Stimuli-responsive shell cross-linked micelles from amphiphilic four-arm star copolymers as potential nanocarriers for “pH/redox-triggered” anticancer drug release

Xiong, Di; Yao, Na; Gu, Huawei; Wang, Jufang; Zhang, Lijuan

doi:10.1016/j.polymer.2017.03.002

Cited by 57 publications

(39 citation statements)

References 77 publications

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“…Stimuli‐responsive block copolymers have frequently been used in a variety of intelligent biomedical applications . When they self‐assemble into polymeric micelles with core‐corona nanostructures, micelles are particularly attractive drug delivery platforms which respond to specific stimuli to deliver and release drugs at target disease sites, such as mildly acidic tumor extracellular environment.…”

Section: Introductionmentioning

confidence: 99%

“…Stimuli-responsive block copolymers have frequently been used in a variety of intelligent biomedical applications. [1][2][3][4][5][6][7][8][9][10] When they self-assemble into polymeric micelles with corecorona nanostructures, micelles are particularly attractive drug delivery platforms which respond to specific stimuli to deliver and release drugs at target disease sites, such as mildly acidic tumor extracellular environment. Some of these micelles rely on stimuli such as temperature (heating/ cooling) and pH to elicit structural and functional changes of constituent intelligent polymers.…”

Section: Introductionmentioning

confidence: 99%

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Surface sulfonamide modification of poly(N‐isopropylacrylamide)‐based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake

Cyphert

Recum

Yamato

et al. 2018

J Biomedical Materials Res

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Two different surface sulfonamide-functionalized poly(N-isopropylacrylamide)-based polymeric micelles were designed as pH-/temperature-responsive vehicles. Both sulfadimethoxine- and sulfamethazine-surface functionalized micelles were characterized to determine physicochemical properties, hydrodynamic diameters, zeta potentials, temperature-dependent size changes, and lower critical solution temperatures (LCST) in both pH 7.4 and 6.8 solutions (simulating both physiological and mild low pH conditions), and tested in the incorporation of a proof-of-concept hydrophobic antiproliferative drug, paclitaxel. Cellular uptake studies were conducted using bovine carotid endothelial cells and fluorescently labeled micelles to evaluate if there was enhanced cellular uptake of the micelles in a low pH environment. Both variations of micelles showed enhanced intracellular uptake under mildly acidic (pH 6.8) conditions at temperatures slightly above their LCST and minimal uptake at physiological (pH 7.4) conditions. Due to the less negative zeta potential of the sulfamethazine-surface micelles compared to sulfadimethoxine-surface micelles, and the proximity of their LCST to physiological temperature (37°C), the sulfamethazine variation was deemed more amenable for clinically relevant temperature and pH-stimulated applications. Nevertheless, we believe both polymeric micelle variations have the capacity to be implemented as an intracellular drug or gene delivery system in response to mildly acidic conditions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1552-1560, 2018.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Surface sulfonamide modification of poly(N‐isopropylacrylamide)‐based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake

Cyphert

Recum

Yamato

et al. 2018

J Biomedical Materials Res

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“…This suggested that the amphiphilic polymers could self-assemble into stable micelles even at low concentrations. The stability of SCMs was investigated by diluting with extensive water and adding organic solvent of DMF to measure the size and distribution changes by DLS, as shown in Figure 3 [12,35]. First, the SCMs still existed even after diluting with a 1000-fold volume of deionized water (C < CMC) and the particle size was slightly increased with a low polydispersity index (PDI).…”

Section: Properties Of Blank and Dox-loaded Scmsmentioning

confidence: 99%

“…The SCMs with a cross-linked structure were more stable when compared with corresponding non-cross-linked micelles, which could prevent premature drug release in the blood vessel and normal tissues. When arriving at the target sites, the SCMs formed smart delivery systems and released drug rapidly by introducing stimulus-responsive groups into their polymers, which achieved high effective therapeutic effects [10][11][12][13][14][15][16]. In past years, with the advantages of stimulus-responsiveness, reversible chemical bonds, such as acetal, hydrazone, imine, diselenide bonds, disulfide, borate, and oxime bonds, are popular and have been used for smart drug delivery by several groups [17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

pH/Reduction Dual-Stimuli-Responsive Cross-Linked Micelles Based on Multi-Functional Amphiphilic Star Copolymer: Synthesis and Controlled Anti-Cancer Drug Release

et al. 2020

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Novel approach has been constructed for preparing the amphiphilic star copolymer pH/reduction stimuli-responsive cross-linked micelles (SCMs) as a smart drug delivery system for the well-controlled anti-tumor drug doxorubicin (DOX) release. The SCMs had a low CMC value of 5.3 mg/L. The blank and DOX-loaded SCMs both had a spherical shape with sizes around 100–180 nm. In addition, the good stability and well pH/reduction-sensitivity of the SCMs were determined by dynamic light scattering (DLS) as well. The SCMs owned a low release of DOX in bloodstream and normal tissues while it had a fast release in tumor higher glutathione (GSH) concentration and/or lower pH value conditions, which demonstrates their pH/reduction dual-responsiveness. Furthermore, we conducted the thermodynamic analysis to study the interactions between the DOX and polymer micelles in the DOX release process. The values of the thermodynamic parameters at pH 7.4 and at pH 5.0 conditions indicated that the DOX release was endothermic and controlled mainly by the forces of an electrostatic interaction. At pH 5.0 with 10 mM GSH condition, electrostatic interaction, chemical bond, and hydrophobic interactions contributed together on DOX release. With the low cytotoxicity of blank SCMs and well cytotoxicity of DOX-loaded SCMs, the results indicated that the SCMs could form a smart cancer microenvironment-responsive drug delivery system. The release kinetic and thermodynamic analysis offer a theoretical foundation for the interaction between drug molecules and polymer matrices, which helps provide a roadmap for the oriented design and control of anti-cancer drug release for cancer therapy.

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“…Many recent studies have proved that reversible crosslinking of the micellar structure (core or shell) can enhance the stability of micelles against dilution efficiently [12][13][14][15]. In our early work, two reversible cross-linked micelles (RCLMs) were designed and synthesized based on the two copolymers, 4-AS-PCL-P(PEGMA-co-MAEBA) and PCL-SS-P(PEGMA-co-MABEA) [16,17]. The RCLMs showed excellent stability against 1000-fold dilution at pH 7.4.…”

Section: Introductionmentioning

confidence: 99%

Reversible Cross-Linked Mixed Micelles for pH Triggered Swelling and Redox Triggered Degradation for Enhanced and Controlled Drug Release

et al. 2020

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Good stability and controlled drug release are important properties of polymeric micelles for drug delivery. A good candidate for drug delivery must have outstanding stability in a normal physiological environment, followed with low drug leakage and side effects. Moreover, the chemotherapeutic drug in the micellar core should also be quickly and “on-demand” released in the intracellular microenvironment at the tumor site, which is in favor of overcoming multidrug resistance (MDR) effects of tumor cells. In this work, a mixed micelle was prepared by the simple mix of two amphiphilic copolymers, namely PCL-SS-P(PEGMA-co-MAEBA) and PCL-SS-PDMAEMA, in aqueous solution. In the mixed micelle’s core–shell structure, PCL blocks were used as the hydrophobic core, while the micellar hydrophilic shell consisted of two blocks, namely P(PEGMA-co-MAEBA) and PDMAEMA. In the micellar shell, PEGMA provided hydrophilicity and stability, while MAEBA introduced the aldehyde sites for reversible crosslinking. Meanwhile, the PDMAEMA blocks were also introduced in the micellar shell for pH-responding protonation and swelling of the micelle. The disulfide bonds between the hydrophobic core and hydrophilic shell had redox sensitive properties. Reversible cross-linked micelles (RCLMs) were obtained by crosslinking the micellar shell with an imine structure. RCLMs showed good stability and excellent ability against extensive dilution by aqueous solution. In addition, the stability in different conditions with various pH values and glutathione (GSH) concentrations was studied. Then, the anticancer drug doxorubicin (DOX) was selected as the model drug to evaluate drug entrapment and release capacity of mixed micelles. The in vitro release profiles indicated that this RCLM had controlled drug release. In the simulated normal physiological environment (pH 7.4), the drug release of the RCLMs was restrained obviously, and the cumulative drug release content was only 25.7 during 72 h. When it came to acidic conditions (pH 5.0), de-crosslinking of the micelles occurred, as well as protonation of PDMAEMA blocks and micellar swelling at the same time, which enhanced the drug release to a large extent (81.4%, 72 h). Moreover, the drug release content was promoted further in the presence of the reductant GSH. In the condition of pH 5.0 with 10 mM GSH, disulfide bonds broke-up between the micelle core and shell, followed by shedding of the shell from the inner core. Then, the micellar disassembly (degradation) happened based on the de-crosslinking and swelling, and the drug release was as high as 95.3%. The MTT assay indicated that the CLSMs showed low cytotoxicity and good biocompatibility against the HepG2 cells. In contrast, the DOX-loaded CLSMs could efficiently restrain the proliferation of tumor cells, and the cell viability after 48 h incubation was just 13.2%, which was close to that of free DOX. This reversible cross-linked mixed micelle with pH/redox responsive behaviors is a potential nanocarrier for chemotherapy.

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Stimuli-responsive shell cross-linked micelles from amphiphilic four-arm star copolymers as potential nanocarriers for “pH/redox-triggered” anticancer drug release

Cited by 57 publications

References 77 publications

Surface sulfonamide modification of poly(N‐isopropylacrylamide)‐based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake

Surface sulfonamide modification of poly(N‐isopropylacrylamide)‐based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake

pH/Reduction Dual-Stimuli-Responsive Cross-Linked Micelles Based on Multi-Functional Amphiphilic Star Copolymer: Synthesis and Controlled Anti-Cancer Drug Release

Reversible Cross-Linked Mixed Micelles for pH Triggered Swelling and Redox Triggered Degradation for Enhanced and Controlled Drug Release

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