Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin

Qiu, Lipeng; Qiao, Mingxi; Qing, Chen; Tian, Chenmin; Long, Miaomiao; Wang, Mingyue; Li, Zhen; Hu, Wen; Li, Gang; Cheng, Liang; Liu, Cheng; Hu, Haiyang; Zhao, Xin; Chen, Dawei

doi:10.1016/j.biomaterials.2014.08.008

Cited by 150 publications

(104 citation statements)

References 53 publications

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“…Various studies reported that TPGS-PLGA NPs had a pH-triggered drug-release behavior under acidic pH environment. 27,[45][46][47] As CS-ALG-DOX NPs enter the nucleus, the release of DOX in the nucleus with pH 7.4 would produce the cytotoxic effect on DNA. From the in vitro drug release experiment, we had proved that S-D1@L-D2 NP was a Co-NDDS with pH-sensitive and biphasic release pattern of drugs in vitro, and preliminary conjectured that it could reduce the toxic and adverse effects on the normal organs and increase the anticancer effects of drugs.…”

Section: Biphasic Release Pattern Of Drugs In Vitromentioning

confidence: 99%

“…It maybe for this reason that TPGS affected the generation of ATP energy by affecting the mitochondria. 24,27,46 The effect of CS-ALG@TPGS-PLGA NPs on apoptosis of MDR cell was explored by flow cytometer technique. As shown in Figure S3C, the NPs had a mild apoptosis on A549/ taxol cell at the concentration of 1.0 mg/mL for 24 h. The results proved that the empty NPs are basically safe.…”

Section: In Vitro Biological Effect Cell Viability Of Empty Npsmentioning

confidence: 99%

“…48 Moreover, while some anticancer drugs belonging to the P-gp substrates, such as DOX, 46 were loaded into Co-NDDS; increasing intracellular concentration of the drugs became a pivotal challenge. Conventional countermeasures are increasing uptake and decreasing P-gp-related efflux.…”

Section: Cellular Internalization and Subcellular Location Of Loaded mentioning

confidence: 99%

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Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

Zhang

Kong

Jie

et al. 2017

IJN

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Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR). Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs) carrying a drug doxorubicin (DOX) were loaded into a larger NP containing another drug (vincristine [VCR]) via water-in-oil-in-water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs) with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles carrying VCR (TPGS-PLGA-VCR NPs) with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS-ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with pH-sensitive characteristics. S-D1@L-D2 NPs could obviously enhance the in vitro cytotoxicity and the in vivo anticancer efficiency of co-delivery drugs, while reducing their adverse effects. Overall, S-D1@L-D2 NPs can be considered an innovative platform for the co-delivery drugs of clinical combination chemotherapy for the treatment of MDR tumor.

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Section: Biphasic Release Pattern Of Drugs In Vitromentioning

confidence: 99%

Section: In Vitro Biological Effect Cell Viability Of Empty Npsmentioning

confidence: 99%

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Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

Zhang

Kong

Jie

et al. 2017

IJN

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“…1 Recently, multifunctional nanocarriers have been emerging as a promising approach to overcome the biologic complexity and heterogeneity during cancer chemotherapy. [2][3][4][5] The most distinguishing benefit of multifunctional nanocarriers is that they can be engineered to achieve targeted delivery of multiple therapeutic agents for multimodal chemotherapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells

Hong

Shi

Qiao

et al. 2017

IJN

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Even though a tremendous number of multifunctional nanocarriers have been developed to tackle heterogeneous cancer cells, little attention has been paid to elucidate how to rationally design a multifunctional nanocarrier. In this study, three individual functions (active targeting, stimuli-triggered release and endo-lysosomal escape) were evaluated in doxorubicin (DOX)-sensitive MCF-7 cells and DOX-resistant MCF-7/ADR cells by constructing four kinds of micelles with active-targeting (AT-M), passive targeting, pH-triggered release ( pH T-M) and endo-lysosomal escape ( endo E-M) function, respectively. AT-M demonstrated the strongest cytotoxicity against MCF-7 cells and the highest cellular uptake of DOX due to the folate-mediated endocytosis. However, AT-M failed to exhibit the best efficacy against MCF-7/ADR cells, while endo E-M exhibited the strongest cytotoxicity against MCF-7/ADR cells and the highest cellular uptake of DOX due to the lowest elimination of DOX from the cells. This was attributed to the carrier-facilitated endo-lysosomal escape of DOX, which avoided exocytosis by lysosome secretion, resulting in an effective accumulation of DOX in the cytoplasm. The enhanced elimination of DOX from the MCF-7/ADR cells also accounted for the remarkable decrease in cytotoxicity against the cells of AT-M. Three micelles were further evaluated with MCF-7 cells and MCF-7/ADR-resistant cells xenografted mice model. In accordance with the in vitro results, AT-M and endo E-M demonstrated the strongest inhibition on the MCF-7 and MCF-7/ADR xenografted tumor, respectively. Active targeting and active targeting in combination with endo-lysosomal escape have been demonstrated to be the primary function for a nanocarrier against doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells, respectively. These results indicate that the rational design of multifunctional nanocarriers for cancer therapy needs to consider the heterogeneous cancer cells and the primary function needs to be integrated to achieve effective payload delivery.

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“…The cells were maintained in RPMI 1640 medium containing 20% FBS (Gibco, Thermo Fisher Scientific) and 1% penicillin-streptomycin in a humidified atmosphere with 5% CO 2 at 37°C. 35 To maintain their multidrug resistance, MCF-7/ADR cells were cultured in a medium containing 1 μg/mL of doxorubicin.…”

Section: Methodsmentioning

confidence: 99%

Anti-EphA10 antibody-conjugated pH-sensitive liposomes for specific intracellular delivery of siRNA

Zang¹,

Ding²,

Zhao³

et al. 2016

IJN

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Therapeutic delivery of small interfering RNA (siRNA) is a major challenge that limits its potential clinical application. Here, a pH-sensitive cholesterol–Schiff base–polyethylene glycol (Chol–SIB–PEG)-modified cationic liposome–siRNA complex, conjugated with the recombinant humanized anti-EphA10 antibody (Eph), was developed as an efficient nonviral siRNA delivery system. Chol–SIB–PEG was successfully synthesized and confirmed with FTIR and 1 H-NMR. An Eph–PEG–SIB–Chol-modified liposome–siRNA complex (EPSLR) was prepared and characterized by size, zeta potential, gel retardation, and encapsulation efficiency. Electrophoresis results showed that EPSLR was resistant to heparin replacement and protected siRNA from fetal bovine serum digestion. EPSLR exhibited only minor cytotoxicity in MCF-7/ADR cells. The results of flow cytometry and confocal laser scanning microscopy suggested that EPSLR enhanced siRNA transfection in MCF-7/ADR cells. Intracellular distribution experiment revealed that EPSLR could escape from the endo-lysosomal organelle and release siRNA into cytoplasm at 4 hours posttransfection. Western blot experiment demonstrated that EPSLR was able to significantly reduce the levels of MDR1 protein in MCF-7/ADR cells. The in vivo study of DIR-labeled complexes in mice bearing MCF-7/ADR tumor indicated that EPSLR could reach the tumor site rather than other organs more effectively. All these results demonstrate that EPSLR has much potential for effective siRNA delivery and may facilitate its therapeutic application.

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Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin

Cited by 150 publications

References 53 publications

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells

Anti-EphA10 antibody-conjugated pH-sensitive liposomes for specific intracellular delivery of siRNA

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