Self-Assembled Peptide Amphiphile Nanofibers Conjugated to MRI Contrast Agents

Bull, Steve R.; Güler, Mustafa O.; Bras, Rafael E.; Meade, Thomas J.; Stupp, Samuel I.

doi:10.1021/nl0484898

Cited by 228 publications

(199 citation statements)

References 15 publications

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“…Previously, researchers have tracked tissue engineering scaffolds in vivo by MRI without using any exogenous CAs (20,21) or using soluble small-molecule CAs with a single Gd(III) chelator (22,23). Recently, Bull et al synthesized a self-assembled peptide amphiphile (PA)-based biomaterial scaffold, in which an MRI CA was incorporated, creating the first biomaterial designed for subsequent MRI-based in vivo fate mapping (24).…”

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confidence: 99%

Use of a Genetically Engineered Protein for the Design of a Multivalent MRI Contrast Agent

et al. 2007

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The majority of clinically used contrast agents (CAs) for magnetic resonance imaging have low relaxivities and thus require high concentrations for signal enhancement. Research has turned to multivalent, macromolecular CAs to increase CA efficiency. However, previously developed macromolecular CAs do not provide high relaxivities, have limited biocompatibility, and/or do not have a structure that is readily modifiable to tailor to particular applications. We report a new family of multivalent, biomacromolecular, genetically engineered protein polymer-based CAs; the protein backbone contains evenly spaced lysines that are derivatized with gadolinium (Gd(III)) chelators. The protein's length and repeating amino acid sequence are genetically specified. We reproducibly obtained conjugates with an average of 8 -9 Gd(III) chelators per protein. These multivalent CAs reproducibly provide a high relaxivity of 7.3 mM -1 s -1 per Gd(III) and 62.6 mM -1 s -1 per molecule. Furthermore, they can be incorporated into biomaterial hydrogels via chemical crosslinking of remaining free lysines, and provide a dramatic contrast enhancement. Thus, these protein polymer CAs could be a useful tool for following the evolution of tissue engineering scaffolds.One significant barrier to the development of new generations of biocompatible materials, particularly tissue engineering hydrogels, is an inability to non-invasively evaluate the properties and performance of the biomaterial over time (1-6). Magnetic Resonance Imaging (MRI) is capable of whole animal or human imaging at high spatial and temporal resolution, and is an ideal modality for evaluating tissue engineering scaffolds in vivo (7-11). Exogenous contrast agents (CAs) increase the relaxation rate (1/T 1 ) of water protons and therefore improve image contrast. However, current clinically used CAs have low relaxivities (3-7 mM -1 s -1 ) (12) and thus must be used at high concentrations for useful MRI signal enhancement (12).T 1 CAs provide positive contrast by employing a paramagnetic ion (typically gadolinium, Gd (III)). The efficacy of a contrast agent is dominated by three parameters: q, the number of We have designed, synthesized and characterized a macromolecular T 1 contrast agent based on artificial proteins. The backbone of these multivalent MRI contrast agents is derived from E. coli expression of monodisperse protein polymers. Gd(III) chelators were chemically conjugated to the backbone to create contrast agents that display high relaxivity in solution and when incorporated into a hydrogel. The covalent incorporation of these protein polymer contrast agents into a gel allows the potential for imaging tissue engineering scaffolds. Here, we report the design, synthesis, and characterization of a novel family of multivalent, macromolecular CAs based on genetically engineered proteins with repetitive sequences that form the backbone for subsequent chemical modification with Gd(III) chelators. These "protein polymer" CAs have high relaxivities in aqueous solution. Mo...

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Use of a Genetically Engineered Protein for the Design of a Multivalent MRI Contrast Agent

et al. 2007

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“…Nanofibers and nanotubes are carbon vapor-grown [243], self-assembled from peptide amphiphiles [244,245] or electrospun from most polymer materials [158]. Carbon nanotubes have attracted attention in nanomedicine although there are also serious concerns regarding their safety [246,247].…”

Section: Other Nanomaterialsmentioning

confidence: 99%

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Kabanov

Gendelman

2007

Progress in Polymer Science

242

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Neurodegenerative and infectious disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population's age. Alzheimer's disease alone currently affects 4.5 million Americans, and more than $100 billion is spent per year on medical and institutional care for affected people. Such numbers will double in the ensuing decades. Currently disease diagnosis for all disorders is made, in large measure, on clinical grounds as laboratory and neuroimaging tests confirm what is seen by more routine examination. Achieving early diagnosis would enable improved disease outcomes. Drugs, vaccines or regenerative proteins present "real" possibilities for positively affecting disease outcomes, but are limited in that their entry into the brain is commonly restricted across the blood-brain barrier. This review highlights how these obstacles can be overcome by polymer science and nanotechnology. Such approaches may improve diagnostic and therapeutic outcomes. New developments in polymer science coupled with cell-based delivery strategies support the notion that diseases that now have limited therapeutic options can show improved outcomes by advances in nanomedicine.

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“…These self-assemble in the same manner as conventional PAs to afford nanofibres (which consequently entangle to produce hydrogels), but additionally allow the multiaddition of functional groups, such as MRI agents 98,184 (to non-invasively image scaffolds as a means of in vivo fate mapping, tracking 5 how the PAs will behave under different physiological conditions), bioactive epitopes 97, 185 and catalytic groups.…”

Section: Peptide-amphiphilesmentioning

confidence: 99%

“…This is where we must turn to different approaches to afford hybrid peptide conjugates with a wider variety of molecular weight, chemical composition and molecular structure. Stupp"s group [96][97][98] have synthesised branched PAs by coupling palmitic acid to the -amine on a lysine residue, which was anchored to the solid surface on a resin. The remainder of the amino acid sequence was then constructed using selective orthogonal protecting groups.…”

Section: Divergent Peptide Incorporationmentioning

confidence: 99%

Peptide conjugate hydrogelators

2010

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5Molecular gelators are currently receiving a great deal of attention. These are small molecules which, under the appropriate conditions, assemble in solution to, in the majority of cases, give long fibrillar structures which entangle to form a three-dimensional network. This immobilises the solvent, resulting in a gel. Such gelators have potential application in a number of important areas from drug delivery to tissue engineering. Recently, the use of peptide-conjugates has become 10 prevalent with oligopeptides (from as short as two amino acids in length) co njugated to a polymer, alkyl chain or aromatic group such as naphthalene or fluorenylmethoxycarbonyl (Fmoc) being shown to be effective molecular gelators. The field of gelation is extremely large; here we will focus our attention on the use of these peptide-conjugates as molecular hydrogelators.

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Self-Assembled Peptide Amphiphile Nanofibers Conjugated to MRI Contrast Agents

Cited by 228 publications

References 15 publications

Use of a Genetically Engineered Protein for the Design of a Multivalent MRI Contrast Agent

Use of a Genetically Engineered Protein for the Design of a Multivalent MRI Contrast Agent

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Peptide conjugate hydrogelators

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