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In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins.
Biomacromolecules. 2013 Apr 08; 14(4):1214-22.B

Abstract

In situ forming reduction-sensitive degradable nanogels were designed and developed based on poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) (PEG-P(HEMA-co-AC)) block copolymers for efficient loading as well as triggered intracellular release of proteins. PEG-P(HEMA-co-AC) copolymers were prepared with controlled Mn of 9.1, 9.5, and 9.9 kg/mol and varying numbers of AC units per molecule of 7, 9 and 11, respectively (denoted as copolymer 1, 2, and 3) by reversible addition-fragmentation chain transfer copolymerization. These copolymers were freely soluble in phosphate buffer but formed disulfide-cross-linked nanogels with defined sizes ranging from 72.5 to 124.1 nm in the presence of cystamine via ring-opening reaction with cyclic carbonate groups. The sizes of nanogels decreased with increasing AC units as a result of increased cross-linking density. Dynamic light scattering studies showed that these nanogels though stable at physiological conditions were rapidly dissociated in response to 10 mM dithiothreitol (DTT). Interestingly, FITC-labeled cytochrome C (FITC-CC) could be readily loaded into nanogels with remarkable loading efficiencies (up to 98.2%) and loading contents (up to 48.2 wt.%). The in vitro release studies showed that release of FITC-CC was minimal under physiological conditions but significantly enhanced under reductive conditions in the presence of 10 mM DTT with about 96.8% of FITC-CC released in 22 h from nanogel 1. In contrast, protein release from 1,4-butanediamine cross-linked nanogels (reduction-insensitive control) remained low under otherwise the same conditions. MTT assays showed that these nanogels were nontoxic to HeLa cells up to a tested concentration of 2 mg/mL. Confocal microscopy results showed that nanogel 1 delivered and released FITC-CC into the perinuclei region of HeLa cells following 8 h incubation. CC-loaded reductively degradable nanogels demonstrated apparently better apoptotic activity than free CC as well as reduction-insensitive controls. These in situ forming, surfactant and oil-free, and reduction-sensitive degradable nanogels are highly promising for targeted protein therapy.

Authors+Show Affiliations

Biomedical Polymers Laboratory, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23477570

Citation

Chen, Wei, et al. "In Situ Forming Reduction-sensitive Degradable Nanogels for Facile Loading and Triggered Intracellular Release of Proteins." Biomacromolecules, vol. 14, no. 4, 2013, pp. 1214-22.
Chen W, Zheng M, Meng F, et al. In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins. Biomacromolecules. 2013;14(4):1214-22.
Chen, W., Zheng, M., Meng, F., Cheng, R., Deng, C., Feijen, J., & Zhong, Z. (2013). In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins. Biomacromolecules, 14(4), 1214-22. https://doi.org/10.1021/bm400206m
Chen W, et al. In Situ Forming Reduction-sensitive Degradable Nanogels for Facile Loading and Triggered Intracellular Release of Proteins. Biomacromolecules. 2013 Apr 8;14(4):1214-22. PubMed PMID: 23477570.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins. AU - Chen,Wei, AU - Zheng,Meng, AU - Meng,Fenghua, AU - Cheng,Ru, AU - Deng,Chao, AU - Feijen,Jan, AU - Zhong,Zhiyuan, Y1 - 2013/03/21/ PY - 2013/3/13/entrez PY - 2013/3/13/pubmed PY - 2013/9/27/medline SP - 1214 EP - 22 JF - Biomacromolecules JO - Biomacromolecules VL - 14 IS - 4 N2 - In situ forming reduction-sensitive degradable nanogels were designed and developed based on poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) (PEG-P(HEMA-co-AC)) block copolymers for efficient loading as well as triggered intracellular release of proteins. PEG-P(HEMA-co-AC) copolymers were prepared with controlled Mn of 9.1, 9.5, and 9.9 kg/mol and varying numbers of AC units per molecule of 7, 9 and 11, respectively (denoted as copolymer 1, 2, and 3) by reversible addition-fragmentation chain transfer copolymerization. These copolymers were freely soluble in phosphate buffer but formed disulfide-cross-linked nanogels with defined sizes ranging from 72.5 to 124.1 nm in the presence of cystamine via ring-opening reaction with cyclic carbonate groups. The sizes of nanogels decreased with increasing AC units as a result of increased cross-linking density. Dynamic light scattering studies showed that these nanogels though stable at physiological conditions were rapidly dissociated in response to 10 mM dithiothreitol (DTT). Interestingly, FITC-labeled cytochrome C (FITC-CC) could be readily loaded into nanogels with remarkable loading efficiencies (up to 98.2%) and loading contents (up to 48.2 wt.%). The in vitro release studies showed that release of FITC-CC was minimal under physiological conditions but significantly enhanced under reductive conditions in the presence of 10 mM DTT with about 96.8% of FITC-CC released in 22 h from nanogel 1. In contrast, protein release from 1,4-butanediamine cross-linked nanogels (reduction-insensitive control) remained low under otherwise the same conditions. MTT assays showed that these nanogels were nontoxic to HeLa cells up to a tested concentration of 2 mg/mL. Confocal microscopy results showed that nanogel 1 delivered and released FITC-CC into the perinuclei region of HeLa cells following 8 h incubation. CC-loaded reductively degradable nanogels demonstrated apparently better apoptotic activity than free CC as well as reduction-insensitive controls. These in situ forming, surfactant and oil-free, and reduction-sensitive degradable nanogels are highly promising for targeted protein therapy. SN - 1526-4602 UR - https://www.unboundmedicine.com/medline/citation/23477570/In_situ_forming_reduction_sensitive_degradable_nanogels_for_facile_loading_and_triggered_intracellular_release_of_proteins_ L2 - https://dx.doi.org/10.1021/bm400206m DB - PRIME DP - Unbound Medicine ER -