%8CPENG%E2%80%83H%E2%80%83S%EF%BC%8CLIU%E2%80%83C%EF%BC%8Cet%E2%80%83al%EF%BC%8EDual%E2%80%83pH%02responsive-charge-reversal%E2%80%83%20micelle%E2%80%83%20platform%E2%80%83%20for%E2%80%83%0Aenhanced%E2%80%83anticancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMater%E2%80%83Sci%E2%80%83Eng%E2%80%83C%E2%80%83%0AMater%E2%80%83Biol%E2%80%83Appl%EF%BC%8C2021%EF%BC%88118%EF%BC%89%EF%BC%9A111527%EF%BC%8E

17、HU%E2%80%83H%EF%BC%8CSTEINMETZ%E2%80%83N%E2%80%83F%EF%BC%8EDoxorubicin-loaded%E2%80%83%0Aphysalis%E2%80%83mottle%E2%80%83virus%E2%80%83particles%E2%80%83function%E2%80%83as%E2%80%83a%E2%80%83pH%02responsive%E2%80%83prodrug%E2%80%83enabling%E2%80%83cancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ABiotechnol%E2%80%83J%EF%BC%8C2020%EF%BC%8C15%EF%BC%8812%EF%BC%89%EF%BC%9Ae2000077%EF%BC%8E

18、LAGES%E2%80%83E%E2%80%83B%EF%BC%8CFERNANDES%E2%80%83R%E2%80%83S%EF%BC%8CANDRADE%E2%80%83%20M%E2%80%83%0AM%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8EpH-sensitive%E2%80%83%20doxorubicin-tocopherol%E2%80%83%0Asuccinate%E2%80%83%20prodrug%E2%80%83%20encapsulated%E2%80%83in%E2%80%83%20docosahexaenoic%E2%80%83%0Aacid-based%E2%80%83nanostructured%E2%80%83lipid%E2%80%83carriers%EF%BC%9AAn%E2%80%83effective%E2%80%83%0Astrategy%E2%80%83to%E2%80%83improve%E2%80%83pharmacokinetics%E2%80%83and%E2%80%83%20reduce%E2%80%83toxic%E2%80%83%0Aeffects%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBiomedecine%E2%80%83Pharmacother%EF%BC%8C2021%0A%EF%BC%88144%EF%BC%89%EF%BC%9A112373%EF%BC%8E

19、LI%E2%80%83J%E2%80%83G%EF%BC%8CLI%E2%80%83X%E2%80%83M%EF%BC%8CPEI%E2%80%83M%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8EAcid-labile%E2%80%83%0Aanhydride-linked%E2%80%83%20doxorubicin-doxorubicin%E2%80%83%20dimer%E2%80%83%0Ananoparticles%E2%80%83%20as%E2%80%83%20drug%E2%80%83%20self-delivery%E2%80%83%20system%E2%80%83%20with%E2%80%83%0Aminimized%E2%80%83premature%E2%80%83drug%E2%80%83leakage%E2%80%83and%E2%80%83enhanced%E2%80%83anti%02tumor%E2%80%83efficacy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EColloids%E2%80%83Surf%E2%80%83B%E2%80%83Biointerfaces%EF%BC%8C%0A2020%EF%BC%88192%EF%BC%89%EF%BC%9A111064%EF%BC%8E

20、%E2%80%83%20MA%E2%80%83Y%EF%BC%8CFAN%E2%80%83X%EF%BC%8CLI%E2%80%83L%EF%BC%8EpH-sensitive%E2%80%83%20polymeric%E2%80%83%0Amicelles%E2%80%83formed%E2%80%83%20by%E2%80%83%20doxorubicin%E2%80%83conjugated%E2%80%83%20prodrugs%E2%80%83%0Afor%E2%80%83co-delivery%E2%80%83of%E2%80%83doxorubicin%E2%80%83and%E2%80%83paclitaxel%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ACarbohydr%E2%80%83Polym%EF%BC%8C2016%EF%BC%88137%EF%BC%89%EF%BC%9A19-29%EF%BC%8E

21、%E2%80%83%20CALDER%C3%93N-GARCIDUEN%20AS%E2%80%83L%EF%BC%8CREYNOSO%02ROBLES%E2%80%83R%EF%BC%8CGONZ%C3%81LEZ-MACIEL%E2%80%83A%EF%BC%8ECombustion%E2%80%83%0Aand%E2%80%83friction-derived%E2%80%83nanoparticles%E2%80%83and%E2%80%83industrial%02sourced%E2%80%83nanoparticles%EF%BC%9AThe%E2%80%83culprit%E2%80%83of%E2%80%83Alzheimer%E2%80%83and%E2%80%83%0AParkinson%E2%80%99s%E2%80%83diseases%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEnviron%E2%80%83Res%EF%BC%8C2019%0A%EF%BC%88176%EF%BC%89%EF%BC%9A108574%EF%BC%8E

22、BUSH%E2%80%83A%E2%80%83I%EF%BC%8EThe%E2%80%83metallobiology%E2%80%83of%E2%80%83Alzheimer%E2%80%99s%E2%80%83disease%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8ETrends%E2%80%83Neurosci%EF%BC%8C2003%EF%BC%8C26%EF%BC%884%EF%BC%89%EF%BC%9A207-214%EF%BC%8E

23、WANG%E2%80%83M%E2%80%83L%EF%BC%8CZHAI%E2%80%83Y%E2%80%83L%EF%BC%8CYE%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8EHigh%E2%80%83co%02loading%E2%80%83capacity%E2%80%83and%E2%80%83stimuli-responsive%E2%80%83%20release%E2%80%83based%E2%80%83%0Aon%E2%80%83%20cascade%E2%80%83%20reaction%E2%80%83%20of%E2%80%83%20self-destructive%E2%80%83%20polymer%E2%80%83for%E2%80%83%0Aimproved%E2%80%83chemo-photodynamic%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EACS%E2%80%83%0ANano%EF%BC%8C2019%EF%BC%8C13%EF%BC%886%EF%BC%89%EF%BC%9A7010-7023%EF%BC%8E

24、PAN%E2%80%83Q%E2%80%83Q%EF%BC%8CDENG%E2%80%83X%EF%BC%8CGAO%E2%80%83W%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EROS%E2%80%83%0Atriggered%E2%80%83%20cleavage%E2%80%83%20of%E2%80%83thioketal%E2%80%83moiety%E2%80%83to%E2%80%83%20dissociate%E2%80%83%0Aprodrug%E2%80%83nanoparticles%E2%80%83for%E2%80%83chemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EColloids%E2%80%83%0ASurf%E2%80%83B%E2%80%83Biointerfaces%EF%BC%8C2020%EF%BC%88194%EF%BC%89%EF%BC%9A111223%EF%BC%8E

25、XU%E2%80%83C%E2%80%83D%EF%BC%8CXU%E2%80%83L%EF%BC%8CHAN%E2%80%83R%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8EBlood%E2%80%83circulation%E2%80%83%0Astable%E2%80%83%20doxorubicin%E2%80%83%20prodrug%E2%80%83%20nanoparticles%E2%80%83containing%E2%80%83%0Ahydrazone%E2%80%83%20and%E2%80%83%20thioketal%E2%80%83%20moieties%E2%80%83%20for%E2%80%83%20antitumor%E2%80%83%0Achemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EColloids%E2%80%83Surf%E2%80%83B%E2%80%83Biointerfaces%EF%BC%8C%0A2021%EF%BC%88201%EF%BC%89%EF%BC%9A111632%EF%BC%8E

26、KIM%E2%80%83Y%EF%BC%8CUTHAMAN%E2%80%83S%EF%BC%8CPILLARISETTI%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ABioactivatable%E2%80%83%20reactive%E2%80%83%20oxygen%E2%80%83%20species-sensitive%E2%80%83%0Ananoparticulate%E2%80%83%20system%E2%80%83%20for%E2%80%83%20chemo-photodynamic%E2%80%83%0Atherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Biomater%EF%BC%8C2020%EF%BC%88108%EF%BC%89%EF%BC%9A273-%0A284%EF%BC%8E

27、ZUO%E2%80%83W%E2%80%83B%EF%BC%8CCHEN%E2%80%83D%E2%80%83Y%EF%BC%8CFAN%E2%80%83Z%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EDesign%E2%80%83%0Aof%E2%80%83light%2FROS%E2%80%83cascade-responsive%E2%80%83tumor-recognizing%E2%80%83%0Ananotheranostics%E2%80%83for%E2%80%83%20spatiotemporally%E2%80%83controlled%E2%80%83drug%E2%80%83%0Arelease%E2%80%83in%E2%80%83locoregional%E2%80%83photo-chemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AActa%E2%80%83Biomater%EF%BC%8C2020%EF%BC%88111%EF%BC%89%EF%BC%9A327-340%EF%BC%8E

28、TONG%E2%80%83F%EF%BC%8CYE%E2%80%83Y%E2%80%83C%EF%BC%8CCHEN%E2%80%83B%EF%BC%8Cet%E2%80%83al%EF%BC%8EBone%02targeting%E2%80%83prodrug%E2%80%83mesoporous%E2%80%83silica-based%E2%80%83nanoreactor%E2%80%83%0Awith%E2%80%83%20reactive%E2%80%83%20oxygen%E2%80%83%20species%E2%80%83%20burst%E2%80%83%20for%E2%80%83%20enhanced%E2%80%83%0Achemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EACS%E2%80%83Appl%E2%80%83Mater%E2%80%83Interfaces%EF%BC%8C%0A2020%EF%BC%8C12%EF%BC%8831%EF%BC%89%EF%BC%9A34630-34642%EF%BC%8E

29、JIN%E2%80%83F%EF%BC%8CQI%E2%80%83J%EF%BC%8CLIU%E2%80%83D%EF%BC%8Cet%E2%80%83al%EF%BC%8ECancer-cell%02biomimetic%E2%80%83%20upconversion%E2%80%83%20nanoparticles%E2%80%83%20combining%E2%80%83%0Achemo-photodynamic%E2%80%83therapy%E2%80%83%20and%E2%80%83%20CD73%E2%80%83%20blockade%E2%80%83%0Afor%E2%80%83metastatic%E2%80%83triple-negative%E2%80%83breast%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83%0AControl%E2%80%83Release%EF%BC%8C2021%EF%BC%88337%EF%BC%89%EF%BC%9A90-104%EF%BC%8E

30、LI%E2%80%83Q%E2%80%83Y%EF%BC%8CHOU%E2%80%83W%EF%BC%8CLI%E2%80%83M%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EUltrasound%E2%80%83%0Acombined%E2%80%83%20with%E2%80%83%20core%E2%80%83%20cross-linked%E2%80%83%20nanosystem%E2%80%83%20for%E2%80%83%0Aenhancing%E2%80%83penetration%E2%80%83of%E2%80%83doxorubicin%E2%80%83prodrug%2Fbeta-lapachone%E2%80%83into%E2%80%83tumors%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Nanomedicine%EF%BC%8C%0A2020%EF%BC%8815%EF%BC%89%EF%BC%9A4825-4845%EF%BC%8E

31、SMEYNE%E2%80%83M%EF%BC%8CSMEYNE%E2%80%83R%E2%80%83J%EF%BC%8EGlutathione%E2%80%83metabolism%E2%80%83%0Aand%E2%80%83Parkinson%E2%80%99s%E2%80%83disease%EF%BC%BBJ%EF%BC%BD%EF%BC%8EFree%E2%80%83Radic%E2%80%83Biol%E2%80%83Med%EF%BC%8C%0A2013%EF%BC%8862%EF%BC%89%EF%BC%9A13-25%EF%BC%8E

32、VANPOUILLE%E2%80%83C%EF%BC%8CJEUNE%E2%80%83N%E2%80%83L%EF%BC%8CKRYZA%E2%80%83D%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AInfluence%E2%80%83of%E2%80%83multidrug%E2%80%83resistance%E2%80%83on%EF%BC%8818%EF%BC%89F-FCH%E2%80%83%0Acellular%E2%80%83uptake%E2%80%83in%E2%80%83a%E2%80%83glioblastoma%E2%80%83model%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEur%E2%80%83J%E2%80%83Nucl%E2%80%83Med%E2%80%83Mol%E2%80%83Imaging%EF%BC%8C2009%EF%BC%8C36%EF%BC%888%EF%BC%89%EF%BC%9A1256-1264%EF%BC%8E

33、%E2%80%83%20CHENG%E2%80%83Y%EF%BC%8CJI%E2%80%83Y%E2%80%83H%EF%BC%8CTONG%E2%80%83J%E2%80%83W%EF%BC%8ETriple%E2%80%83stimuli-responsive%E2%80%83%20sup%20ramolecula%20r%E2%80%83%20nanoassembly%E2%80%83%20with%E2%80%83%0Amitochondrial%E2%80%83targetability%E2%80%83for%E2%80%83%20chemophotothermal%E2%80%83%0Atherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Control%E2%80%83Release%EF%BC%8C2020%EF%BC%88327%EF%BC%89%EF%BC%9A%0A35-49%EF%BC%8E

34、YANG%E2%80%83Y%E2%80%83X%EF%BC%8CSUN%E2%80%83B%E2%80%83J%EF%BC%8CZUO%E2%80%83S%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ETrisulfide%E2%80%83%0Abo%20n%20d-me%20diate%20d%E2%80%83%20doxo%20r%20u%20bici%20n%E2%80%83%20dime%20ric%E2%80%83%20p%20ro%20d%20r%20ug%E2%80%83%0Ananoassemblies%E2%80%83with%E2%80%83high%E2%80%83drug%E2%80%83loading%EF%BC%8Chigh%E2%80%83self%02assembly%E2%80%83stability%EF%BC%8Cand%E2%80%83high%E2%80%83tumor%E2%80%83selectivity%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ASci%E2%80%83Adv%EF%BC%8C2020%EF%BC%8C6%EF%BC%8845%EF%BC%89%EF%BC%9Aeabc1725%EF%BC%8E

35、宫宇，周春娜，许琛．还原响应型阿霉素前药胶束的制备及其抑制肺癌A549和乳腺癌MCF-7细胞增殖研究［J］．中国新药杂志，2018，27（23）：2825-2832．

36、MA%E2%80%83N%E2%80%83X%EF%BC%8CSONG%E2%80%83A%E2%80%83X%EF%BC%8CLI%E2%80%83Z%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8ERedox-sensitive%E2%80%83prodrug%E2%80%83molecules%E2%80%83meet%E2%80%83graphene%E2%80%83oxide%EF%BC%9A%0AAn%E2%80%83efficient%E2%80%83graphene%E2%80%83oxide-based%E2%80%83nanovehicle%E2%80%83toward%E2%80%83%0Acancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EACS%E2%80%83Biomater%E2%80%83Sci%E2%80%83Eng%EF%BC%8C2019%EF%BC%8C%0A5%EF%BC%883%EF%BC%89%EF%BC%9A1384-1391%EF%BC%8E

37、HUANG%E2%80%83C%E2%80%83Z%EF%BC%8CWU%E2%80%83J%E2%80%83L%EF%BC%8CJIANG%E2%80%83W%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AAmphiphilic%E2%80%83%20prodrug-decorated%E2%80%83%20graphene%E2%80%83%20oxide%E2%80%83%20as%E2%80%83%0Aa%E2%80%83multi-functional%E2%80%83%20drug%E2%80%83%20delivery%E2%80%83%20system%E2%80%83for%E2%80%83efficient%E2%80%83%0Acancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMater%E2%80%83%20Sci%E2%80%83Eng%E2%80%83C%E2%80%83Mater%E2%80%83Biol%E2%80%83%0AAppl%EF%BC%8C2018%EF%BC%8889%EF%BC%89%EF%BC%9A15-24%EF%BC%8E

38、SONG%E2%80%83Q%EF%BC%8CWANG%E2%80%83X%EF%BC%8CWANG%E2%80%83Y%E2%80%83Q%EF%BC%8Cet%E2%80%83al%EF%BC%8EReduction%E2%80%83%0Aresponsive%E2%80%83%20self-assembled%E2%80%83%20nanoparticles%E2%80%83%20based%E2%80%83%20on%E2%80%83%0Adisulfide-linked%E2%80%83drug-drug%E2%80%83conjugate%E2%80%83with%E2%80%83high%E2%80%83drug%E2%80%83%0Aloading%E2%80%83and%E2%80%83antitumor%E2%80%83efficacy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMol%E2%80%83Pharm%EF%BC%8C%0A2016%EF%BC%8C13%EF%BC%881%EF%BC%89%EF%BC%9A190-201%EF%BC%8E

39、SANTRA%E2%80%83S%EF%BC%8CKAITTANIS%E2%80%83C%EF%BC%8CSANTIESTEBAN%E2%80%83O%E2%80%83J%EF%BC%8C%0Aet%E2%80%83al%EF%BC%8ECell-specific%EF%BC%8Cactivatable%EF%BC%8Cand%E2%80%83theranostic%E2%80%83%0Aprodrug%E2%80%83for%E2%80%83dual-targeted%E2%80%83cancer%E2%80%83imaging%E2%80%83and%E2%80%83therapy%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Am%E2%80%83Chem%E2%80%83Soc%EF%BC%8C2011%EF%BC%8C133%EF%BC%8841%EF%BC%89%EF%BC%9A16680-%0A16688%EF%BC%8E

40、%E2%80%83%20MA%E2%80%83X%E2%80%83D%EF%BC%8C%C3%96ZLISELI%E2%80%83E%EF%BC%8CZHANG%E2%80%83Y%E2%80%83Z%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AFabrication%E2%80%83%20of%E2%80%83%20redox-responsive%E2%80%83%20doxorubicin%E2%80%83%20and%E2%80%83%0Apaclitaxel%E2%80%83prodrug%E2%80%83nanoparticles%E2%80%83with%E2%80%83microfluidics%E2%80%83for%E2%80%83%0Aselective%E2%80%83cancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBiomater%E2%80%83Sci%EF%BC%8C2019%EF%BC%8C%0A7%EF%BC%882%EF%BC%89%EF%BC%9A634-644%EF%BC%8E

41、陈瑶，张洪源，刘雨婷，等．肿瘤氧化还原微环境智能响应型前药纳米组装体的研究进展［J］．药学进展，2021，45（5）：337-348．

42、YANG%E2%80%83Y%E2%80%83X%EF%BC%8CSUN%E2%80%83B%E2%80%83J%EF%BC%8CZUO%E2%80%83S%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ETrisulfide%E2%80%83%0Abo%20n%20d-me%20diate%20d%E2%80%83%20doxorubici%20n%E2%80%83%20dimeric%E2%80%83%20prodrug%E2%80%83nanoassemblies%E2%80%83with%E2%80%83high%E2%80%83drug%E2%80%83loading%EF%BC%8Chigh%E2%80%83self-assembly%E2%80%83stability%EF%BC%8Cand%E2%80%83high%E2%80%83tumor%E2%80%83selectivity%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ASci%E2%80%83Adv%EF%BC%8C2020%EF%BC%8C6%EF%BC%8845%EF%BC%89%EF%BC%9Aeabc1725%EF%BC%8E

43、HE%E2%80%83F%EF%BC%8CCAO%E2%80%83L%EF%BC%8CZHANG%E2%80%83X%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8EThe%E2%80%83application%E2%80%83%0Aof%E2%80%83%20enzyme-sensitive%E2%80%83%20activatable%E2%80%83%20cell-penetrating%E2%80%83%0Apeptides%E2%80%83to%E2%80%83targeted%E2%80%83delivery%E2%80%83system%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Pharm%E2%80%83%0ASin%EF%BC%8C2015%EF%BC%8C50%EF%BC%882%EF%BC%89%EF%BC%9A141-147%EF%BC%8E

44、王相宜，张锦，李燕，等．肿瘤代谢调控与肿瘤免疫治疗以及代谢分析方法研究进展［J］．药学学报，2020，55（9）：2080-2091．

45、LIU%E2%80%83Y%EF%BC%8CCORRALES-GUERRERO%E2%80%83S%EF%BC%8CKUO%E2%80%83J%E2%80%83C%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AImproved%E2%80%83targeting%E2%80%83and%E2%80%83safety%E2%80%83of%E2%80%83doxorubicin%E2%80%83through%E2%80%83a%E2%80%83%0Anovel%E2%80%83albumin%E2%80%83binding%E2%80%83prodrug%E2%80%83approach%EF%BC%BBJ%EF%BC%BD%EF%BC%8EACS%E2%80%83%0AOmega%EF%BC%8C2024%EF%BC%8C9%EF%BC%881%EF%BC%89%EF%BC%9A977-987%EF%BC%8E

46、雷帅权．对肿瘤微环境响应的抗癌纳米药物的研究［D］．天津：天津工业大学，2019．

47、杨雨琦，巩飞，柏上，等．肿瘤微环境响应型纳米诊疗制剂的研究进展［J］．药学学报，2021，56（2）：465-475．

48、ZHU%E2%80%83Q%EF%BC%8CFAN%E2%80%83Z%EF%BC%8CZUO%E2%80%83W%EF%BC%8Cet%E2%80%83al%EF%BC%8ESelf-distinguishing%E2%80%83%0Aand%E2%80%83%20stimulus-responsive%E2%80%83%20carrier-free%E2%80%83theranostic%E2%80%83%0Ananoagents%E2%80%83for%E2%80%83imaging-guided%E2%80%83chemo-photothermal%E2%80%83%0Atherapy%E2%80%83in%E2%80%83small-cell%E2%80%83lung%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EACS%E2%80%83Appl%E2%80%83%0AMater%E2%80%83Interfaces%EF%BC%8C2020%EF%BC%8C12%EF%BC%8846%EF%BC%89%EF%BC%9A51314-51328%EF%BC%8E

49、YU%E2%80%83L%EF%BC%8CZHANG%E2%80%83M%EF%BC%8CHE%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83%20nanomedicine%E2%80%83%0Acomposed%E2%80%83%20of%E2%80%83%20polymer-ss-DOX%E2%80%83%20and%E2%80%83%20polymer-Ce6%E2%80%83%0Aprodrugs%E2%80%83with%E2%80%83monoclonal%E2%80%83antibody%E2%80%83targeting%E2%80%83effect%E2%80%83for%E2%80%83%0Aanti-tumor%E2%80%83chemo-photodynamic%E2%80%83synergetic%E2%80%83therapy%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Biomater%EF%BC%8C2024%EF%BC%88179%EF%BC%89%EF%BC%9A272-283%EF%BC%8E

50、LIAO%E2%80%83J%E2%80%83H%EF%BC%8CPENG%E2%80%83H%E2%80%83S%EF%BC%8CWEI%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83bio%02responsive%E2%80%83%206-mercaptopurine%2Fdoxorubicin%E2%80%83%20based%E2%80%83%0A%E2%80%9CClick%E2%80%83Chemistry%E2%80%9D%E2%80%83%20polymeric%E2%80%83%20prodrug%E2%80%83for%E2%80%83%20cancer%E2%80%83%0Atherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMater%E2%80%83Sci%E2%80%83Eng%E2%80%83C%E2%80%83Mater%E2%80%83Biol%E2%80%83Appl%EF%BC%8C%0A2020%EF%BC%88108%EF%BC%89%EF%BC%9A110461%EF%BC%8E

51、JIN%E2%80%83Q%E2%80%83Y%EF%BC%8CZHOU%E2%80%83X%E2%80%83H%EF%BC%8CNIU%E2%80%83X%E2%80%83M%EF%BC%8Cet%E2%80%83al%EF%BC%8ECo-delivery%E2%80%83%0Aof%E2%80%83%20doxorubicin-dihydroartemisinin%E2%80%83%20prodrug%2FTEPP-46%E2%80%83%0Anano-liposomes%E2%80%83for%E2%80%83improving%E2%80%83antitumor%E2%80%83and%E2%80%83decreasing%E2%80%83%0Acardiotoxicity%E2%80%83in%E2%80%83B16-F10%E2%80%83tumor-bearing%E2%80%83mice%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AColloids%E2%80%83Surf%E2%80%83B%E2%80%83Biointerfaces%EF%BC%8C2024%EF%BC%88241%EF%BC%89%EF%BC%9A113992%EF%BC%8E

52、HU%E2%80%83Y%E2%80%83R%EF%BC%8CLIU%E2%80%83P%EF%BC%8EDiselenide-bridged%E2%80%83%20doxorubicin%E2%80%83%0Adimeric%E2%80%83prodrug%EF%BC%9Asynthesis%E2%80%83and%E2%80%83%20redox-triggered%E2%80%83drug%E2%80%83%0Arelease%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMolecules%EF%BC%8C2024%EF%BC%8C29%EF%BC%888%EF%BC%89%EF%BC%9A1709%EF%BC%8E

53、WANG%E2%80%83J%EF%BC%8CZHANG%E2%80%83H%E2%80%83X%EF%BC%8CLV%E2%80%83J%E2%80%83Z%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83tumor%02specific%E2%80%83ROS%E2%80%83self-supply%E2%80%83enhanced%E2%80%83cascade%02responsive%E2%80%83prodrug%E2%80%83activation%E2%80%83nanosystem%E2%80%83for%E2%80%83amplified%E2%80%83chemotherapy%E2%80%83against%E2%80%83multidrug-resistant%E2%80%83tumors%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AActa%E2%80%83Biomater%EF%BC%8C2023%EF%BC%88164%EF%BC%89%EF%BC%9A522-537%EF%BC%8E

54、DING%E2%80%83Y%EF%BC%8CWANG%E2%80%83C%E2%80%83W%EF%BC%8CMA%E2%80%83Y%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EpH%2FROS%E2%80%83%0Adual-responsive%E2%80%83%20supramolecular%E2%80%83%20polypeptide%E2%80%83%20prodrug%E2%80%83%0Ananomedicine%E2%80%83%20based%E2%80%83%20on%E2%80%83%20host-guest%E2%80%83%20recognition%E2%80%83for%E2%80%83%0Acancer%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Biomaterialia%EF%BC%8C2022%0A%EF%BC%88143%EF%BC%89%EF%BC%9A381-391%EF%BC%8E

55、%E2%80%83%20WANG%E2%80%83L%E2%80%83L%EF%BC%8CHE%E2%80%83S%E2%80%83S%EF%BC%8CLIU%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83pH%2FROS%E2%80%83dual-responsive%E2%80%83%20system%E2%80%83for%E2%80%83effective%E2%80%83chemoimmunotherapy%E2%80%83%0Aagainst%E2%80%83%20melanoma%E2%80%83%20via%E2%80%83%20remodeling%E2%80%83%20tumor%E2%80%83%20immune%E2%80%83%0Amicroenvironment%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Pharm%E2%80%83Sin%E2%80%83B%EF%BC%8C2024%EF%BC%8C%0A14%EF%BC%885%EF%BC%89%EF%BC%9A2263-2280%EF%BC%8E

56、XI%E2%80%83L%EF%BC%8CWANG%E2%80%83J%EF%BC%8CWANG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EDual-targeting%E2%80%83%0Apolymeric%E2%80%83%20nanocarriers%E2%80%83to%E2%80%83%20deliver%E2%80%83ROS-responsive%E2%80%83%0Aprodrugs%E2%80%83and%E2%80%83combat%E2%80%83multidrug%E2%80%83%20resistance%E2%80%83of%E2%80%83cancer%E2%80%83%0Acells%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMacromol%E2%80%83Biosci%EF%BC%8C2021%EF%BC%8C21%EF%BC%889%EF%BC%89%EF%BC%9A%0Ae2100091%EF%BC%8E

57、REN%E2%80%83Q%EF%BC%8CLIANG%E2%80%83Z%E2%80%83G%EF%BC%8CJIANG%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EEnzyme%E2%80%83%0Aand%E2%80%83pH%E2%80%83dual-responsive%E2%80%83hyaluronic%E2%80%83acid%E2%80%83nanoparticles%E2%80%83%0Amediated%E2%80%83%20combination%E2%80%83of%E2%80%83%20photodynamic%E2%80%83therapy%E2%80%83and%E2%80%83%0Achemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Biol%E2%80%83Macromol%EF%BC%8C2019%0A%EF%BC%88130%EF%BC%89%EF%BC%9A845-852%EF%BC%8E

58、REN%E2%80%83Q%EF%BC%8CLIANG%E2%80%83Z%E2%80%83G%EF%BC%8CJIANG%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8EEnzyme%E2%80%83%0Aand%E2%80%83pH%E2%80%83dual-responsive%E2%80%83hyaluronic%E2%80%83acid%E2%80%83nanoparticles%E2%80%83%0Amediated%E2%80%83%20combination%E2%80%83of%E2%80%83%20photodynamic%E2%80%83therapy%E2%80%83and%E2%80%83%0Achemotherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Biol%E2%80%83Macromol%EF%BC%8C2019%0A%EF%BC%88130%EF%BC%89%EF%BC%9A845-852%EF%BC%8E

59、LUO%E2%80%83Q%EF%BC%8CLIN%E2%80%83L%EF%BC%8CHUANG%E2%80%83Q%EF%BC%8Cet%E2%80%83al%EF%BC%8EDual%E2%80%83stimuli%02responsive%E2%80%83dendronized%E2%80%83prodrug%E2%80%83derived%E2%80%83from%E2%80%83poly%0A%EF%BC%88oligo-%EF%BC%88ethylene%E2%80%83glycol%EF%BC%89methacrylate%EF%BC%89-based%E2%80%83%0Acopolymers%E2%80%83for%E2%80%83enhanced%E2%80%83anti-cancer%E2%80%83therapeutic%E2%80%83effect%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EActa%E2%80%83Biomater%EF%BC%8C2022%EF%BC%88143%EF%BC%89%EF%BC%9A320-332%EF%BC%8E

60、%E2%80%83%20LUO%E2%80%83L%EF%BC%8CXU%E2%80%83F%E2%80%83S%EF%BC%8CPENG%E2%80%83H%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8EStimuli-responsive%E2%80%83%20polymeric%E2%80%83%20prodrug-based%E2%80%83%20nanomedicine%E2%80%83%0Adelivering%E2%80%83nifuroxazide%E2%80%83and%E2%80%83doxorubicin%E2%80%83against%E2%80%83primary%E2%80%83%0Abreast%E2%80%83cancer%E2%80%83and%E2%80%83pulmonary%E2%80%83metastasis%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83%0AControl%E2%80%83Release%EF%BC%8C2020%EF%BC%88318%EF%BC%89%EF%BC%9A124-135%EF%BC%8E

61、韩天娇，胡玉玺，付宏征．高分子前药的研究进展［J］．中国药科大学学报，2019，50（4）：397-404．

62、ZHAO%E2%80%83H%E2%80%83B%EF%BC%8CYU%E2%80%83J%EF%BC%8CZHANG%E2%80%83R%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8EDoxorubicin%E2%80%83%0Aprodrug-based%E2%80%83%20nanomedicines%E2%80%83for%E2%80%83the%E2%80%83treatment%E2%80%83%20of%E2%80%83%0Acancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEur%E2%80%83J%E2%80%83Med%E2%80%83Chem%EF%BC%8C2023%EF%BC%88258%EF%BC%89%EF%BC%9A%0A115612%EF%BC%8E

63、%E2%80%83%20RANI%E2%80%83P%EF%BC%8CRAHIM%E2%80%83J%E2%80%83U%EF%BC%8CPATRA%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8ETumor%E2%80%83%0Amic%20roenvi%20ronment-%20responsive%E2%80%83%20self-assembling%E2%80%83%0Apolymeric%E2%80%83%20prodrug-based%E2%80%83%20nanomaterials%E2%80%83for%E2%80%83%20cancer%E2%80%83%0Atherapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Drug%E2%80%83Deliv%E2%80%83Sci%E2%80%83Technol%EF%BC%8C2024%0A%EF%BC%8896%EF%BC%89%EF%BC%9A105715%EF%BC%8E

64、王朝辉，刘玉玲．抗肿瘤纳米药物的临床转化进展及展望［J］．药学学报，2022，57（1）：134-141，277．

65、仲曼，胡慧慧，缪明星，等．纳米药物制剂体内分析方法及药动学研究进展和问题策略分析［J］．药物评价研究，2022，45（7）：1413-1425．

66、%E2%80%83%20YAO%E2%80%83M%E2%80%83N%EF%BC%8CMA%E2%80%83X%E2%80%83T%EF%BC%8CZHANG%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8ELectin-mediated%E2%80%83pH-sensitive%E2%80%83doxorubicin%E2%80%83prodrug%E2%80%83for%E2%80%83pre%02targeted%E2%80%83%20chemotherapy%E2%80%83%20of%E2%80%83%20colorectal%E2%80%83%20cancer%E2%80%83%20with%E2%80%83%0Aenhanced%E2%80%83efficacy%E2%80%83and%E2%80%83reduced%E2%80%83side%E2%80%83effects%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ATheranostics%EF%BC%8C2019%EF%BC%8C9%EF%BC%883%EF%BC%89%EF%BC%9A747-760%EF%BC%8E

67、李玲，汪哲，谭宁华．天然产物靶向肿瘤微环境的研究进展［J］．药学学报，2021，56（6）：1580-1590．

1、安徽省教育厅高校科学研究一般项目（KJ2021B16）()