Coacervate delivery systems for proteins and small molecule drugs

Johnson, Noah R.; Wang, Yadong

doi:10.1517/17425247.2014.941355

Cited by 119 publications

(101 citation statements)

References 29 publications

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“…The coacervate contains heparin and a biocompatible polycation, PEAD, which closely and advantageously imitates the native signaling environment involving extracellular matrix proteoglycans, ligands, and cell receptors [33, 55–57]. This vehicle can protect the GFs from rapid enzymatic degradation and potentiate their bioactivities [24, 25, 27–33]. In this study, we demonstrated that the fibrin gel-coacervate system achieved early release of VEGF to trigger EC proliferation and sprouting and delayed release of PDGF to recruit pericytes that stabilize the newly formed vessels.…”

Section: Discussionmentioning

confidence: 99%

Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction

Awada

Johnson

Wang

2015

Journal of Controlled Release

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112

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Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination.

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Section: Discussionmentioning

confidence: 99%

Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction

Awada

Johnson

Wang

2015

Journal of Controlled Release

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112

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“…73, 74 Although the complex coacervate is also an important drug delivery system for biomedical applications, it will not be included in this review and readers can refer to several recent publications for their interesting applications. 75, 95–100 To use a synthetic polyelectrolyte to form a hydrogel, an ABA triblock copolymer architecture is used. 78, 101 Fig.…”

Section: Ionic Interaction-based Hydrogelsmentioning

confidence: 99%

Weak bond-based injectable and stimuli responsive hydrogels for biomedical applications

Ding

Wang

2017

J. Mater. Chem. B

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Here we define hydrogels crosslinked by weak bonds as physical hydrogels. They possess unique features including reversible bonding, shear thinning and stimuli-responsiveness. Unlike covalently crosslinked hydrogels, physical hydrogels do not require triggers to initiate chemical reactions for in situ gelation. The drug can be fully loaded in a pre-formed hydrogel for delivery with minimal cargo leakage during injection. These benefits make physical hydrogels useful as delivery vehicles for applications in biomedical engineering. This review focuses on recent advances of physical hydrogels crosslinked by weak bonds: hydrogen bonds, ionic interactions, host-guest chemistry, hydrophobic interactions, coordination bonds and π-π stacking interactions. Understanding the principles and the state of the art of gels with these dynamic bonds may give rise to breakthroughs in many biomedical research areas including drug delivery and tissue engineering.

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“…phase separation | elastin | NMR | protein structure | dynamics T he liquid-liquid phase separation (LLPS) of molecules has long been exploited to concentrate and encapsulate molecules for drug delivery and food preparation (1,2). In biology, there is increasing awareness that many proteins exhibit this type of phase behavior, allowing transient microenvironments to be quickly assembled and disassembled in response to changing solution conditions, or the availability of binding partners (3,4).…”

mentioning

confidence: 99%

Direct observation of structure and dynamics during phase separation of an elastomeric protein

Reichheld

Muiznieks

Keeley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

225

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Despite its growing importance in biology and in biomaterials development, liquid-liquid phase separation of proteins remains poorly understood. In particular, the molecular mechanisms underlying simple coacervation of proteins, such as the extracellular matrix protein elastin, have not been reported. Coacervation of the elastin monomer, tropoelastin, in response to heat and salt is a critical step in the assembly of elastic fibers in vivo, preceding chemical crosslinking. Elastin-like polypeptides (ELPs) derived from the tropoelastin sequence have been shown to undergo a similar phase separation, allowing formation of biomaterials that closely mimic the material properties of native elastin. We have used NMR spectroscopy to obtain site-specific structure and dynamics of a self-assembling elastin-like polypeptide along its entire self-assembly pathway, from monomer through coacervation and into a cross-linked elastic material. Our data reveal that elastin-like hydrophobic domains are composed of transient β-turns in a highly dynamic and disordered chain, and that this disorder is retained both after phase separation and in elastic materials. Cross-linking domains are also highly disordered in monomeric and coacervated ELP 3 and form stable helices only after chemical cross-linking. Detailed structural analysis combined with dynamic measurements from NMR relaxation and diffusion data provides direct evidence for an entropy-driven mechanism of simple coacervation of a protein in which transient and nonspecific intermolecular hydrophobic contacts are formed by disordered chains, whereas bulk water and salt are excluded.phase separation | elastin | NMR | protein structure | dynamics T he liquid-liquid phase separation (LLPS) of molecules has long been exploited to concentrate and encapsulate molecules for drug delivery and food preparation (1, 2). In biology, there is increasing awareness that many proteins exhibit this type of phase behavior, allowing transient microenvironments to be quickly assembled and disassembled in response to changing solution conditions, or the availability of binding partners (3, 4). Protein phase separation occurs intracellularly to generate various membraneless organelles, such as ribonucleoprotein (RNP) bodies involved in nucleic acid processing, transport, and storage (5). A similar phenomenon is observed in the extracellular matrix as a critical step in the synthesis of elastic fibers, which provide extensibility, recoil, and resilience to tissues (6, 7). In the latter system, LLPS of monomeric elastin results in hydrated protein-rich coacervate droplets that are deposited and crosslinked to form an elastic matrix (7,8). In addition to their fundamental importance to biology, the dynamic reversibility of LLPS makes phase-separated states of proteins an attractive platform for development of responsive biomaterials with broad application, for instance as scaffolds for tissue engineering or as carriers in drug delivery systems (9-11).Despite the keen interest in proteins that undergo s...

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Coacervate delivery systems for proteins and small molecule drugs

Cited by 119 publications

References 29 publications

Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction

Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction

Weak bond-based injectable and stimuli responsive hydrogels for biomedical applications

Direct observation of structure and dynamics during phase separation of an elastomeric protein

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