6 research outputs found
Molecular Precision and Enzymatic Degradation: From Readily to Undegradable Polymeric Micelles by Minor Structural Changes
Studying the enzymatic degradation of synthetic polymers is crucial for the design of suitable materials for biomedical applications ranging from advanced drug delivery systems to tissue engineering. One of the key parameters that governs enzymatic activity is the limited accessibility of the enzyme to its substrates that may be collapsed inside hydrophobic domains. PEG-dendron amphiphiles can serve as powerful tools for the study of enzymatic hydrolysis of polymeric amphiphiles due to the monodispersity and symmetry of the hydrophobic dendritic block, which significantly simplifies kinetic analyses. Using these hybrids, we demonstrate how precise, minor changes in the hydrophobic block are manifested into tremendous changes in the stability of the assembled micelles toward enzymatic degradation. The obtained results emphasize the extreme sensitivity of self-assembly and its great importance in regulating the accessibility of enzymes to their substrates. Furthermore, the demonstration that the structural differences between readily degradable and undegradable micelles are rather minor, points to the critical roles that self-assembly and polydispersity play in designing biodegradable materials
Enzyme-Responsive Amphiphilic PEG-Dendron Hybrids and Their Assembly into Smart Micellar Nanocarriers
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
Reversible Dimerization of Polymeric Amphiphiles Acts as a Molecular Switch of Enzymatic Degradability
Enzyme-responsive
polymeric micelles have great potential as drug
delivery systems due to the high selectivity and overexpression of
disease-associated enzymes, which could be utilized to trigger the
release of active drugs only at the target site. We previously demonstrated
that enzymatic degradation rates of amphiphilic PEG-dendron hybrids
could be precisely tuned by gradually increasing the hydrophobic to
hydrophilic ratio. However, with the increase in hydrophobicity, the
micelles rapidly became too stable and could not be degraded, as often
encountered for many other amphiphilic assemblies. Here we address
the challenge to balance between stability and reactivity of enzymatically
degradable assemblies by utilizing reversible dimerization of diblock
polymeric amphiphiles to yield jemini amphiphiles. This molecular
transformation serves as a tool to control the critical micelle concentration
of the amphiphiles in order to tune their micellar stability and enzymatic
degradability. To demonstrate this approach, we show that simple dimerization
of two polymeric amphiphiles through a single reversible disulfide
bond significantly increased the stability of their micellar assemblies
toward enzymatic degradation, although the hydrophilic to hydrophobic
ratio was not changed. Reduction of the disulfide bond led to dedimerization
of the polymeric hybrids and allowed their degradation by the activating
enzyme. The generality of the approach is demonstrated by designing
both esterase- and amidase-responsive micellar systems. This new molecular
design can serve as a simple tool to increase the stability of polymeric
micelles without impairing their enzymatic degradability
Molecular Precision and Enzymatic Degradation: From Readily to Undegradable Polymeric Micelles by Minor Structural Changes
Studying the enzymatic degradation
of synthetic polymers is crucial
for the design of suitable materials for biomedical applications ranging
from advanced drug delivery systems to tissue engineering. One of
the key parameters that governs enzymatic activity is the limited
accessibility of the enzyme to its substrates that may be collapsed
inside hydrophobic domains. PEG-dendron amphiphiles can serve as powerful
tools for the study of enzymatic hydrolysis of polymeric amphiphiles
due to the monodispersity and symmetry of the hydrophobic dendritic
block, which significantly simplifies kinetic analyses. Using these
hybrids, we demonstrate how precise, minor changes in the hydrophobic
block are manifested into tremendous changes in the stability of the
assembled micelles toward enzymatic degradation. The obtained results
emphasize the extreme sensitivity of self-assembly and its great importance
in regulating the accessibility of enzymes to their substrates. Furthermore,
the demonstration that the structural differences between readily
degradable and undegradable micelles are rather minor, points to the
critical roles that self-assembly and polydispersity play in designing
biodegradable materials
Encapsulation and Covalent Binding of Molecular Payload in Enzymatically Activated Micellar Nanocarriers
The
high selectivity and often-observed overexpression of specific
disease-associated enzymes make them extremely attractive for triggering
the release of hydrophobic drug or probe molecules from stimuli-responsive
micellar nanocarriers. Here we utilized highly modular amphiphilic
polymeric hybrids, composed of a linear hydrophilic polyethylene glycol
(PEG) and an esterase-responsive hydrophobic dendron, to prepare and
study two diverse strategies for loading of enzyme-responsive micelles.
In the first type of micelles, hydrophobic coumarin-derived dyes were
encapsulated noncovalently inside the hydrophobic core of the micelle,
which was composed of lipophilic enzyme-responsive dendrons. In the
second type of micellar nanocarrier the hydrophobic molecular cargo
was covalently linked to the end-groups of the dendron through enzyme-cleavable
bonds. These amphiphilic hybrids self-assembled into micellar nanocarriers
with their cargo covalently encapsulated within the hydrophobic core.
Both types of micelles were highly responsive toward the activating
enzyme and released their molecular cargo upon enzymatic stimulus.
Importantly, while faster release was observed with noncovalent encapsulation,
higher loading capacity and slower release rate were achieved with
covalent encapsulation. Our results clearly indicate the great potential
of enzyme-responsive micellar delivery platforms due to the ability
to tune their payload capacities and release rates by adjusting the
loading strategy