Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles

Shi, Chunwei; Guo, Xing; Qu, Qianqian; Tang, Zhaomin; Wang, Yi; Zhou, Shaobing

doi:10.1016/j.biomaterials.2014.06.036

Cited by 174 publications

(125 citation statements)

References 41 publications

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“…The excitation and emission wavelength was set at 505 and 565 nm, respectively. 24 Encapsulation efficiency and drug loading were calculated using the following equations:…”

Section: Synthesis and Characterization Of Dex-ss-indmentioning

confidence: 99%

“…The 1 mL DEX-SS-IND/DOX micelle solution was transferred into a dialysis membrane (MWCO 7.0 kDa) and then immersed in 20 mL incubation media with constant shaking at 70 rpm at 37°C. At predetermined time intervals (1,2,4,6,8,10,12,24,36, and 48 hours), the samples were collected and replaced with fresh medium. DOX content was measured using fluorescence spectrophotometry.…”

Section: Synthesis and Characterization Of Dex-ss-indmentioning

confidence: 99%

See 1 more Smart Citation

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

Zhou¹,

Wang²,

Ying³

et al. 2017

IJN

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Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.

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“…The excitation and emission wavelength was set at 505 and 565 nm, respectively. 24 Encapsulation efficiency and drug loading were calculated using the following equations:…”

Section: Synthesis and Characterization Of Dex-ss-indmentioning

confidence: 99%

Section: Synthesis and Characterization Of Dex-ss-indmentioning

confidence: 99%

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

Zhou¹,

Wang²,

Ying³

et al. 2017

IJN

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“…27 Shi et al developed multifunctional star-shaped micelles by combining active targeting with redox-responsive payload release. 28 Dong et al constructed folate-conjugated and pH-responsive micelles loaded with vascular endothelial growth factor targeting small interfering RNA and DOX. 29 Encouraged by the promise of multifunctional nanocarriers in addressing the heterogeneity of cancer, more and more effort has been put to develop various multifunctional micelles.…”

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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“…[2][3][4][5][6] Various architectural polymers including linear polymers, dendrimers, hyperbranched polymers, and dendronized polymers have been utilized to construct nanocarriers. [7][8][9][10][11] Compared to the linear polymers, branched polymers possess some advantages, including a number of surface groups and hollow voids of the branching architecture, which make them attractive in drug delivery applications.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

Qiu

Pan

2015

IJN

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Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP) n s, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP) n s (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system.

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Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles

Cited by 174 publications

References 41 publications

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

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

Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

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