TY - JOUR
T1 - Degradable redox-responsive disulfide-based nanogel drug carriers
T2 - Via dithiol oxidation polymerization
AU - Elkassih, Sussana A.
AU - Kos, Petra
AU - Xiong, Hu
AU - Siegwart, Daniel J.
N1 - Funding Information:
D. J. S. acknowledges financial support from the Cancer Prevention and Research Institute of Texas (CPRIT) (R1212), the Welch Foundation (I-1855), the American Cancer Society (RSG-17-012-01), a National Institutes of Health (NIH) Cancer Center Support Grant (CCSG), the Mary Kay Foundation (049-15), and the NIH (R01 EB025192-01A1). S. A. E. acknowledges the National Science Foundation (NSF) (GRFP 1000198224) for fellowship support. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the above-mentioned funding agencies.
Publisher Copyright:
© 2019 The Royal Society of Chemistry.
PY - 2019/2
Y1 - 2019/2
N2 - Stimuli-responsive nanogels are important drug and gene carriers that mediate the controlled release of therapeutic molecules. Herein, we report the synthesis of fully degradable disulfide cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2′-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA). Because the poly(EDDET) backbone repeat structure and cross-linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Cross-linked nanogels were synthesized using controlled microfluidic mixing in the presence of a nonionic Pluronic surfactant PLU-127 to increase the nanogel stability. Adjusting the monomer to cross-linker ratio from 5:1 to 100:1 (mol/mol) tuned the cross-linking density, resulting in swelling ratios from 1.65 to >3. Increasing the amount of stabilizing Pluronic surfactant resulted in a decrease of nanogel diameter, as expected due to increased surface area of the resulting nanogels. The monomer to cross-linker ratio in the feed had no effect on the formed nanogel diameter, providing a way to control cross-linking density with constant nanogel size but tunable drug release kinetics. Nanogels exhibited an entrapment efficiency of up to 75% for loading of Rhodamine B dye. In vitro studies showed low cytotoxicity, quick uptake, and fast degradation kinetics. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer potential for use in a variety of drug delivery applications.
AB - Stimuli-responsive nanogels are important drug and gene carriers that mediate the controlled release of therapeutic molecules. Herein, we report the synthesis of fully degradable disulfide cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2′-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA). Because the poly(EDDET) backbone repeat structure and cross-linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Cross-linked nanogels were synthesized using controlled microfluidic mixing in the presence of a nonionic Pluronic surfactant PLU-127 to increase the nanogel stability. Adjusting the monomer to cross-linker ratio from 5:1 to 100:1 (mol/mol) tuned the cross-linking density, resulting in swelling ratios from 1.65 to >3. Increasing the amount of stabilizing Pluronic surfactant resulted in a decrease of nanogel diameter, as expected due to increased surface area of the resulting nanogels. The monomer to cross-linker ratio in the feed had no effect on the formed nanogel diameter, providing a way to control cross-linking density with constant nanogel size but tunable drug release kinetics. Nanogels exhibited an entrapment efficiency of up to 75% for loading of Rhodamine B dye. In vitro studies showed low cytotoxicity, quick uptake, and fast degradation kinetics. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer potential for use in a variety of drug delivery applications.
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U2 - 10.1039/c8bm01120f
DO - 10.1039/c8bm01120f
M3 - Article
C2 - 30462102
AN - SCOPUS:85060647244
SN - 2047-4830
VL - 7
SP - 607
EP - 617
JO - Biomaterials Science
JF - Biomaterials Science
IS - 2
ER -