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Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization.

ABSTRACT: 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.

SUBMITTER: Elkassih SA

PROVIDER: S-EPMC7031860 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization.

Elkassih Sussana A SA Kos Petra P Xiong Hu H Siegwart Daniel J DJ

Biomaterials science 20190101 2

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 compose ...[more]

PMID: 30462102

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Project description:PurposeThe aim of the study is to synthesize and characterize nanogel carriers composed of amphiphilic polymers and cationic polyethylenimine for encapsulation and delivery of cytotoxic nucleoside analogs 5'-triphosphates (NTPs) into cancer cells.MethodsNanogels were synthesized by a novel micellar approach and compared with carriers prepared by the emulsification/evaporation method. Complexes of nanogels with NTP were prepared; particle size and in vitro drug release were characterized. Resistance of the nanogel-encapsulated NTP to enzymatic hydrolysis was analyzed by ion-pair high-performance liquid chromatography. Binding to isolated cellular membranes, cellular accumulation and cytotoxicity were compared using breast carcinoma cell lines CL-66, MCF-7, and MDA-MB-231. In vivo biodistribution of the 3H-labeled NTP encapsulated in different types of nanogels was evaluated in comparison to the injected NTP alone.ResultsNanogels with a particle size of 100-300 nm in the unloaded form and less than 140 nm in the NTP-loaded form were prepared. An in vitro release of NTP was >50% during the first 24 h. Nanogel formulations ensured increased NTP drug stability against enzymatic hydrolysis as compared to the drug alone. Pluronic-based nanogels NG(F68), NG(F127), NG(P85), and NGM(P123) demonstrated 2-2.5 times enhanced interaction with cellular membranes and association with various cancer cells compared to NG(PEG). Among them, NG(F68) and NG(F127) exhibited the lowest cytotoxicity. Injection of nanogel-formulated NTP significantly modulated the drug accumulation in different mouse organs.ConclusionsNanogels composed of Pluronic F68 and P123 were shown to display certain advanced properties compared to NG(PEG) as a drug delivery system for NTP analogs. Formulations of nucleoside analogs in active NTP form with these nanogels will improve the delivery of these cytotoxic drugs to cancer cells and the therapeutic potential of this anticancer chemotherapy.

Dataset Information

Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization.

Publications

Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization.

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