Enzyme-Responsive Amphiphilic PEG-Dendron Hybrids and Their Assembly into Smart Micellar Nanocarriers

Abstract

Enzyme-responsive micelles have great potential as drug delivery platforms due to the high selectivity of the activating enzymes. Here we report a highly modular design for the efficient and simple synthesis of amphiphilic block copolymers based on a linear hydrophilic polyethyleneglycol (PEG) and an enzyme-responsive hydrophobic dendron. These amphiphilic hybrids self-assemble in water into micellar nanocontainers that can disassemble and release encapsulated molecular cargo upon enzymatic activation. The utilization of monodisperse dendrons as the stimuli-responsive block enabled a detailed kinetic study of the molecular mechanism of the enzymatically triggered disassembly. The modularity of these PEG-dendron hybrids allows control over the disassembly rate of the formed micelles by simply tuning the PEG length. Such smart amphiphilic hybrids could potentially be applied for the fabrication of nanocarriers with adjustable release rates for delivery applications.

Azobenzene-aminoglycoside: Self-assembled smart amphiphilic nanostructures for drug delivery

“…Biological stimulus, such as enzyme, represents an attractive alternative in the synthetic assemblies that have been recognized as promising class of drug delivery systems [15,16].…”

“…Applying external stimuli such as light [10,11], heat [12], pH [5,6,13] and also biological stimuli such as enzyme [14][15][16], assembly and disassembly of these systems can be regulated. Recently, light irradiation, which is quite energy-saving and easily controllable, is considered as the most reliable external stimulus [17][18][19].…”

“…Amongst them, azobenzene and their derivatives have attracted much more attention, because of their ability to undergo reversible N=N trans-cis isomerization under alternating UV-and visible light irradiations [21]. These molecules also offer an added advantage that azo moiety can also be cleaved by the enzymes (such as azoreductase) [14][15][16][17][18][19][20][21][22]. In aqueous media, azobenzene containing amphiphilic materials form self-aggregated structures having hydrophobic core via π-π interaction between aromatic residues which on UV and Vis light irradiation, display change in the aggregation behavior as trans-and cis-isomers have different polarities that affect hydrophobic properties of the systems.…”

Redox-sensitive Pluronic F127-tocopherol micelles: synthesis, characterization, and cytotoxicity evaluation

“…14,15 Studies demonstrated that designed functional polymeric micelles were able to stably encapsulate drugs and release them at tumor sites in response to external stimuli such as redox, pH, temperature, and enzyme conditions. [16][17][18][19] In particular, redox-sensitive micelles were designed to trigger burst drug release owing to the high concentration of glutathione (GSH, 4 μΜ/g) that is normally found in tumor tissues. 20,21 Disulfide bond is stable under normal physiological conditions yet responsive to the reductive environment (eg, GSH) of intracellular fluids in cancer cells, indicating that disulfide bonds can be used as the linker of hydrophilic and hydrophobic portions in the redox-sensitive polymeric micelles for controlling the delivery of intracellular drug.…”

Simple Fabrication of Glutathione-Responsive PEGylated Micellar Nanocarriers for Dual Drugs Delivery

“…Stimuli-responsive DDCs can release encapsulated anticancer drug upon environmental stimuli, which is playing an increasingly crucial role in the disease treatment [21]. These environmental stimuli involve pH [22], redox reactions [23], enzymatic expression [24], temperature [25], irradiated light [26], magnetic field [27], or their combination. Among the various redox sensitive DDCs, disulfide bond is of great interest because of its instability under the reduced glutathione (GSH).…”