聚磷酸酯的控制合成及其在药物传递中的应用
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摘要
聚磷酸酯是一类以磷酸酯键为链接结构的生物可降解高分子。由于其良好的生物相容性,以及可以通过水解和酶催化的可降解性,聚磷酸酯在生物医学领域的应用引起了广泛关注。
本论文发展了两种聚磷酸酯的控制聚合体系,改变了聚磷酸酯合成不可控的状况,并籍此构建了性能可调控的“智能型”纳米药物载体。我们研究了两种聚磷酸酯的开环聚合体系,证明其聚合过程具有活性特征,可用于准确控制聚磷酸酯的分子量、组成及结构。我们进一步利用上述聚磷酸酯的控制合成方法,结合聚磷酸酯的独特性能,构建了多种尺度和性能可调控的纳米胶束和纳米凝胶药物载体,用于化疗药物的靶向传递、胞内响应性药物输送和克服肿瘤细胞的多药耐药性。
本论文的工作内容和主要结论如下：
1、研究了以三异丙醇铝和异辛酸亚锡分别为引发体系的磷酸酯环状单体的聚合及聚合反应的动力学,发现磷酸酯单体的聚合具有活性特征。通过调节单体与引发剂的比例、反应时间等可以控制单体的聚合,获得具有不同分子量和结构组成的聚合物,包括各种嵌段共聚物。研究还发现,以异辛酸亚锡为催化剂的磷酸酯单体的聚合速率与磷酸酯单体的侧基、环取代基密切相关,而且可以方便利用聚磷酸酯侧基对高分子进行功能化修饰。
2、基于聚磷酸酯的可降解性、相对亲水性和良好的生物相容性,利用上述可控合成方法,发展了一系列具有不同分子量及组成的聚ε-己内酯及聚(乙基乙撑磷酸酯)(PCL-b-PEEP)的两亲性嵌段共聚物,研究了其在水溶液中的自组装行为,构建了以聚(乙基乙撑磷酸酯)(PEEP)为壳的纳米胶束药物载体,探索了影响纳米胶束性能和药物释放特性的影响因素。研究发现以PEEP为壳PCL为核的纳米胶束具有良好的细胞相容性,尺寸与聚合物的结构密切相关,较聚乙二醇(PEG)为壳的纳米胶束具有更低的临界胶束浓度,因而具有更好的稳定性,同时紫杉醇药物从PCL-b-PEEP纳米胶束的释放性能受聚合物结构的调控。
以三异丙醇铝或异辛酸亚锡／醇引发体系合成的PCL-b-PEEP均具有可修饰的亲水链段羟基末端。我们将其端羟基进行功能化修饰,探索了外壳靶向性修饰的纳米药物载体的构建方法,研究了其靶向输送药物到肿瘤细胞的功能。通过将PCL-b-PEEP胶束表面氨基半乳糖化,获得了与HepG2细胞表面去唾液酸糖蛋白受体特异性结合的靶向纳米载药纳米胶束。它通过受体介导内吞携载更多的紫杉醇进入HepG2细胞,并显示靶向能力和对HepG2更强的杀伤能力。
3、从研究PEEP及其与聚(异丙基乙撑磷酸酯)(PPEP)或聚(甲基乙撑磷酸酯)(PMEP)的温度敏感性能入手,发展了对多重环境刺激具有响应性的纳米药物载体,并研究了其胞内药物传递的性能。首先设计合成了大量由聚ε-己内酯和温度敏感性聚磷酸酯组成的嵌段共聚物,发现其纳米胶束的温度响应性可以精确通过调节聚磷酸酯的组成和分子量而在较大的范围内进行调控。进一步对胶束亲水性壳层进行微小末端修饰可以使胶束获得对温度、pH、光照等多重响应性,并可精确调控。这些具有多重响应性的载药纳米胶束显示对多重环境刺激的响应性药物控制释放行为,并受亲水性聚磷酸酯链段端基的特性调控。亲水性聚磷酸酯链段端基修饰成羧基后,纳米胶束载体具有pH及温度双重响应性药物释放特性,酸性溶酶体及内涵体的pH (pH5.5)降低其最低临界溶解温度(LCST)至37℃以下,从而触发其在体温37℃下的快速药物释放,而在pH 7.4和37℃下药物释放速度显著减慢。这种pH及温度双重响应性纳米载药胶束进入细胞后,显著增强药物对MCF-7细胞及MCF-7/ADR耐药细胞的毒性。
4、设计合成了由聚乙二醇和温度敏感性聚磷酸酯组成的双亲水性嵌段共聚物,利用聚磷酸酯的温度响应性及其受盐浓度调控的特点,发展了无模版法制备多功能聚磷酸酯纳米凝胶的制备方法,并研究了其药物传递性能。首先研究了聚合物组成、盐离子浓度对PEG和聚磷酸酯嵌段共聚物的温度响应性的影响,发现上述双亲水性聚合物在温度高于其LCST的情况下,在水溶液中形成尺度与高分子溶液浓度和盐离子浓度密切相关的纳米颗粒,这些颗粒表现出良好的细胞和组织相容性,可以降解。接着利用盐离子调控上述温度响应性聚合物组装的特性,发展了盐诱导和光交联的无模版法合成亲水性纳米凝胶的新方法,并进一步通过在体系中掺入键和含有靶向基团(乳糖基,Lac-)和丙烯酰基(Acr-)的杂双功能化Lac-PEG3.4K-b-PEEP172-Acr,方便地制备了通过配体-受体相互作用特异性传递药物到HepG2细胞的纳米凝胶,增强了药物对细胞的杀伤作用。
5、肿瘤细胞对药物的多药耐药性是造成化疗失败的一个重要原因。为了克服其多药耐药性,我们设计合成了用二硫键桥连的PCL和PEEP的嵌段共聚物(PCL-S-S-PEEP),构建了对细胞内还原物质(如谷胱甘肽)刺激响应性的纳米药物载体,用于逆转肿瘤细胞的多药耐药性。我们研究发现,一方面,基于PCL-S-S-PEEP的纳米胶束可以包载阿霉素药物分子,通过内吞的途径进入耐药的MCF-7/ADR乳腺癌细胞,使药物分子避开耐药细胞表面P-糖蛋白的泵出作用,从而造成药物在细胞内的大量富集；另一方面,细胞内的还原环境使聚合物二硫桥键的断裂,导致胶束在胞内被迅速破坏,从而快速释放包载的阿霉素药物。这种响应性从纳米胶束的胞内药物快速释放使药物的细胞半致死剂量降低到游离药物的15%,有效逆转了肿瘤细胞的多药耐药性。
Polyphosphoesters are a series of biodegradable polymers with repeating phosphoester bonds in the backbone. Owing to their good biocompatibility, and biodegradability through hydrolysis as well as enzyme catalytic degradation, polyphosphoester are raising great interest in biomedical applications.
The purposes of this dissertation are to overcome the problem of uncontrollability encountered by traditional syntheses methods of polyphosphoesters, and to develop nano-drug carriers based on polyphosphoesters with controllable properties. We have studied two catalytic systems for ring-opening polymerization of cyclic phosphoester monomers, and demonstrated that the polymerization is with living characteristics and thus can be utilized to synthesize polyphosphoesters with controlled molecular weight, composition and structure. Taking the advantages of the controlled synthesis methods and the unique properties of polyphosphoester, we have constructed a few nano-carriers for drug delivery, including micellar nanoparticles and nanogels with tunable sizes and properties, which have been applied for targeted delivery of chemotherapeutic drugs, intracellular responsive drug delivery and reversal of multi-drug resistance of cancer cells.
The main content and conclusions of this dissertation are summarized below:
1. We have investigated the ring-opening polymerization of cyclic phosphoester monomers using aluminum isopropoxide and stannous octoate as the initiators. The polymerization kinetics studies reveal the living characteristics of polymerization. The molecular weight and molecular architecture of polymers, including block copolymers, can be well-controlled by adjusting the molar ratios of monomers and the initiator as well as the reaction time. It has also been found that, the polymerization rate of cyclic phosphoester monomer is highly depended on the structure of pendant side group and the ring substituent group when using stannous octoate as the catalyst. The polymerization method also facilitates the synthesis of functionalized polyphosphoesters with pendant functional modification (e.g. by "click" chemistry).
2. Taking the advantages of the controlled synthesis methods above and the unique properties of polyphosphoester, including the biodegradability, water solubility and good biocompatibility, we have developed a series of triblock copolymers of poly(s-caprolactone) and poly(ethyl ethylene phosphate) (PCL-b-PEEP). We have investigated the self-assembly behavior of those block copolymers, and constructed micellar nanoparticles with hydrophilic poly(ethyl ethylene phosphate) (PEEP) as the shell material for drug delivery. It has been proved that micelles with PCL core and PEEP shell are cytocompatible, while the size of micelles can be finely tuned by adjusting the molecular weight and composition of the copolymers. Moreover, the critical micellization concentrations of the micelles are relatively lower compared with micelles bearing poly(ethylene glycol) (PEG) shell, indicating that micelles with PEEP shell can be more stable thermodynamically. The drug release of paclitaxel from those micelles is correlative to the polymer structures.
PCL-b-PEEP copolymers obtained through ring-opening polymerization catalyzed by Al(O'Pr)3 or stannous octoate bear hydroxyl end groups. The hydroxyl groups have been further modified to achieve active targeting in drug delivery for cancer therapy. With surface conjugation of galactose to the end of PEEP chain, the micellar nanoparticles can targeted deliver paclitaxel to HepG2 cells via interaction with asialoglycoprotein receptor (ASGP-R) presented on the cell membranes, leading to higher cytotoxicity when compared with the micelles without galactose ligands.
3. We have developed multi-responsive micelles as nano-drug carriers based on the thermoresponsibility of polyphosphoesters, and investigated the intracellular drug release behaviors. The responsibility of micelles composed of poly(ε-caprolactone) and thermoresponsive polyphosphoester can be widely tuned by adjusting the molecular weight and polymer composition. The multi-responsibilities (thermo-, pH-and light-responsibilities) have been simply achieved and finely controlled by subtle chain terminal modification of polyphosphoester chain. Such stimuli-responsive micelles lead to responsive drug release properties in response to multi-environmental stimuli, which are adjustable by the subtle chain terminal groups. The micelles with carboxyl groups on the surface exhibit thermo-sensitivity in responsive to pH variation, thus the endosomal/lysosomal pH (pH 5.5) triggers rapid drug release from the micelles at 37℃, owing to that pH lowers the lowest critical solution temperature (LCST) of micelles to a temperature lower than 37℃. On the contrast, at pH 7.4, the LCST of the micelles is higher than 37℃and the drug release is much slower. Thus, with the encapsulation of doxorubicin, the dual pH-/thermo responsive micelles significantly increase the cytotoxicity of doxorubicin against both MCF-7 and drug-resistant MCF-7/ADR cancer cells.
4. We have designed and synthesized water soluble block copolymers composed of poly(ethylene glycol) and thermoresponsive polyphosphoesters. Based on the influence of salt on the thermoresponsibility, we have developed multi-functional nano-hydrogel with polyphosphoester core using a template-free method, and investigated the drug delivery behaviors. It is demonstrated that the composition of polymer, salt concentration and molecular weight of the polymer influence the thermoresponsibility. The polymers form self-assemblies when the environmental temperature is higher than its LCST, and the size of assemblies depends on the concentration of both polymer and salt. The self-assemblies are proven to be biocompatible and biodegradable. Photo-crosslinking of the salt-induced assemblies leads to formation of nanogels. Moreover, with the integration of lactosyl moieties onto the surface of nanogels, the nanogels can specifically bind HepG2 cells mediated by ligand-receptor interaction, thus deliver drug to cells more efficiently, resulting enhanced cytotoxicity.
5. The multidrug resistance of cancer cells against chemotherapeutic drugs is a major factor in the failure of chemotherapy. To overcome the multidrug resistance, we have designed and synthesized a disulfide-linked biodegradable diblock copolymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) (PCL-S-S-PEEP), which forms micellar nanoparticles but detaches the PEEP shell in response to the intracellular reduction conditions (e.g., GSH). In one aspect, the micelles can enter cancer cells through internalization pathways, which protecting the drug from the efflux by P-glycoprotein located on the cell membranes, and resulting in drug accumulation in MCF-7/ADR drug resistant cells. In another aspect, the intracellular reduction conditions break the disulfide linkages between hydrophobic PCL and hydrophilic PEEP chains, thus destroy the micelles and accelerate the intracellular rapid release of doxorubicin incorporated in the micelles. The shell-detachable drug-loaded micelles in response to intracellular reduction conditions significantly overcome the drug resistance of MCF-7/ADR cells, lowering the IC50 to 15% of the free doxorubicin drug.
本论文发展了两种聚磷酸酯的控制聚合体系,改变了聚磷酸酯合成不可控的状况,并籍此构建了性能可调控的“智能型”纳米药物载体。我们研究了两种聚磷酸酯的开环聚合体系,证明其聚合过程具有活性特征,可用于准确控制聚磷酸酯的分子量、组成及结构。我们进一步利用上述聚磷酸酯的控制合成方法,结合聚磷酸酯的独特性能,构建了多种尺度和性能可调控的纳米胶束和纳米凝胶药物载体,用于化疗药物的靶向传递、胞内响应性药物输送和克服肿瘤细胞的多药耐药性。
本论文的工作内容和主要结论如下：
1、研究了以三异丙醇铝和异辛酸亚锡分别为引发体系的磷酸酯环状单体的聚合及聚合反应的动力学,发现磷酸酯单体的聚合具有活性特征。通过调节单体与引发剂的比例、反应时间等可以控制单体的聚合,获得具有不同分子量和结构组成的聚合物,包括各种嵌段共聚物。研究还发现,以异辛酸亚锡为催化剂的磷酸酯单体的聚合速率与磷酸酯单体的侧基、环取代基密切相关,而且可以方便利用聚磷酸酯侧基对高分子进行功能化修饰。
2、基于聚磷酸酯的可降解性、相对亲水性和良好的生物相容性,利用上述可控合成方法,发展了一系列具有不同分子量及组成的聚ε-己内酯及聚(乙基乙撑磷酸酯)(PCL-b-PEEP)的两亲性嵌段共聚物,研究了其在水溶液中的自组装行为,构建了以聚(乙基乙撑磷酸酯)(PEEP)为壳的纳米胶束药物载体,探索了影响纳米胶束性能和药物释放特性的影响因素。研究发现以PEEP为壳PCL为核的纳米胶束具有良好的细胞相容性,尺寸与聚合物的结构密切相关,较聚乙二醇(PEG)为壳的纳米胶束具有更低的临界胶束浓度,因而具有更好的稳定性,同时紫杉醇药物从PCL-b-PEEP纳米胶束的释放性能受聚合物结构的调控。
以三异丙醇铝或异辛酸亚锡／醇引发体系合成的PCL-b-PEEP均具有可修饰的亲水链段羟基末端。我们将其端羟基进行功能化修饰,探索了外壳靶向性修饰的纳米药物载体的构建方法,研究了其靶向输送药物到肿瘤细胞的功能。通过将PCL-b-PEEP胶束表面氨基半乳糖化,获得了与HepG2细胞表面去唾液酸糖蛋白受体特异性结合的靶向纳米载药纳米胶束。它通过受体介导内吞携载更多的紫杉醇进入HepG2细胞,并显示靶向能力和对HepG2更强的杀伤能力。
3、从研究PEEP及其与聚(异丙基乙撑磷酸酯)(PPEP)或聚(甲基乙撑磷酸酯)(PMEP)的温度敏感性能入手,发展了对多重环境刺激具有响应性的纳米药物载体,并研究了其胞内药物传递的性能。首先设计合成了大量由聚ε-己内酯和温度敏感性聚磷酸酯组成的嵌段共聚物,发现其纳米胶束的温度响应性可以精确通过调节聚磷酸酯的组成和分子量而在较大的范围内进行调控。进一步对胶束亲水性壳层进行微小末端修饰可以使胶束获得对温度、pH、光照等多重响应性,并可精确调控。这些具有多重响应性的载药纳米胶束显示对多重环境刺激的响应性药物控制释放行为,并受亲水性聚磷酸酯链段端基的特性调控。亲水性聚磷酸酯链段端基修饰成羧基后,纳米胶束载体具有pH及温度双重响应性药物释放特性,酸性溶酶体及内涵体的pH (pH5.5)降低其最低临界溶解温度(LCST)至37℃以下,从而触发其在体温37℃下的快速药物释放,而在pH 7.4和37℃下药物释放速度显著减慢。这种pH及温度双重响应性纳米载药胶束进入细胞后,显著增强药物对MCF-7细胞及MCF-7/ADR耐药细胞的毒性。
4、设计合成了由聚乙二醇和温度敏感性聚磷酸酯组成的双亲水性嵌段共聚物,利用聚磷酸酯的温度响应性及其受盐浓度调控的特点,发展了无模版法制备多功能聚磷酸酯纳米凝胶的制备方法,并研究了其药物传递性能。首先研究了聚合物组成、盐离子浓度对PEG和聚磷酸酯嵌段共聚物的温度响应性的影响,发现上述双亲水性聚合物在温度高于其LCST的情况下,在水溶液中形成尺度与高分子溶液浓度和盐离子浓度密切相关的纳米颗粒,这些颗粒表现出良好的细胞和组织相容性,可以降解。接着利用盐离子调控上述温度响应性聚合物组装的特性,发展了盐诱导和光交联的无模版法合成亲水性纳米凝胶的新方法,并进一步通过在体系中掺入键和含有靶向基团(乳糖基,Lac-)和丙烯酰基(Acr-)的杂双功能化Lac-PEG3.4K-b-PEEP172-Acr,方便地制备了通过配体-受体相互作用特异性传递药物到HepG2细胞的纳米凝胶,增强了药物对细胞的杀伤作用。
5、肿瘤细胞对药物的多药耐药性是造成化疗失败的一个重要原因。为了克服其多药耐药性,我们设计合成了用二硫键桥连的PCL和PEEP的嵌段共聚物(PCL-S-S-PEEP),构建了对细胞内还原物质(如谷胱甘肽)刺激响应性的纳米药物载体,用于逆转肿瘤细胞的多药耐药性。我们研究发现,一方面,基于PCL-S-S-PEEP的纳米胶束可以包载阿霉素药物分子,通过内吞的途径进入耐药的MCF-7/ADR乳腺癌细胞,使药物分子避开耐药细胞表面P-糖蛋白的泵出作用,从而造成药物在细胞内的大量富集；另一方面,细胞内的还原环境使聚合物二硫桥键的断裂,导致胶束在胞内被迅速破坏,从而快速释放包载的阿霉素药物。这种响应性从纳米胶束的胞内药物快速释放使药物的细胞半致死剂量降低到游离药物的15%,有效逆转了肿瘤细胞的多药耐药性。
Polyphosphoesters are a series of biodegradable polymers with repeating phosphoester bonds in the backbone. Owing to their good biocompatibility, and biodegradability through hydrolysis as well as enzyme catalytic degradation, polyphosphoester are raising great interest in biomedical applications.
The purposes of this dissertation are to overcome the problem of uncontrollability encountered by traditional syntheses methods of polyphosphoesters, and to develop nano-drug carriers based on polyphosphoesters with controllable properties. We have studied two catalytic systems for ring-opening polymerization of cyclic phosphoester monomers, and demonstrated that the polymerization is with living characteristics and thus can be utilized to synthesize polyphosphoesters with controlled molecular weight, composition and structure. Taking the advantages of the controlled synthesis methods and the unique properties of polyphosphoester, we have constructed a few nano-carriers for drug delivery, including micellar nanoparticles and nanogels with tunable sizes and properties, which have been applied for targeted delivery of chemotherapeutic drugs, intracellular responsive drug delivery and reversal of multi-drug resistance of cancer cells.
The main content and conclusions of this dissertation are summarized below:
1. We have investigated the ring-opening polymerization of cyclic phosphoester monomers using aluminum isopropoxide and stannous octoate as the initiators. The polymerization kinetics studies reveal the living characteristics of polymerization. The molecular weight and molecular architecture of polymers, including block copolymers, can be well-controlled by adjusting the molar ratios of monomers and the initiator as well as the reaction time. It has also been found that, the polymerization rate of cyclic phosphoester monomer is highly depended on the structure of pendant side group and the ring substituent group when using stannous octoate as the catalyst. The polymerization method also facilitates the synthesis of functionalized polyphosphoesters with pendant functional modification (e.g. by "click" chemistry).
2. Taking the advantages of the controlled synthesis methods above and the unique properties of polyphosphoester, including the biodegradability, water solubility and good biocompatibility, we have developed a series of triblock copolymers of poly(s-caprolactone) and poly(ethyl ethylene phosphate) (PCL-b-PEEP). We have investigated the self-assembly behavior of those block copolymers, and constructed micellar nanoparticles with hydrophilic poly(ethyl ethylene phosphate) (PEEP) as the shell material for drug delivery. It has been proved that micelles with PCL core and PEEP shell are cytocompatible, while the size of micelles can be finely tuned by adjusting the molecular weight and composition of the copolymers. Moreover, the critical micellization concentrations of the micelles are relatively lower compared with micelles bearing poly(ethylene glycol) (PEG) shell, indicating that micelles with PEEP shell can be more stable thermodynamically. The drug release of paclitaxel from those micelles is correlative to the polymer structures.
PCL-b-PEEP copolymers obtained through ring-opening polymerization catalyzed by Al(O'Pr)3 or stannous octoate bear hydroxyl end groups. The hydroxyl groups have been further modified to achieve active targeting in drug delivery for cancer therapy. With surface conjugation of galactose to the end of PEEP chain, the micellar nanoparticles can targeted deliver paclitaxel to HepG2 cells via interaction with asialoglycoprotein receptor (ASGP-R) presented on the cell membranes, leading to higher cytotoxicity when compared with the micelles without galactose ligands.
3. We have developed multi-responsive micelles as nano-drug carriers based on the thermoresponsibility of polyphosphoesters, and investigated the intracellular drug release behaviors. The responsibility of micelles composed of poly(ε-caprolactone) and thermoresponsive polyphosphoester can be widely tuned by adjusting the molecular weight and polymer composition. The multi-responsibilities (thermo-, pH-and light-responsibilities) have been simply achieved and finely controlled by subtle chain terminal modification of polyphosphoester chain. Such stimuli-responsive micelles lead to responsive drug release properties in response to multi-environmental stimuli, which are adjustable by the subtle chain terminal groups. The micelles with carboxyl groups on the surface exhibit thermo-sensitivity in responsive to pH variation, thus the endosomal/lysosomal pH (pH 5.5) triggers rapid drug release from the micelles at 37℃, owing to that pH lowers the lowest critical solution temperature (LCST) of micelles to a temperature lower than 37℃. On the contrast, at pH 7.4, the LCST of the micelles is higher than 37℃and the drug release is much slower. Thus, with the encapsulation of doxorubicin, the dual pH-/thermo responsive micelles significantly increase the cytotoxicity of doxorubicin against both MCF-7 and drug-resistant MCF-7/ADR cancer cells.
4. We have designed and synthesized water soluble block copolymers composed of poly(ethylene glycol) and thermoresponsive polyphosphoesters. Based on the influence of salt on the thermoresponsibility, we have developed multi-functional nano-hydrogel with polyphosphoester core using a template-free method, and investigated the drug delivery behaviors. It is demonstrated that the composition of polymer, salt concentration and molecular weight of the polymer influence the thermoresponsibility. The polymers form self-assemblies when the environmental temperature is higher than its LCST, and the size of assemblies depends on the concentration of both polymer and salt. The self-assemblies are proven to be biocompatible and biodegradable. Photo-crosslinking of the salt-induced assemblies leads to formation of nanogels. Moreover, with the integration of lactosyl moieties onto the surface of nanogels, the nanogels can specifically bind HepG2 cells mediated by ligand-receptor interaction, thus deliver drug to cells more efficiently, resulting enhanced cytotoxicity.
5. The multidrug resistance of cancer cells against chemotherapeutic drugs is a major factor in the failure of chemotherapy. To overcome the multidrug resistance, we have designed and synthesized a disulfide-linked biodegradable diblock copolymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) (PCL-S-S-PEEP), which forms micellar nanoparticles but detaches the PEEP shell in response to the intracellular reduction conditions (e.g., GSH). In one aspect, the micelles can enter cancer cells through internalization pathways, which protecting the drug from the efflux by P-glycoprotein located on the cell membranes, and resulting in drug accumulation in MCF-7/ADR drug resistant cells. In another aspect, the intracellular reduction conditions break the disulfide linkages between hydrophobic PCL and hydrophilic PEEP chains, thus destroy the micelles and accelerate the intracellular rapid release of doxorubicin incorporated in the micelles. The shell-detachable drug-loaded micelles in response to intracellular reduction conditions significantly overcome the drug resistance of MCF-7/ADR cells, lowering the IC50 to 15% of the free doxorubicin drug.
引文
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