Precise control of intracellular drug release and anti-tumor activity of biodegradable micellar drugs via reduction-sensitive shell-shedding

Wang, Wei; Sun, Huanli; Meng, Fenghua; Ma, Shenglin; Liu, Haiyan; Zhong, Zhiyuan

doi:10.1039/c2sm07461c

Cited by 70 publications

(46 citation statements)

References 38 publications

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“…In contrast, negligible DOX fluorescence was observed in HepG2 cells after 8 h incubation with DOXloaded PEG-PCL/Gal20 micelles (reduction-insensitive control), though intracellular FITC fluorescence was strong ( Figure 4D). Notably, our previous results showed that nontargeting shell-sheddable micelles based on PEG-SS-PCL and dextran-SS-PCL transported and released DOX primarily to the cytosol and perinuclear regions of tumor cells under similar conditions, 12,13 indicating that targeting facilitates nuclear delivery of DOX. In the following, flow cytometry was employed for the quantitative determination of free DOX levels in HepG2 cells.…”

Section: ■ Results and Discussionmentioning

confidence: 96%

Ligand-Directed Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Actively Deliver Doxorubicin into the Nuclei of Target Cancer Cells

et al. 2013

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The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that about 81.1 and 75.0% DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under nonreducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced antitumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 μg DOX equiv/mL, which was comparable to free DOX and approximately six times lower than that for nontargeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and nontargeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.

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Section: ■ Results and Discussionmentioning

confidence: 96%

Ligand-Directed Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Actively Deliver Doxorubicin into the Nuclei of Target Cancer Cells

et al. 2013

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“…Even though these polymers show good biocompatibility, the sustained drug release from nanomicelles over a period of days may not only decrease the therapeutic efficacy of anticancer drugs but also cause drug resistance after injection. 5 In order to solve this problem, biodegradable nanomicelles with various microenvironmentresponsive mechanisms [6][7][8][9] that can significantly change the physiochemical properties of nanomicelles and trigger the selectively rapid drug release under certain microconditions in response to the related stimuli in cells have been explored.…”

Section: Introductionmentioning

confidence: 99%

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Xiao¹,

Wang²

2015

IJN

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To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA) 2 -SS-4-arm-PEG 2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA) 2 -SS-4-arm-PEG 2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA) 2 -SS-4-arm-PEG 2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.

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“…Moreover, the gels swelled in acidic environment, which also offers potential for releasing compounds in acidic (inflamed) tissue. Besides hydrogels and nanogels [79][80][81][82], redox-responsive disulfide containing polymers were for example also used for the synthesis of hollow microspheres [83], star polymers [84][85][86] and micelles [87,88].…”

Section: Thiol Introduction In Macromolecular Structures With Releasementioning

confidence: 99%

Protected thiol strategies in macromolecular design

Goethals

Frank

Prez

2017

Progress in Polymer Science

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Precise control of intracellular drug release and anti-tumor activity of biodegradable micellar drugs via reduction-sensitive shell-shedding

Cited by 70 publications

References 38 publications

Ligand-Directed Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Actively Deliver Doxorubicin into the Nuclei of Target Cancer Cells

Ligand-Directed Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Actively Deliver Doxorubicin into the Nuclei of Target Cancer Cells

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Protected thiol strategies in macromolecular design

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