The development of microgels/nanogels for drug delivery applications

Oh, Jung Kwon; Drumright, Ray; Siegwart, Daniel J.; Matyjaszewski, Krzysztof

doi:10.1016/j.progpolymsci.2008.01.002

Cited by 1,429 publications

(1,015 citation statements)

References 310 publications

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“…Cationic nanogels were prepared by activators generated by electron transfer atom transfer radical polymerization [5,35,36,[45][46][47][48][49]64] in inverse miniemulsion by copolymerizing quaternized dimethyl aminoethylmethacrylate, oligo(ethylene oxide) methacrylate (M n = 300), and a water-soluble disulfide methacrylate crosslinker with a poly(ethylene glycol 2-bromoisobutyrate) initiator and a copper bromide tris(2-[dimethylamino]ethyl)amine catalyst system dissolved in water. The inverse miniemulsion was prepared by ultrasonication of the aqueous phase in a cyclohexane Span80 solution.…”

Section: Nanogel Synthesismentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. Questions/purposes We hypothesized that (1) nanogelmediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. Methods Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImage TM assay). Results Gene expression assays demonstrated that nanogelbased RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% ± 19.53% (p \ 0.001) and 43.22% ± 18.01% (both p \ 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% ± 10.85% and 47.65% ± 9.80% (both p \ 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% ± 12.0% and 33.6% ± 13.8% (both p \ 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% ± 14.0% and 47.7% ± 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that Two of the authors (ARS, EH) contributed equally.

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Section: Nanogel Synthesismentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…88 Additional advantages include the ease of preparation, high stability, and the good dispersibility in water. 88,108,279 This chapter first describes the development of pH-sensitive p(HEMA-co-MAA) microgels as model systems for biomedical release applications. In the second part the introduction of light-cleavable crosslinking points in these materials results in double stimuliresponsive hydrogel nanoparticles exhibiting pH-dependent swelling and light-induced degradation in water.…”

Section: Photo-sensitive Hydrogel Nanoparticlesmentioning

confidence: 99%

Light-Sensitive Polymeric Nanoparticles Based on Photo-Cleavable Chromophores

Klinger

2013

Springer Theses

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This thesis focuses on the design, synthesis and characterization of novel photo-sensitive microgels and nanoparticles as potential materials for the loading and light-triggered release/accessibility of functional compounds. In order to realize this concept, different approaches to irradiation-dependent response mechanisms have been investigated.Novel light-cleavable divinyl functionalized monomeric crosslinkers based on o-nitrobenzyl derivatives were synthesized and used for the preparation of either PMMA or hydroxyl functionalized PHEMA microgels swellable and degradable in organic solvents. By the introduction of anionic MAA moieties into the PHEMA microgels, this concept was successfully transferred to double stimuli-responsive p(HEMA-co-MAA) hydrogel nanoparticles exhibiting a pH-dependent swelling and light-induced degradation behavior in aqueous media. This sensitivity to two orthogonal triggers is proposed to combine a pHinduced post-formation loading mechanism with a pH-and light-triggered release. In addition, a new class of enzyme-and light-sensitive PAAm microgels based on (meth-)acrylate functionalized dextrans as photo-and enzymatically degradable macromolecular crosslinkers was developed by introducing a photo-labile linker between the enzymatically degradable dextran chain and the polymerizable vinyl moieties. Here, the water solubility of the crosslinkers is assumed to enable an in situ loading approach of hydrophilic compounds.A different approach to the loading of microgels is based on photo-labile covalent microgel-drug conjugates. The first step to the realization of this concept was achieved by the development of a novel functional monomer consisting of a doxorubicin molecule covalently attached to a radically polymerizable methacrylate group via a photo-cleavable linker.Moreover, in order to enable the release of hydrophobic substances in aqueous media, hydrophobic nanoparticles consisting of a photo-resist polymer were designed to be degradable upon irradiation in water. Light-triggered conversion of the initial hydrophobic polymer into hydrophilic PMAA induced in situ particle dissolution and release of nile red.Since the introduction of a stimuli-responsive shell around a microgel is assumed to prevent leakage of embedded compounds, studies on non-stimuli-responsive shell formation around preformed microgel seed particles and the formation of microgel cores in polymeric shells were conducted to investigate potential synthetic pathways to this approach.In a last attempt, the surface of PHEMA and p(HEMA-co-MAA) microgels was functionalized with cinnamoyl groups in order to trigger the (reversible) particles interaction with each other by light-induced [2+2] cycloaddition reactions.

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“…Abundant applications of the microgels have been reported in sensing, fabrication of photonic crystals (Lyon and Debord 2000), template-based synthesis of nanoparticles (Kawaguchi and Suzuki 2005), even separation and purification field (Amalvy et al 2004). Particularly, pharmaceutical applications have seen a great interest in the encapsulation of drugs in microgels, with the latest advancement in stimuli-triggered drug release and targeted site-specific drug delivery (Oh et al 2008). Microgels composed of biopolymers or biocompatible synthetic polymers can provide an opportunity for encapsulation of biologically active species due to low toxicity and good biocompatibility.…”

Section: Introductionmentioning

confidence: 99%

High throughput generation and trapping of individual agarose microgel using microfluidic approach

Shi

Gao

Chen

et al. 2013

Microfluid Nanofluid

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Microgel is a kind of biocompatible polymeric material, which has been widely used as micro-carriers in materials synthesis, drug delivery and cell biology applications. However, high-throughput generation of individual microgel for on-site analysis in a microdevice still remains a challenge. Here, we presented a simple and stable droplet microfluidic system to realize high-throughput generation and trapping of individual agarose microgels based on the synergetic effect of surface tension and hydrodynamic forces in microchannels and used it for 3-D cell culture in real-time. The established system was mainly composed of droplet generators with flow focusing T-junction and a series of array individual trap structures. The whole process including the independent agarose microgel formation, immobilization in trapping array and gelation in situ via temperature cooling could be realized on the integrated microdevice completely. The performance of this system was demonstrated by successfully encapsulating and culturing adenoid cystic carcinoma (ACCM) cells in the gelated agarose microgels. This established approach is simple, easy to operate, which can not only generate the micro-carriers with different components in parallel, but also monitor the cell behavior in 3D matrix in real-time. It can also be extended for applications in the area of material synthesis and tissue engineering.

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The development of microgels/nanogels for drug delivery applications

Cited by 1,429 publications

References 310 publications

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Light-Sensitive Polymeric Nanoparticles Based on Photo-Cleavable Chromophores

High throughput generation and trapping of individual agarose microgel using microfluidic approach

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