Supramolecular Translation of Enzymatically Triggered Disassembly of Micelles into Tunable Fluorescent Responses

Buzhor, Marina; Harnoy, Assaf J.; Tirosh, Einat; Barak, Ayana; Schwartz, Tal; Amir, Roey J.

doi:10.1002/chem.201502988

Cited by 14 publications

(26 citation statements)

References 45 publications

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“…The System: Amphiphilic PEG-Dendron Micelles and Microfluidic Cancer-on-a-Chip. Three amphiphilic PEGdendron hybrids, differing by their lipophilic end-groups in the hydrophobic block, were synthesized and characterized following the previously reported methodology; 19,46 the structures are shown in Figure 1a. The amphiphiles were labeled with a responsive dye, 7-diethylamino-3-carboxy coumarin, which forms an excimer when the hybrids selfassemble into micelles, resulting in a red-shift of the dye emission spectra, allowing to discriminate the assembled state from the disassembled state, as shown in Figure 1a.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip

Feiner‐Gracia

Mares

Buzhor

et al. 2020

ACS Appl. Bio Mater.

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The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by physiological barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix, and eventually cancer cell membrane. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is the key factor for the rational design of these systems. One of the main challenges is that current 2D in vitro models do not provide exhaustive information, as they fail to recapitulate the 3D tumor microenvironment. This deficiency in the 2D model complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic cancer-on-a-chip. The combination of advanced imaging and a reliable 3D model allows tracking of micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation continuously followed by spectral imaging during the crossing of barriers, revealing the interplay between carrier structure, micellar stability, and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip resulted in the establishment of a robust testing platform suitable for real-time imaging and evaluation of supramolecular drug delivery carrier’s stability.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip

Feiner‐Gracia

Mares

Buzhor

et al. 2020

ACS Appl. Bio Mater.

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“…A series of four fluorescently labeled amphiphilic PEG–dendron hybrids that can report their self-assembly and disassembly through spectral response were synthesized following a previously reported methodology (Figure a) . The hybrids were labeled with 7-diethylamino-3-carboxy coumarin, which was shown to form excimers when the hybrids self-assemble into micelles, leading to a significant red-shift of the emission peak, from 480 nm to approximately 560 nm .…”

Section: Resultsmentioning

confidence: 99%

“…The undecanoate end-groups of hybrid 1 were selected based on our previous results for nonlabeled hybrids with similar end-groups, which showed remarkable stability toward enzymatic degradation . To systemically decrease the hydrophobicity of the dendrons, we synthesized hybrids 2 and 3 , which had eight carbon atoms in each of their end-groups; the end-group of 2 was aliphatic end-groups, and that of 3 was aromatic. We expected that the dendron with the aromatic end-groups would be slightly less hydrophobic due to the higher polarity of the aromatic rings in comparison with the aliphatic chains.…”

Section: Resultsmentioning

confidence: 99%

Micellar Stability in Biological Media Dictates Internalization in Living Cells

et al. 2017

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The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG-dendron hybrids and their self-assembled micelles in order to determine their structure-stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability-activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.

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“…Three amphiphilic PEG-dendron hybrids, differing by their lipophilic end-groups in the hydrophobic block, were synthesized following a previously reported methodology, [34], [35] structures are shown in Figure 1a. The amphiphiles were labeled with a responsive dye, 7diethylamino-3-carboxy coumarin, which forms and excimer when the hybrids self-assemble into micelles.…”

Section: The System: Amphiphilic Peg-dendron Micelles and Microfluidimentioning

confidence: 99%

Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

Feiner‐Gracia

Mares

Buzhor

et al. 2020

Preprint

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The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by confronting different barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix and eventually cancer cell membranes. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is a key factor for the rational design of these systems. One of the key challenges is that current 2D in vitro models do not provide exhaustive information, as they do not fully recapitulate the 3D tumor microenvironment. This deficiency of the 2D models complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers.Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic tumor-on-a-chip. The combination of advanced imaging and a reliable organ-on-a-chip model allow us to track micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation followed during the crossing of barriers by spectral imaging, revealing the interplay between carrier structure, micellar stability and extravasation. Integrating

show abstract

Supramolecular Translation of Enzymatically Triggered Disassembly of Micelles into Tunable Fluorescent Responses

Cited by 14 publications

References 45 publications

Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip

Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip

Micellar Stability in Biological Media Dictates Internalization in Living Cells

Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

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