阿霉素纳米自组装体克服肿瘤的多药耐药及促进口服吸收的研究
|
摘要
化疗是肿瘤治疗的主要途径。目前肿瘤的多药耐药和化疗引发的毒副作用,影响了化疗的临床疗效,因此克服肿瘤的多药耐药性(multidrug resistance, MDR)和化疗的增效减毒研究,是肿瘤治疗发展的新方向。
本课题设计并合成多功能两亲性星形聚合物(以赖氨酸为桥连的聚乙二醇二维生素E琥珀酸酯衍生物),纳米载体具有显著的长循环、P-gp抑制作用和协同抗肿瘤功能,能显著地提高疏水性抗肿瘤药物的化疗疗效。本课题以阿霉素(DOX)为模型药物,以自合成星形聚合物为纳米材料,制备阿霉素纳米胶束。本论文主要对星形聚合物的合成及结构确证,阿霉素纳米胶束的制备和制剂学性质,细胞毒性和细胞摄取及机制,体内药动学和药效学行为进行研究,同时对阿霉素纳米胶束的口服吸收促进作用进行考察。
以维生素E琥珀酸酯为疏水基团,聚乙醇为亲水基团,以赖氨酸为桥连,合成了不同亲水链的聚乙二醇二维生素E琥珀酸酯衍生物(mPEG2000-Lys-di-VES、mPEG5000-Lys-di-VES、mPEG2000-NH-Lys-di-VES)和聚乙二醇2000维生素E琥珀酸酯(简称TPGS2K)作为对照。采用1H-NMR确证了目标化合物的结构,同时采用芘荧光探针法测定自合成聚合物的临界胶束浓度,约为2μg/mL。且随着亲水链PEG含量增加,临界胶束浓度有所提高。
以阿霉素为模型药物,以自合成的星形聚合物为纳米材料,制备阿霉素纳米胶束。以粒径和包封率为指标,对纳米胶束的制备工艺和处方进行了优化和筛选,确定采用薄膜水化法制备了阿霉素纳米胶束,并对胶束的制剂学性质进行了考察。结果表明,mPEG2000-Lys-di-VES(简称PLV2K-DOX)、mPEG5000-Lys-di-VES(简称PLV5K-DOX)、mPEG2000-NH-Lys-di-VES (PLV2K-NH2-DOX)、 TPGS2K-DOX和TPGS-DOX胶束的包封率分别为97.11%、96.81%、96.45%、91.68%和91.18%,粒径分别为13.26+2.86、16.4+2.70、34.1+0.90、11.10±0.10和13.5+2.44nm。不同载药的纳米胶束粒径均一,呈球形。由于PEG为亲水端,胶束的Zeta电位为0mV左右。DSC结果表明阿霉素可能包裹于胶束的疏水性内核中并以无定性状态分散在胶束中。采用透析法考察了阿霉素纳米胶束的体外释放,结果表明阿霉素纳米胶束的药物释放具有一定的pH依赖性,pH值越低释放越快,而在生理条件下缓慢释放,此种释放方式有利于肿瘤内部阿霉素的智能型释放。
以MCF-7和MCF-7/Adr细胞为模型,对纳米胶束的细胞毒性、细胞摄取及摄取机制进行研究。体外细胞毒性实验表明自合成的纳米材料(PLV2K、PLV5K、 PLV2K-NH2、TPGS2K)均具有抗肿瘤的作用。在载体的协同作用下,阿霉素载药胶束在耐药的MCF-7/Adr细胞中呈现显著的细胞毒性,能较好地克服肿瘤的MDR。采用流式细胞仪和共聚焦显微镜技术评价了载药胶束在MCF-7/Adr细胞中摄取情况,结果表明阿霉素纳米胶束能显著提高DOX在耐药细胞的摄取。P-gp抑制实验表明自合成的纳米材料能抑制P-gp的活性且为P-gp ATPase的反竞争性抑制剂；阿霉素纳米胶束能避免P-gp识别且在纳米材料抑制P-gp作用协同下而显著增加药物的摄取。内吞抑制实验表明胶束以能量依赖的胞吞方式摄取,通过小窝蛋白介导、网格蛋白介导、非网格蛋白非小窝蛋白介导的内吞和巨胞饮中的一种或多种途径入胞。
采用UPLC/MS/MS测定了DOX和各载药胶束在大鼠静注体内药动学,结果表明PLV2K-DOX、PLV5K-DOX、PLV2K-NH2-DOX、TPGS2K-DOX和TPGS-DOX胶束分别使DOX-Sol的t1/2由8.1h延长至183.8h、94.6h、181.6h、82.4h和42.0h,AUC(0-t)分别是DOX-Sol的10.4、7.5、5.1、7.2和4.9倍。表明阿霉素纳米胶束均能够提高阿霉素药时曲线下面积,增加药物在血浆中的循环时间,达到长循环的效果,从而能更好地使纳米胶束通过EPR效应分布到肿瘤区域,发挥疗效。体内药效学结果表明阿霉素纳米胶束能显著抑制Balb/C小鼠4T1鼠乳腺癌移植瘤的增长,同时降低毒副作用。PLV2K-DOX/PLV2K-NH2-DOX、TPGS-DOX的抑瘤率分别为62.92%、51.86%、56.95%,分别为DOX-Sol抑瘤率的2.17、1.80、1.97倍。
人结肠癌细胞Caco-2摄取和转运结果表明PLV2K-DOX能显著增加DOX在Caco-2细胞的摄取和转运。PLV2K-DOX跨肠细胞膜转运的方式并非打开紧密连接而是以能量依赖的、网格蛋白介导的、小窝蛋白介导的和非小窝蛋白非网格蛋白介导的内吞和巨胞饮途径而主动转运。PLV2K-DOX的膜渗透率为35.75+2.30,是DOX的4.8倍(P<0.05)。这样阿霉素纳米胶束可显著提高药物的肠渗透性,进而提高阿霉素的口服生物利用度。大鼠口服PLV2K-DOX纳米胶束后,PLV2K-DOX的口服绝对生物利用度是DOX-Sol的5倍。从而表明基于PLV2K的纳米胶束是提高P-gp底物口服吸收的有效载体。
Chemotherapy is the major route for tumor therapy. Nowadays, multidrug resistance and side effects of drug limit the effectiveness of chemotherapies in clinic. The strategies and approaches for oncotherapy are to circumvent multidrug resistance (short by MDR) and decrease the toxic and side-effects.
The main aims of this research were to design a multifunctional amphiphilic star-shape polymer of lysine-linked di-tocopherol polyethylene glycol succinate. Star-shape copolymers have striking triple functions to prepare a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs by virtue of the following characteristics:long-time circulation, P-gp transporter reversible inhibitor and synergistic anticancer efficacy. Self-synthetic amphiphilic polymers were used as nanocarrier and hydrophobic doxorubicin were used as model drug to self-assemble in aqueous medium to prepare smart nanomicelles. The main contents of this study include the synthesis and identification of the polymer, preparation of the micelles, evaluation of the pharmaceutical pharmacy, cytotoxicity, cellular uptake,endocytosis mechanism, pharmacokinetic study and pharmacodynamics. Meanwhile, we also investigate the oral chemotherapy of nanomicelles in vitro and in vivo.
First, lysine-linked di-tocopherol polyethylene glycol succinates were synthesized with vitamin E succinate as hydrophobic group and polyethylene glycol as hydrophilic group with the linker of lysine. Based on the different chain length of polyethylene glycol, the polymer were named as mPEG2000-Lys-di-VES (PLV2K-DOX), mPEG5000-Lys-di-VES (PLV5K-DOX), mPEG2000-NH-Lys-di-VES (PLV2K-NH2-DOX) and TPGS2K was synthesized as reference. Then the chemical structure of the synthesized copolymer was identified by1H NMR. The critical micelle concentration (CMC) of self-synthetic polymer was determined by pyrene as a fluorescent probe. The CMC of the copolymers were around2μg/mL, and with the content of polyethylene glycol, the CMC increased.
Self-synthetic amphiphilic polymers as nanomaterials and hydrophobic doxorubicin as model drug to prepare smart nanomicelles, named as PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX. The preparation and formulations were optimized and screened based on particle size and encapsulation efficiency. The micelles were prepared by film-thin hydration and the physicochemical properties of nanomicelles were investigated. The encapsulation efficiency of PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX micelles were97.11%,96.81%,96.45%,91.68%and91.18%, and the particle size were13.26±2.86,16.4±2.70,34.1±0.90,11.10±0.10and13.5±2.44nm, respectively. DOX-loaded micelles were spherical with uniform size. Zeta potentials were around0mV because of hydrophilic surface of polyethylene glycol. DSC analysis suggested that DOX encapsulated in the core of micelles or DOX loaded in micelles in the state of amorphous state. The in vitro release of DOX was conducted by dialysis bag method. The results implied that the release of DOX from micelles was pH dependent, released rapidly at low pH conditions but slowly at physical condition, which was benefit for smart release of DOX in tumor cells.
The cytotoxicity, cellular uptake and endocytosis mechanism of different DOX-loaded micelles were studied in MCF-7cells and MCF-7/Adr cells. In vitro cytotoxicity tests, the self-synthetic copolymers have abilities to inhibit the tumor growth. With the synthetic cytotoxicity of copolymer, DOX-loaded micelles shown significantly cytotoxicity in resistant MCF-7/Adr cells and overcome MDR compared with DOX-Sol. The cellular uptake of DOX-loaded micelles was conducted by flow cytometry and confocal laser scanning microscopy in P-gp over-expressed MCF-7/Adr cells. The DOX-loaded nanomicelles exhibited higher cellular accumulation than DOX-Sol. The P-gp inhibitory trials suggested that self-made nanocarriers have abilities to inhibit the activity of P-gp. Further investigation was conducted to show that self-made polymer was P-gp ATPase inhibitor. With the effect of P-gp inhibition of nanocarrier and bypass the recognition of P-gp by micelles, DOX-loaded micelles significantly improve cellular uptake. The endocytosis of micelles was energy-dependent. The mechanism of endocytosis included caveolae-mediated, clathrin-mediated, caveolae-and clathrn-independent endocytosis and macropinocytosis.
UPLC/MS/MS method was developed to determine DOX-Sol and DOX-loaded micelles in rat pharmacokinetics after intravenous injection. In vivo pharmacokinetic results suggested that t1/2of DOX was8.1h, but the t1/2of PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX micelles was prolonged to183.8h,94.6h,181.6h,82.4h and42.0h, respectively. The AUC(0-t) of those micelles were10.4,7.5,5.1,7.2and4.9times compared with DOX-Sol, respectively. DOX-loaded micelles could increase the AUC and extend plasma circulation time to arrive the effect of long-time circulation, which could benefit drug to accumulate in target cells through EPR effect to improve the therapy effect. Balb/C mice bearing4T1breast transplanted tumor were used as models to study the antitumor activities of DOX-loaded micelles in vivo. The results implied that DOX-loaded micelles could significantly inhibit the growth of tumor and decrease the toxicity in mice by drug. The inhibitory rate of tumor of PLV2K-DOX, PLV2K-NH2-DOX and TPGS-DOX was62.92%,51.86%and56.95%, which was2.17,1.80and1.97times compared with DOX-Sol.
In oral chemotherapy tests, human colon cancer cells Caco-2was selective as model to investigate the uptake and transport of DOX. The results suggested that PLV2K-DOX nanomicelles significantly increase the uptake and transport of DOX in intestinal cells. The transport path of PLV2K-DOX micelles was not opening the tight connection, but through energy dependent, caveolae-mediated and clathrin, caveolin-independent endocytosis. The membrane permeability of PLV2K-DOX was35.75±2.30, which was4.8times of DOX-Sol. So micelles which were used for oral chemotherapy could improve the intestinal permeability and increase the oral bioavailability of DOX. After oral administration of PLV2K-DOX micelles in SD rat, the oral absolute bioavailability of PLV2K-DOX was5times of that in DOX. So micelles could provide effective pathways to improve oral absorption of P-gp substrates.
本课题设计并合成多功能两亲性星形聚合物(以赖氨酸为桥连的聚乙二醇二维生素E琥珀酸酯衍生物),纳米载体具有显著的长循环、P-gp抑制作用和协同抗肿瘤功能,能显著地提高疏水性抗肿瘤药物的化疗疗效。本课题以阿霉素(DOX)为模型药物,以自合成星形聚合物为纳米材料,制备阿霉素纳米胶束。本论文主要对星形聚合物的合成及结构确证,阿霉素纳米胶束的制备和制剂学性质,细胞毒性和细胞摄取及机制,体内药动学和药效学行为进行研究,同时对阿霉素纳米胶束的口服吸收促进作用进行考察。
以维生素E琥珀酸酯为疏水基团,聚乙醇为亲水基团,以赖氨酸为桥连,合成了不同亲水链的聚乙二醇二维生素E琥珀酸酯衍生物(mPEG2000-Lys-di-VES、mPEG5000-Lys-di-VES、mPEG2000-NH-Lys-di-VES)和聚乙二醇2000维生素E琥珀酸酯(简称TPGS2K)作为对照。采用1H-NMR确证了目标化合物的结构,同时采用芘荧光探针法测定自合成聚合物的临界胶束浓度,约为2μg/mL。且随着亲水链PEG含量增加,临界胶束浓度有所提高。
以阿霉素为模型药物,以自合成的星形聚合物为纳米材料,制备阿霉素纳米胶束。以粒径和包封率为指标,对纳米胶束的制备工艺和处方进行了优化和筛选,确定采用薄膜水化法制备了阿霉素纳米胶束,并对胶束的制剂学性质进行了考察。结果表明,mPEG2000-Lys-di-VES(简称PLV2K-DOX)、mPEG5000-Lys-di-VES(简称PLV5K-DOX)、mPEG2000-NH-Lys-di-VES (PLV2K-NH2-DOX)、 TPGS2K-DOX和TPGS-DOX胶束的包封率分别为97.11%、96.81%、96.45%、91.68%和91.18%,粒径分别为13.26+2.86、16.4+2.70、34.1+0.90、11.10±0.10和13.5+2.44nm。不同载药的纳米胶束粒径均一,呈球形。由于PEG为亲水端,胶束的Zeta电位为0mV左右。DSC结果表明阿霉素可能包裹于胶束的疏水性内核中并以无定性状态分散在胶束中。采用透析法考察了阿霉素纳米胶束的体外释放,结果表明阿霉素纳米胶束的药物释放具有一定的pH依赖性,pH值越低释放越快,而在生理条件下缓慢释放,此种释放方式有利于肿瘤内部阿霉素的智能型释放。
以MCF-7和MCF-7/Adr细胞为模型,对纳米胶束的细胞毒性、细胞摄取及摄取机制进行研究。体外细胞毒性实验表明自合成的纳米材料(PLV2K、PLV5K、 PLV2K-NH2、TPGS2K)均具有抗肿瘤的作用。在载体的协同作用下,阿霉素载药胶束在耐药的MCF-7/Adr细胞中呈现显著的细胞毒性,能较好地克服肿瘤的MDR。采用流式细胞仪和共聚焦显微镜技术评价了载药胶束在MCF-7/Adr细胞中摄取情况,结果表明阿霉素纳米胶束能显著提高DOX在耐药细胞的摄取。P-gp抑制实验表明自合成的纳米材料能抑制P-gp的活性且为P-gp ATPase的反竞争性抑制剂；阿霉素纳米胶束能避免P-gp识别且在纳米材料抑制P-gp作用协同下而显著增加药物的摄取。内吞抑制实验表明胶束以能量依赖的胞吞方式摄取,通过小窝蛋白介导、网格蛋白介导、非网格蛋白非小窝蛋白介导的内吞和巨胞饮中的一种或多种途径入胞。
采用UPLC/MS/MS测定了DOX和各载药胶束在大鼠静注体内药动学,结果表明PLV2K-DOX、PLV5K-DOX、PLV2K-NH2-DOX、TPGS2K-DOX和TPGS-DOX胶束分别使DOX-Sol的t1/2由8.1h延长至183.8h、94.6h、181.6h、82.4h和42.0h,AUC(0-t)分别是DOX-Sol的10.4、7.5、5.1、7.2和4.9倍。表明阿霉素纳米胶束均能够提高阿霉素药时曲线下面积,增加药物在血浆中的循环时间,达到长循环的效果,从而能更好地使纳米胶束通过EPR效应分布到肿瘤区域,发挥疗效。体内药效学结果表明阿霉素纳米胶束能显著抑制Balb/C小鼠4T1鼠乳腺癌移植瘤的增长,同时降低毒副作用。PLV2K-DOX/PLV2K-NH2-DOX、TPGS-DOX的抑瘤率分别为62.92%、51.86%、56.95%,分别为DOX-Sol抑瘤率的2.17、1.80、1.97倍。
人结肠癌细胞Caco-2摄取和转运结果表明PLV2K-DOX能显著增加DOX在Caco-2细胞的摄取和转运。PLV2K-DOX跨肠细胞膜转运的方式并非打开紧密连接而是以能量依赖的、网格蛋白介导的、小窝蛋白介导的和非小窝蛋白非网格蛋白介导的内吞和巨胞饮途径而主动转运。PLV2K-DOX的膜渗透率为35.75+2.30,是DOX的4.8倍(P<0.05)。这样阿霉素纳米胶束可显著提高药物的肠渗透性,进而提高阿霉素的口服生物利用度。大鼠口服PLV2K-DOX纳米胶束后,PLV2K-DOX的口服绝对生物利用度是DOX-Sol的5倍。从而表明基于PLV2K的纳米胶束是提高P-gp底物口服吸收的有效载体。
Chemotherapy is the major route for tumor therapy. Nowadays, multidrug resistance and side effects of drug limit the effectiveness of chemotherapies in clinic. The strategies and approaches for oncotherapy are to circumvent multidrug resistance (short by MDR) and decrease the toxic and side-effects.
The main aims of this research were to design a multifunctional amphiphilic star-shape polymer of lysine-linked di-tocopherol polyethylene glycol succinate. Star-shape copolymers have striking triple functions to prepare a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs by virtue of the following characteristics:long-time circulation, P-gp transporter reversible inhibitor and synergistic anticancer efficacy. Self-synthetic amphiphilic polymers were used as nanocarrier and hydrophobic doxorubicin were used as model drug to self-assemble in aqueous medium to prepare smart nanomicelles. The main contents of this study include the synthesis and identification of the polymer, preparation of the micelles, evaluation of the pharmaceutical pharmacy, cytotoxicity, cellular uptake,endocytosis mechanism, pharmacokinetic study and pharmacodynamics. Meanwhile, we also investigate the oral chemotherapy of nanomicelles in vitro and in vivo.
First, lysine-linked di-tocopherol polyethylene glycol succinates were synthesized with vitamin E succinate as hydrophobic group and polyethylene glycol as hydrophilic group with the linker of lysine. Based on the different chain length of polyethylene glycol, the polymer were named as mPEG2000-Lys-di-VES (PLV2K-DOX), mPEG5000-Lys-di-VES (PLV5K-DOX), mPEG2000-NH-Lys-di-VES (PLV2K-NH2-DOX) and TPGS2K was synthesized as reference. Then the chemical structure of the synthesized copolymer was identified by1H NMR. The critical micelle concentration (CMC) of self-synthetic polymer was determined by pyrene as a fluorescent probe. The CMC of the copolymers were around2μg/mL, and with the content of polyethylene glycol, the CMC increased.
Self-synthetic amphiphilic polymers as nanomaterials and hydrophobic doxorubicin as model drug to prepare smart nanomicelles, named as PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX. The preparation and formulations were optimized and screened based on particle size and encapsulation efficiency. The micelles were prepared by film-thin hydration and the physicochemical properties of nanomicelles were investigated. The encapsulation efficiency of PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX micelles were97.11%,96.81%,96.45%,91.68%and91.18%, and the particle size were13.26±2.86,16.4±2.70,34.1±0.90,11.10±0.10and13.5±2.44nm, respectively. DOX-loaded micelles were spherical with uniform size. Zeta potentials were around0mV because of hydrophilic surface of polyethylene glycol. DSC analysis suggested that DOX encapsulated in the core of micelles or DOX loaded in micelles in the state of amorphous state. The in vitro release of DOX was conducted by dialysis bag method. The results implied that the release of DOX from micelles was pH dependent, released rapidly at low pH conditions but slowly at physical condition, which was benefit for smart release of DOX in tumor cells.
The cytotoxicity, cellular uptake and endocytosis mechanism of different DOX-loaded micelles were studied in MCF-7cells and MCF-7/Adr cells. In vitro cytotoxicity tests, the self-synthetic copolymers have abilities to inhibit the tumor growth. With the synthetic cytotoxicity of copolymer, DOX-loaded micelles shown significantly cytotoxicity in resistant MCF-7/Adr cells and overcome MDR compared with DOX-Sol. The cellular uptake of DOX-loaded micelles was conducted by flow cytometry and confocal laser scanning microscopy in P-gp over-expressed MCF-7/Adr cells. The DOX-loaded nanomicelles exhibited higher cellular accumulation than DOX-Sol. The P-gp inhibitory trials suggested that self-made nanocarriers have abilities to inhibit the activity of P-gp. Further investigation was conducted to show that self-made polymer was P-gp ATPase inhibitor. With the effect of P-gp inhibition of nanocarrier and bypass the recognition of P-gp by micelles, DOX-loaded micelles significantly improve cellular uptake. The endocytosis of micelles was energy-dependent. The mechanism of endocytosis included caveolae-mediated, clathrin-mediated, caveolae-and clathrn-independent endocytosis and macropinocytosis.
UPLC/MS/MS method was developed to determine DOX-Sol and DOX-loaded micelles in rat pharmacokinetics after intravenous injection. In vivo pharmacokinetic results suggested that t1/2of DOX was8.1h, but the t1/2of PLV2K-DOX, PLV5K-DOX, PLV2K-NH2-DOX, TPGS2K-DOX and TPGS-DOX micelles was prolonged to183.8h,94.6h,181.6h,82.4h and42.0h, respectively. The AUC(0-t) of those micelles were10.4,7.5,5.1,7.2and4.9times compared with DOX-Sol, respectively. DOX-loaded micelles could increase the AUC and extend plasma circulation time to arrive the effect of long-time circulation, which could benefit drug to accumulate in target cells through EPR effect to improve the therapy effect. Balb/C mice bearing4T1breast transplanted tumor were used as models to study the antitumor activities of DOX-loaded micelles in vivo. The results implied that DOX-loaded micelles could significantly inhibit the growth of tumor and decrease the toxicity in mice by drug. The inhibitory rate of tumor of PLV2K-DOX, PLV2K-NH2-DOX and TPGS-DOX was62.92%,51.86%and56.95%, which was2.17,1.80and1.97times compared with DOX-Sol.
In oral chemotherapy tests, human colon cancer cells Caco-2was selective as model to investigate the uptake and transport of DOX. The results suggested that PLV2K-DOX nanomicelles significantly increase the uptake and transport of DOX in intestinal cells. The transport path of PLV2K-DOX micelles was not opening the tight connection, but through energy dependent, caveolae-mediated and clathrin, caveolin-independent endocytosis. The membrane permeability of PLV2K-DOX was35.75±2.30, which was4.8times of DOX-Sol. So micelles which were used for oral chemotherapy could improve the intestinal permeability and increase the oral bioavailability of DOX. After oral administration of PLV2K-DOX micelles in SD rat, the oral absolute bioavailability of PLV2K-DOX was5times of that in DOX. So micelles could provide effective pathways to improve oral absorption of P-gp substrates.
引文
[1]Stein W, Bates S, Fojo T. Intractable cancers:the many faces of multidrug resistance and the many targets it presents for therapeutic attack. Current drug targets.2004;5:333-46.
[2]Takara K, Sakaeda T, Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. Current pharmaceutical design.2006; 12:273-86.
[3]刘新春,程玉峰,李德爱.抗肿瘤耐药机制.实用抗肿瘤药物治疗学；2002.
[4]Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, et al. Molecular targeting therapy of cancer:drug resistance, apoptosis and survival signal. Cancer science.2003;94:15-21.
[5]Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, et al. MRP8, ATP-binding cassette Cll (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl) adenine. Journal of Biological Chemistry.2003;278:29509-14.
[6]Palissot V, Morjani H, Belloc F, Cotteret S, Dufer J, Berchem G. From molecular characteristics to cellular events in apoptosis-resistant HL-60 cells. International journal of oncology.2005;26:825-34.
[7]Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Current opinion in oncology.2000; 12:450.
[8]Shman T, Savitskii V, Potapnev M, Aleinikova O. Study of expression and functional activity of P-GP membrane glycoprotein in children with acute leukemia. Bulletin of experimental biology and medicine.2006; 141:727-30.
[9]Longley D, Johnston P. Molecular mechanisms of drug resistance. The Journal of pathology. 2005;205:275-92.
[10]Nobili S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance. Current drug targets.2006;7:861-79.
[11]Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene.2003;22:7512-23.
[12]Pauli-Magnus C, Kroetz DL. Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharmaceutical research.2004;21:904-13.
[13]Castaing M, Loiseau A, Cornish-Bowden A. Synergy between verapamil and other multidrug-resistance modulators in model membranes. Journal of Biosciences.2007;32:737-46.
[14]Kingsley JD, Dou H, Morehead J, Rabinow B, Gendelman HE, Destache CJ. Nanotechnology:a focus on nanoparticles as a drug delivery system. Journal of Neuroimmune Pharmacology. 2006; 1:340-50.
[15]Hu CMJ, Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochemical Pharmacology.2012.
[16]Prasad P, Cheng J, Shuhendler A, Rauth AM, Wu XY. A novel nanoparticle formulation overcomes multiple types of membrane efflux pumps in human breast cancer cells. Drug Delivery and Translational Research.2012:1-11.
[17]Sun Y, Chen XY, Zhu YJ, Liu PF, Zhu MJ, Duan YR. Synthesis of calcium phosphate/GPC-mPEG hybrid porous nanospheres for drug delivery to overcome multidrug resistance in human breast cancer. J Mater Chem.2012;22:5128-36.
[18]Deng Z, Yan F, Li L, Jin Q, Li F, Zheng H. Cytotoxicity enhancement of DOX-liposome-containing microbubbles combined with ultrasound to the multi-drug resistant cell. The Journal of the Acoustical Society of America.2012; 131:3366.
[19]Liu Y. The Cytotoxic Effect and Mechanism of Antisense Oligonucledtides and Epirubicin in Liposomes on Cancer.2012.
[20]Huh KM, Kang HC, Lee YJ, Bae YH. pH-sensitive polymers for drug delivery. Macromolecular Research.2012;20:224-33.
[21]Huang G, Khemtong C, Bey EA, Boothman DA, Sumer BD, Gao J. Theranostic Polymeric Micelles for Cancer Imaging and Therapy. Multifunctional Nanoparticles for Drug Delivery Applications.2012:257-76.
[22]Sarisozen C, Vural I, Levchenko T, Hincal AA, Torchilin VP. PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells. Drug Delivery.2012:1-8.
[23]Binkhathlan Z, Shayeganpour A, Brocks DR, Lavasanifar A. Encapsulation of P-glycoprotein inhibitors by polymeric micelles can reduce their pharmacokinetic interactions with doxorubicin. European Journal of Pharmaceutics and Biopharmaceutics.2012.
[24]Tian Y, Mao S. Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs. Expert Opinion on Drug Delivery.2012:1-14.
[25]陆彬.作为载药系统的聚合物胶束和泡囊的研究.河南大学学报：医学版.2008；27：1-7.
[26]Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Release.2001;73:137-72.
[27]Mikhail AS, Allen C. Block copolymer micelles for delivery of cancer therapy:transport at the whole body, tissue and cellular levels. Journal of Controlled Release.2009; 138:214-23.
[28]Nishiyama N, Kataoka K. Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. Pharmacology & therapeutics.2006; 112:630-48.
[29]Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced drug delivery reviews.2004;56:1273-89.
[30]Rosler A, Vandermeulen GWM, Klok HA. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced drug delivery reviews.2001;53:95-108.
[31]Chung J, Yokoyama M, Aoyagi T, Sakurai Y, Okano T. Effect of molecular architecture of hydrophobically modified poly (N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. Journal of Controlled Release.1998;53:119-30.
[32]李远达,朱亮.聚合物胶束在肿瘤治疗中的研究进展.中国医药工业杂志.2010；41：615-21.
[33]Montazeri Aliabadi H, Brocks DR, Lavasanifar A. Polymeric micelles for the solubilization and delivery of cyclosporine A:pharmacokinetics and biodistribution. Biomaterials.2005;26:7251-9.
[34]Matsumura Y, Kataoka K. Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer science.2009; 100:572-9.
[35]Yokoyama M. Clinical Applications of Polymeric Micelle Carrier Systems in Chemotherapy and Image Diagnosis of Solid Tumors. Journal of Experimental and Clinical Medicine.2011;3:151-8.
[36]Gong J, Chen M, Zheng Y, Wang S, Wang Y. Polymeric micelles drug delivery system in oncology. Journal of Controlled Release.2012.
[37]刁媛媛,韩曼,陈大为,高建青.胶束传递系统逆转肿瘤多药耐药的研究进展.药学学报.2009;7.
[38]Chen D, Yan L, Qiao M, Hu H, Zhao X, Chen X, et al. Preparation of docetaxel-loaded pH-sensitive block copolymer micelles]. Yao xue xue bao= Acta pharmaceutica Sinica.2008;43:1066.
[39]Hugger ED, Cole CJ, Raub TJ, Burton PS, Borchardt RT. Automated analysis of polyethylene glycol-induced inhibition of P-glycoprotein activity in vitro. Journal of pharmaceutical sciences. 2003;92:21-6.
[40]焦真,王星,陈志明.两亲嵌段聚合物载药胶束研究进展.高分子通报.2010.
[41]Werle M. Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharmaceutical research.2008;25:500-11.
[42]黄雷鸣,赵锦花,王国成,周建平.聚合物辅料对P-糖蛋白抑制机制的研究进展.药学学报.2010;45：1224-31.
[43]Shaik N, Pan G, Elmquist WE Interactions of pluronic block copolymers on P-gp efflux activity: Experience with HIV-1 protease inhibitors. Journal of pharmaceutical sciences.2008;97:5421-33.
[44]Batrakova EV, Li S, Li Y, Alakhov VY, Kabanov AV. Effect of pluronic P85 on ATPase activity of drug efflux transporters. Pharmaceutical research.2004;21:2226-33.
[45]Collnot EM, Baldes C, Wempe MF, Kappl R, Huttermann J, Hyatt JA, et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS:influence on ATPase activity and membrane fluidity. Molecular pharmaceutics.2007;4:465-74.
[46]Batrakova E, Li S, Elmquist W, Miller D, Alakhov VY, Kabanov A. Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. British journal of cancer. 2001;85:1987.
[47]Batrakova EV, Kelly DL, Li S, Li Y, Yang Z, Xiao L, et al. Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient:pluronic P85. Molecular pharmaceutics.2006;3:113-23.
[48]Sriadibhatla S, Yang Z, Gebhart C, Alakhov VY, Kabanov A. Transcriptional activation of gene expression by pluronic block copolymers in stably and transiently transfected cells. Molecular therapy. 2006;13:804-13.
[49]Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharmaceutical research.1999; 16:1550-6.
[50]Zhao H, Yung LYL. Addition of TPGS to folate-conjugated polymer micelles for selective tumor targeting. Journal of Biomedical Materials Research Part A.2009;91:505-18.
[51]Mi Y, Liu Y, Feng SS. Formulation of Docetaxel by folic acid-conjugated d-[alpha]-tocopheryl polyethylene glycol succinate 2000(Vitamin E TPGS2k) micelles for targeted and synergistic chemotherapy. Biomaterials.2011.
[52]Turley JM, Funakoshi S, Ruscetti FW, Kasper J, Murphy WJ, Longo DL, et al. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid:role for transforming growth factor beta. Cell growth & differentiation:the molecular biology journal of the American Association for Cancer Research.1995;6:655.
[53]Venkateswaran V, Fleshner NE, Klotz LH. Modulation of cell proliferation and cell cycle regulators by vitamin E in human prostate carcinoma cell lines. The Journal of urology. 2002;168:1578-82.
[54]Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice. Surgery.2002; 131:85-91.
[55]Israel K, Sanders BG, Kline K. RRR-a-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways.1995.
[56]Gu X, Song X, Dong Y, Cai H, Walters E, Zhang R, et al. Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo. Clinical cancer research.2008; 14:1840-8.
[57]Israel K, Yu W, Sanders BG, Kline K. Vitamin E succinate induces apoptosis in human prostate cancer cells:role for Fas in vitamin E succinate-triggered apoptosis. Nutrition and cancer. 2000;36:90-100.
[58]Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clinical cancer research.2002;8:863-9.
[59]Prasad KN, Kumar B, Yan XD, Hanson AJ, Cole WC. a-Tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment:a review. Journal of the American College of Nutrition. 2003;22:108-17.
[60]Neuzil J, Weber T, Gellert N, Weber C. Selective cancer cell killing by a-tocopheryl succinate. British journal of cancer.2001;84:87.
[61]Kozin SV, Shkarin P, Gerweck LE. The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer research.2001;61:4740.
[62]陈东,丁平田,邓意辉.聚合物胶束口服吸收机制的研究进展.沈阳药科大学学报.2010；8.
[63]Ottino P, Duncan JR. Effect of [alpha]-Tocopherol Succinate on Free Radical and Lipid Peroxidation Levels in BL6 Melanoma Cells. Free Radical Biology and Medicine.1997;22:1145-51.
[64]Wang XF, Witting PK, Salvatore BA, Neuzil J. Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway. Biochemical and biophysical research communications.2005;326:282-9.
[65]McCormick DL, Rao K. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat. European urology.1999;35:464-7.
[66]Luo J, Xiao K, Li Y, Lee JS, Shi L, Tan YH, et al. Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment. Bioconjugate chemistry. 2010;21:1216-24.
[67]Kalyanasundaram K, Thomas J. Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems. Journal of the American Chemical Society.1977;99:2039-44.
[68]Martic PA, Nair M. Microenvironment sensing of block copolymer micelles by fluorescence spectroscopy. Journal of colloid and interface science.1994; 163:517-9.
[69]Yekta A, Duhamel J, Brochard P, Adiwidjaja H, Winnik MA. A fluorescent probe study of micelle-like cluster formation in aqueous solutions of hydrophobically modified poly (ethylene oxide). Macromolecules.1993;26:1829-36.
[70]Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Molecular pharmaceutics.2008;5:505-15.
[71]Kievit FM, Wang FY, Fang C, Mok H, Wang K, Silber JR, et al. Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. Journal of Controlled Release.2011.
[72]Guo M, Yan Y, Liu X, Yan H, Liu K, Zhang H, et al. Multilayer nanoparticles with a magnetite core and a polycation inner shell as pH-responsive carriers for drug delivery. Nanoscale. 2009;2:434-41.
[73]Zhou R, Zhang F, He PL, Zhou WL, Wu QL, Xu JY, et al. (5< i> R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. International immunopharmacology.2005;5:1895-903.
[74]Teng Y, Morrison M, Munk P, Webber S, Prochazka K. Release kinetics studies of aromatic molecules into water from block polymer micelles. Macromolecules.1998;31:3578-87.
[75]Batrakova EV, Kabanov AV. Pluronic block copolymers:evolution of drug delivery concept from inert nanocarriers to biological response modifiers. Journal of Controlled Release.2008; 130:98-106.
[76]Batrakova EV, Li S, Brynskikh AM, Sharma AK, Li Y, Boska M, et al. Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers. Journal of Controlled Release.2010;143:290-301.
[77]Kabanov AV, Batrakova EV, Alakhov VY. Pluronic(?) block copolymers for overcoming drug resistance in cancer. Advanced drug delivery reviews.2002;54:759-79.
[78]Bates SE, Robey R, Miyake K, Rao K, Ross DD, Litman T. The role of half-transporters in multidrug resistance. Journal of bioenergetics and biomembranes.2001;33:503-11.
[79]Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annual review of biochemistry.2002;71:537-92.
[80]Gergely SAC, Katalin J, Ferenc A, Balazs S. Diagnostics of multidrug resistance in cancer. Pathology & Oncology Research.1998;4:251-7.
[81]Renschler MF. The emerging role of reactive oxygen species in cancer therapy. European Journal of Cancer.2004;40:1934-40.
[82]Youk HJ, Lee E, Choi MK, Lee YJ, Chung JH, Kim SH, et al. Enhanced anticancer efficacy of a-tocopheryl succinate by conjugation with polyethylene glycol. Journal of Controlled Release. 2005;107:43-52.
[83]Borowski E, Bontemps-Gracz MM, Piwkowska A. Strategies for overcoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells. ACTA BIOCHIMICA POLONICA-ENGLISH EDITION-.2005;52:609.
[84]Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, et al. Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci. 2007;10:350-7.
[85]Wempe MF, Wright C, Little JL, Lightner JW, Large SE, Caflisch GB, et al. Inhibiting efflux with novel non-ionic surfactants:Rational design based on vitamin E TPGS. International journal of pharmaceutics.2009;370:93-102.
[86]Collnot EM, Baldes C, Wempe MF, Hyatt J, Navarro L, Edgar KJ, et al. Influence of vitamin E TPGS poly (ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. Journal of Controlled Release.2006; 111:35-40.
[87]Omelyanenko V, Gentry C. Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate. Journal of Controlled Release.1998;53:25-37.
[88]Yu L, Wu WKK, Li ZJ, Liu QC, Li HT, Wu YC, et al. Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC236) via inhibiting P-glycoprotein activity. Molecular pharmacology.2009;75:1364-73.
[89]Ma B, Chai S, Li N, To KKW, Kan WLT, Yang D, et al. Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic a-aminoxy peptidomimetic. International journal of pharmaceutics. 2012.
[90]Takei K, Haucke V. Clathrin-mediated endocytosis:membrane factors pull the trigger. Trends in cell biology.2001;11:385-91.
[91]Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. Journal of Controlled Release.2010;145:182-95.
[92]Huth US, Schubert R, Peschka-Suss R. Investigating the uptake and intracellular fate of pH-sensitive liposomes by flow cytometry and spectral bio-imaging. Journal Controlled Release. 2006; 110:490-504.
[93]Brandenberger C, Muhlfeld C, Ali Z, Lenz AG, Schmid O, Parak WJ, et al. Quantitative Evaluation of Cellular Uptake and Trafficking of Plain and Polyethylene Glycol-Coated Gold Nanoparticles. Small.2010;6:1669-78.
[94]Legen 1, Zakelj S, Kristl A. Polarised transport of monocarboxylic acid type drugs across rat jejunum in vitro:the effect of mucolysis and ATP-depletion. International journal of pharmaceutics. 2003;256:161-6.
[95]Kim JS, Yoon TJ, Yu KN, Noh MS, Woo M, Kim BG, et al. Cellular uptake of magnetic nanoparticle is mediated through energy-dependent endocytosis in A549 cells. Journal of veterinary science.2006;7:321.
[96]Torchilin VP, Rammohan R, Weissig V, Levchenko TS. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proceedings of the National Academy of Sciences.2001;98:8786.
[97]Swanson JA, Watts C. Macropinocytosis. Trends in cell biology.1995;5:424-8.
[98]Chang J, Jallouli Y, Kroubi M, Yuan X, Feng W, Kang C, et al. Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood-brain barrier. International journal of pharmaceutics.2009;379:285-92.
[99]Sahay G, Kim JO, Kabanov AV, Bronich TK. The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents. Biomaterials.2010;31:923-33.
[100]Zhang W, Sun J, Feng Z, Su X, Zhu M, Sui X, et al. Quantification of Doxorubicin in Pegylated Polymer Micelles in Rat Plasma by Methanol Precipitation-Ultrasonic Emulsion Breaking Method and UPLC-MS-MS. Chromatographia.2011:1-8.
[101]Wanliang L, Shuli W, Qiang Z, Xianrong Q, Huadong S. Doxorubicin stealth liposomes prepared with PEG-distearoyl phosphatidylethanolamine and distribution as well as antitumor activity in mice. Journal of Chinese Pharmaceutical Sciences.2000;9:191-5.
[102]Dressman JB, Lennernas H. Oral drug absorption:Prediction and assessment:Informa Healthcare; 2000.
[103]Kotze AR, Lueβen HL, de Leeuw BJ, De Boer BQ Verhoef JC, Junginger HE. N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces:in vitro evaluation in intestinal epithelial cells (Caco-2). Pharmaceutical research.1997; 14:1197-202.
[104]洪庆涛,宋岳涛,唐一鹏,刘春梅.细胞培养液乳酸脱氢酶漏出率的比色测定及其应用.细胞生物学杂志.2004；26：89-92.
[105]Jonker C, Hamman J, Kotze A. Intestinal paracellular permeation enhancement with quaternised chitosan:in situ and in vitro evaluation. International journal of pharmaceutics.2002;238:205-13.
[106]Li H, Huo M, Zhou J, Dai Y, Deng Y, Shi X, et al. Enhanced oral absorption of paclitaxel in N-deoxycholic acid-N, O-hydroxyethyl chitosan micellar system. Journal of pharmaceutical sciences. 2010;99:4543-53.
[107]Ho PY, Yeh TK, Yao HT, Lin HL, Wu HY, Lo YK, et al. Enhanced oral bioavailability of paclitaxel by d-a-tocopheryl polyethylene glycol 400 succinate in mice. International journal of pharmaceutics.2008;359:174-81.
[2]Takara K, Sakaeda T, Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. Current pharmaceutical design.2006; 12:273-86.
[3]刘新春,程玉峰,李德爱.抗肿瘤耐药机制.实用抗肿瘤药物治疗学；2002.
[4]Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, et al. Molecular targeting therapy of cancer:drug resistance, apoptosis and survival signal. Cancer science.2003;94:15-21.
[5]Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, et al. MRP8, ATP-binding cassette Cll (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl) adenine. Journal of Biological Chemistry.2003;278:29509-14.
[6]Palissot V, Morjani H, Belloc F, Cotteret S, Dufer J, Berchem G. From molecular characteristics to cellular events in apoptosis-resistant HL-60 cells. International journal of oncology.2005;26:825-34.
[7]Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Current opinion in oncology.2000; 12:450.
[8]Shman T, Savitskii V, Potapnev M, Aleinikova O. Study of expression and functional activity of P-GP membrane glycoprotein in children with acute leukemia. Bulletin of experimental biology and medicine.2006; 141:727-30.
[9]Longley D, Johnston P. Molecular mechanisms of drug resistance. The Journal of pathology. 2005;205:275-92.
[10]Nobili S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance. Current drug targets.2006;7:861-79.
[11]Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene.2003;22:7512-23.
[12]Pauli-Magnus C, Kroetz DL. Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharmaceutical research.2004;21:904-13.
[13]Castaing M, Loiseau A, Cornish-Bowden A. Synergy between verapamil and other multidrug-resistance modulators in model membranes. Journal of Biosciences.2007;32:737-46.
[14]Kingsley JD, Dou H, Morehead J, Rabinow B, Gendelman HE, Destache CJ. Nanotechnology:a focus on nanoparticles as a drug delivery system. Journal of Neuroimmune Pharmacology. 2006; 1:340-50.
[15]Hu CMJ, Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochemical Pharmacology.2012.
[16]Prasad P, Cheng J, Shuhendler A, Rauth AM, Wu XY. A novel nanoparticle formulation overcomes multiple types of membrane efflux pumps in human breast cancer cells. Drug Delivery and Translational Research.2012:1-11.
[17]Sun Y, Chen XY, Zhu YJ, Liu PF, Zhu MJ, Duan YR. Synthesis of calcium phosphate/GPC-mPEG hybrid porous nanospheres for drug delivery to overcome multidrug resistance in human breast cancer. J Mater Chem.2012;22:5128-36.
[18]Deng Z, Yan F, Li L, Jin Q, Li F, Zheng H. Cytotoxicity enhancement of DOX-liposome-containing microbubbles combined with ultrasound to the multi-drug resistant cell. The Journal of the Acoustical Society of America.2012; 131:3366.
[19]Liu Y. The Cytotoxic Effect and Mechanism of Antisense Oligonucledtides and Epirubicin in Liposomes on Cancer.2012.
[20]Huh KM, Kang HC, Lee YJ, Bae YH. pH-sensitive polymers for drug delivery. Macromolecular Research.2012;20:224-33.
[21]Huang G, Khemtong C, Bey EA, Boothman DA, Sumer BD, Gao J. Theranostic Polymeric Micelles for Cancer Imaging and Therapy. Multifunctional Nanoparticles for Drug Delivery Applications.2012:257-76.
[22]Sarisozen C, Vural I, Levchenko T, Hincal AA, Torchilin VP. PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells. Drug Delivery.2012:1-8.
[23]Binkhathlan Z, Shayeganpour A, Brocks DR, Lavasanifar A. Encapsulation of P-glycoprotein inhibitors by polymeric micelles can reduce their pharmacokinetic interactions with doxorubicin. European Journal of Pharmaceutics and Biopharmaceutics.2012.
[24]Tian Y, Mao S. Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs. Expert Opinion on Drug Delivery.2012:1-14.
[25]陆彬.作为载药系统的聚合物胶束和泡囊的研究.河南大学学报：医学版.2008；27：1-7.
[26]Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Release.2001;73:137-72.
[27]Mikhail AS, Allen C. Block copolymer micelles for delivery of cancer therapy:transport at the whole body, tissue and cellular levels. Journal of Controlled Release.2009; 138:214-23.
[28]Nishiyama N, Kataoka K. Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. Pharmacology & therapeutics.2006; 112:630-48.
[29]Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced drug delivery reviews.2004;56:1273-89.
[30]Rosler A, Vandermeulen GWM, Klok HA. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced drug delivery reviews.2001;53:95-108.
[31]Chung J, Yokoyama M, Aoyagi T, Sakurai Y, Okano T. Effect of molecular architecture of hydrophobically modified poly (N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. Journal of Controlled Release.1998;53:119-30.
[32]李远达,朱亮.聚合物胶束在肿瘤治疗中的研究进展.中国医药工业杂志.2010；41：615-21.
[33]Montazeri Aliabadi H, Brocks DR, Lavasanifar A. Polymeric micelles for the solubilization and delivery of cyclosporine A:pharmacokinetics and biodistribution. Biomaterials.2005;26:7251-9.
[34]Matsumura Y, Kataoka K. Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer science.2009; 100:572-9.
[35]Yokoyama M. Clinical Applications of Polymeric Micelle Carrier Systems in Chemotherapy and Image Diagnosis of Solid Tumors. Journal of Experimental and Clinical Medicine.2011;3:151-8.
[36]Gong J, Chen M, Zheng Y, Wang S, Wang Y. Polymeric micelles drug delivery system in oncology. Journal of Controlled Release.2012.
[37]刁媛媛,韩曼,陈大为,高建青.胶束传递系统逆转肿瘤多药耐药的研究进展.药学学报.2009;7.
[38]Chen D, Yan L, Qiao M, Hu H, Zhao X, Chen X, et al. Preparation of docetaxel-loaded pH-sensitive block copolymer micelles]. Yao xue xue bao= Acta pharmaceutica Sinica.2008;43:1066.
[39]Hugger ED, Cole CJ, Raub TJ, Burton PS, Borchardt RT. Automated analysis of polyethylene glycol-induced inhibition of P-glycoprotein activity in vitro. Journal of pharmaceutical sciences. 2003;92:21-6.
[40]焦真,王星,陈志明.两亲嵌段聚合物载药胶束研究进展.高分子通报.2010.
[41]Werle M. Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharmaceutical research.2008;25:500-11.
[42]黄雷鸣,赵锦花,王国成,周建平.聚合物辅料对P-糖蛋白抑制机制的研究进展.药学学报.2010;45：1224-31.
[43]Shaik N, Pan G, Elmquist WE Interactions of pluronic block copolymers on P-gp efflux activity: Experience with HIV-1 protease inhibitors. Journal of pharmaceutical sciences.2008;97:5421-33.
[44]Batrakova EV, Li S, Li Y, Alakhov VY, Kabanov AV. Effect of pluronic P85 on ATPase activity of drug efflux transporters. Pharmaceutical research.2004;21:2226-33.
[45]Collnot EM, Baldes C, Wempe MF, Kappl R, Huttermann J, Hyatt JA, et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS:influence on ATPase activity and membrane fluidity. Molecular pharmaceutics.2007;4:465-74.
[46]Batrakova E, Li S, Elmquist W, Miller D, Alakhov VY, Kabanov A. Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. British journal of cancer. 2001;85:1987.
[47]Batrakova EV, Kelly DL, Li S, Li Y, Yang Z, Xiao L, et al. Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient:pluronic P85. Molecular pharmaceutics.2006;3:113-23.
[48]Sriadibhatla S, Yang Z, Gebhart C, Alakhov VY, Kabanov A. Transcriptional activation of gene expression by pluronic block copolymers in stably and transiently transfected cells. Molecular therapy. 2006;13:804-13.
[49]Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharmaceutical research.1999; 16:1550-6.
[50]Zhao H, Yung LYL. Addition of TPGS to folate-conjugated polymer micelles for selective tumor targeting. Journal of Biomedical Materials Research Part A.2009;91:505-18.
[51]Mi Y, Liu Y, Feng SS. Formulation of Docetaxel by folic acid-conjugated d-[alpha]-tocopheryl polyethylene glycol succinate 2000(Vitamin E TPGS2k) micelles for targeted and synergistic chemotherapy. Biomaterials.2011.
[52]Turley JM, Funakoshi S, Ruscetti FW, Kasper J, Murphy WJ, Longo DL, et al. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid:role for transforming growth factor beta. Cell growth & differentiation:the molecular biology journal of the American Association for Cancer Research.1995;6:655.
[53]Venkateswaran V, Fleshner NE, Klotz LH. Modulation of cell proliferation and cell cycle regulators by vitamin E in human prostate carcinoma cell lines. The Journal of urology. 2002;168:1578-82.
[54]Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice. Surgery.2002; 131:85-91.
[55]Israel K, Sanders BG, Kline K. RRR-a-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways.1995.
[56]Gu X, Song X, Dong Y, Cai H, Walters E, Zhang R, et al. Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo. Clinical cancer research.2008; 14:1840-8.
[57]Israel K, Yu W, Sanders BG, Kline K. Vitamin E succinate induces apoptosis in human prostate cancer cells:role for Fas in vitamin E succinate-triggered apoptosis. Nutrition and cancer. 2000;36:90-100.
[58]Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clinical cancer research.2002;8:863-9.
[59]Prasad KN, Kumar B, Yan XD, Hanson AJ, Cole WC. a-Tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment:a review. Journal of the American College of Nutrition. 2003;22:108-17.
[60]Neuzil J, Weber T, Gellert N, Weber C. Selective cancer cell killing by a-tocopheryl succinate. British journal of cancer.2001;84:87.
[61]Kozin SV, Shkarin P, Gerweck LE. The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer research.2001;61:4740.
[62]陈东,丁平田,邓意辉.聚合物胶束口服吸收机制的研究进展.沈阳药科大学学报.2010；8.
[63]Ottino P, Duncan JR. Effect of [alpha]-Tocopherol Succinate on Free Radical and Lipid Peroxidation Levels in BL6 Melanoma Cells. Free Radical Biology and Medicine.1997;22:1145-51.
[64]Wang XF, Witting PK, Salvatore BA, Neuzil J. Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway. Biochemical and biophysical research communications.2005;326:282-9.
[65]McCormick DL, Rao K. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat. European urology.1999;35:464-7.
[66]Luo J, Xiao K, Li Y, Lee JS, Shi L, Tan YH, et al. Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment. Bioconjugate chemistry. 2010;21:1216-24.
[67]Kalyanasundaram K, Thomas J. Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems. Journal of the American Chemical Society.1977;99:2039-44.
[68]Martic PA, Nair M. Microenvironment sensing of block copolymer micelles by fluorescence spectroscopy. Journal of colloid and interface science.1994; 163:517-9.
[69]Yekta A, Duhamel J, Brochard P, Adiwidjaja H, Winnik MA. A fluorescent probe study of micelle-like cluster formation in aqueous solutions of hydrophobically modified poly (ethylene oxide). Macromolecules.1993;26:1829-36.
[70]Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Molecular pharmaceutics.2008;5:505-15.
[71]Kievit FM, Wang FY, Fang C, Mok H, Wang K, Silber JR, et al. Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. Journal of Controlled Release.2011.
[72]Guo M, Yan Y, Liu X, Yan H, Liu K, Zhang H, et al. Multilayer nanoparticles with a magnetite core and a polycation inner shell as pH-responsive carriers for drug delivery. Nanoscale. 2009;2:434-41.
[73]Zhou R, Zhang F, He PL, Zhou WL, Wu QL, Xu JY, et al. (5< i> R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. International immunopharmacology.2005;5:1895-903.
[74]Teng Y, Morrison M, Munk P, Webber S, Prochazka K. Release kinetics studies of aromatic molecules into water from block polymer micelles. Macromolecules.1998;31:3578-87.
[75]Batrakova EV, Kabanov AV. Pluronic block copolymers:evolution of drug delivery concept from inert nanocarriers to biological response modifiers. Journal of Controlled Release.2008; 130:98-106.
[76]Batrakova EV, Li S, Brynskikh AM, Sharma AK, Li Y, Boska M, et al. Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers. Journal of Controlled Release.2010;143:290-301.
[77]Kabanov AV, Batrakova EV, Alakhov VY. Pluronic(?) block copolymers for overcoming drug resistance in cancer. Advanced drug delivery reviews.2002;54:759-79.
[78]Bates SE, Robey R, Miyake K, Rao K, Ross DD, Litman T. The role of half-transporters in multidrug resistance. Journal of bioenergetics and biomembranes.2001;33:503-11.
[79]Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annual review of biochemistry.2002;71:537-92.
[80]Gergely SAC, Katalin J, Ferenc A, Balazs S. Diagnostics of multidrug resistance in cancer. Pathology & Oncology Research.1998;4:251-7.
[81]Renschler MF. The emerging role of reactive oxygen species in cancer therapy. European Journal of Cancer.2004;40:1934-40.
[82]Youk HJ, Lee E, Choi MK, Lee YJ, Chung JH, Kim SH, et al. Enhanced anticancer efficacy of a-tocopheryl succinate by conjugation with polyethylene glycol. Journal of Controlled Release. 2005;107:43-52.
[83]Borowski E, Bontemps-Gracz MM, Piwkowska A. Strategies for overcoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells. ACTA BIOCHIMICA POLONICA-ENGLISH EDITION-.2005;52:609.
[84]Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, et al. Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci. 2007;10:350-7.
[85]Wempe MF, Wright C, Little JL, Lightner JW, Large SE, Caflisch GB, et al. Inhibiting efflux with novel non-ionic surfactants:Rational design based on vitamin E TPGS. International journal of pharmaceutics.2009;370:93-102.
[86]Collnot EM, Baldes C, Wempe MF, Hyatt J, Navarro L, Edgar KJ, et al. Influence of vitamin E TPGS poly (ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. Journal of Controlled Release.2006; 111:35-40.
[87]Omelyanenko V, Gentry C. Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate. Journal of Controlled Release.1998;53:25-37.
[88]Yu L, Wu WKK, Li ZJ, Liu QC, Li HT, Wu YC, et al. Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC236) via inhibiting P-glycoprotein activity. Molecular pharmacology.2009;75:1364-73.
[89]Ma B, Chai S, Li N, To KKW, Kan WLT, Yang D, et al. Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic a-aminoxy peptidomimetic. International journal of pharmaceutics. 2012.
[90]Takei K, Haucke V. Clathrin-mediated endocytosis:membrane factors pull the trigger. Trends in cell biology.2001;11:385-91.
[91]Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. Journal of Controlled Release.2010;145:182-95.
[92]Huth US, Schubert R, Peschka-Suss R. Investigating the uptake and intracellular fate of pH-sensitive liposomes by flow cytometry and spectral bio-imaging. Journal Controlled Release. 2006; 110:490-504.
[93]Brandenberger C, Muhlfeld C, Ali Z, Lenz AG, Schmid O, Parak WJ, et al. Quantitative Evaluation of Cellular Uptake and Trafficking of Plain and Polyethylene Glycol-Coated Gold Nanoparticles. Small.2010;6:1669-78.
[94]Legen 1, Zakelj S, Kristl A. Polarised transport of monocarboxylic acid type drugs across rat jejunum in vitro:the effect of mucolysis and ATP-depletion. International journal of pharmaceutics. 2003;256:161-6.
[95]Kim JS, Yoon TJ, Yu KN, Noh MS, Woo M, Kim BG, et al. Cellular uptake of magnetic nanoparticle is mediated through energy-dependent endocytosis in A549 cells. Journal of veterinary science.2006;7:321.
[96]Torchilin VP, Rammohan R, Weissig V, Levchenko TS. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proceedings of the National Academy of Sciences.2001;98:8786.
[97]Swanson JA, Watts C. Macropinocytosis. Trends in cell biology.1995;5:424-8.
[98]Chang J, Jallouli Y, Kroubi M, Yuan X, Feng W, Kang C, et al. Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood-brain barrier. International journal of pharmaceutics.2009;379:285-92.
[99]Sahay G, Kim JO, Kabanov AV, Bronich TK. The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents. Biomaterials.2010;31:923-33.
[100]Zhang W, Sun J, Feng Z, Su X, Zhu M, Sui X, et al. Quantification of Doxorubicin in Pegylated Polymer Micelles in Rat Plasma by Methanol Precipitation-Ultrasonic Emulsion Breaking Method and UPLC-MS-MS. Chromatographia.2011:1-8.
[101]Wanliang L, Shuli W, Qiang Z, Xianrong Q, Huadong S. Doxorubicin stealth liposomes prepared with PEG-distearoyl phosphatidylethanolamine and distribution as well as antitumor activity in mice. Journal of Chinese Pharmaceutical Sciences.2000;9:191-5.
[102]Dressman JB, Lennernas H. Oral drug absorption:Prediction and assessment:Informa Healthcare; 2000.
[103]Kotze AR, Lueβen HL, de Leeuw BJ, De Boer BQ Verhoef JC, Junginger HE. N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces:in vitro evaluation in intestinal epithelial cells (Caco-2). Pharmaceutical research.1997; 14:1197-202.
[104]洪庆涛,宋岳涛,唐一鹏,刘春梅.细胞培养液乳酸脱氢酶漏出率的比色测定及其应用.细胞生物学杂志.2004；26：89-92.
[105]Jonker C, Hamman J, Kotze A. Intestinal paracellular permeation enhancement with quaternised chitosan:in situ and in vitro evaluation. International journal of pharmaceutics.2002;238:205-13.
[106]Li H, Huo M, Zhou J, Dai Y, Deng Y, Shi X, et al. Enhanced oral absorption of paclitaxel in N-deoxycholic acid-N, O-hydroxyethyl chitosan micellar system. Journal of pharmaceutical sciences. 2010;99:4543-53.
[107]Ho PY, Yeh TK, Yao HT, Lin HL, Wu HY, Lo YK, et al. Enhanced oral bioavailability of paclitaxel by d-a-tocopheryl polyethylene glycol 400 succinate in mice. International journal of pharmaceutics.2008;359:174-81.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |