27 research outputs found
Selective Sequence for the Peptide-Triggered Phase Transition of Lyotropic Liquid-Crystalline Structures
A novel
concept of using mixed lipids to construct selective peptide-sequence-sensing
lyotropic liquid-crystalline (LLC) dispersion systems was investigated.
The LLC systems were constructed using a mixture of phytantriol, a
lipid that forms lyotropic liquid-crystalline phases, and a novel
synthesized peptide–lipid (peplipid) for sensing a target peptide
with the RARAR sequence. The internal structure of the dispersed LLC
particles was converted from the lamellar structure (liposomes) to
the inverse bicontinuous cubic phase (cubosomes) in the presence of
the target peptide. The addition of common human proteins did not
induce any structural change, indicating a high selectivity of interaction
with the target peptide. The concept has potential for the design
of targeted controlled release drug delivery agents
Understanding the Mechanism of Enzyme-Induced Formation of Lyotropic Liquid Crystalline Nanoparticles
Liquid crystalline nanoparticles
have shown great potential for
application in fields of drug delivery and agriculture. However, optimized
approaches to generating these dispersions have long been sought after.
This study focused on understanding
the mechanism of formation of cubosomes during the recently reported
enzymatic approach and extending the approach to alternative lipid
types other than phytantriol. The chain length of digestible lipids
was found to influence the effectiveness of triglycerides in disrupting
the equilibrium cubic phase structure to form the emulsion precursor.
In general, a greater hydrophobicity of the triglyceride required
a lower concentration to inhibit liquid crystal structure formation.
Selachyl alcohol was also examined due to its nondigestible trait
and ability to form the inverted hexagonal phase. Digestion of its
precursor emulsion formed hexosomes analogous to the phytantriol-based
systems. Finally, the assumption that fatty acids liberated during
digestion needed to partition out of the nondigestible lipids for
the re-formation of the phase structure was found to be untrue. Their
ionization state, however, did have an effect on the resulting nanostructure,
and this unique property could potentially provide a useful attribute
for oral drug delivery systems
Naphthalocyanine as a New Photothermal Actuator for Lipid-Based Drug Delivery Systems
One
approach to address the substantial global burden of ocular
diseases such as aged related macular degeneration is using light-activated
drug delivery to obviate the need for highly invasive and frequent,
costly intravitreal injections. To enable such systems, new light
responsive materials are required. This communication reports the
use of silicon 2,3-naphthalocyanine bisÂ(trihexylsilyloxide) (SiNC),
a small molecule photosensitizer, as a new actuator for triggering
light responsive lipid-based drug delivery systems. Small-angle X-ray
scattering was used to confirm that the addition of SiNC imparted
light sensitivity to the lipid systems, resulting in a complete phase
transition within 20 s of near-infrared irradiation. The phase transition
was also reversible, suggesting the potential for on-demand drug delivery.
When compared to the phase transitions induced using alternative light
responsive actuators, gold nanorods and graphene, there were some
differences in phase behavior. Namely, the phytantriol with SiNC system
transitioned directly to the inverse micellar phase, skipping the
intermediate inverse hexagonal structure. The photodynamic properties
and efficiency in controlling the release of drug suggest that SiNC-actuated
lipid systems have the potential to reduce the burden of repeated
intravitreal injections
pH-Driven Colloidal Transformations Based on the Vasoactive Drug Nicergoline
The structure of colloidal self-assembled
drug delivery systems
can be influenced by intermolecular interactions between drug and
amphiphilic molecules, and is important to understand in the context
of designing improved delivery systems. Controlling these structures
can enable controlled or targeted release systems for poorly water-soluble
drugs. Here we present the interaction of the hydrophobic vasoactive
drug nicergoline with the internal structure of nanostructured emulsion
particles based on the monoglyceride–water system. Addition
of this drug leads to modification of the internal bicontinuous cubic
structure to generate highly pH-responsive systems. The colloidal
structures were characterized with small-angle X-ray scattering and
visualized using cryogenic transmission electron microscopy. Reversible
transformations to inverse micelles at high pH, vesicles at low pH,
and the modification of the spacing of the bicontinuous cubic structure
at intermediate pH were observed, and enabled the <i>in situ</i> determination of an apparent p<i>K</i><sub>a</sub> for
the drug in this systemî—¸a difficult task using solution-based
approaches. The characterization of this phase behavior is also highly
interesting for the design of pH-responsive controlled release systems
for poorly water-soluble drug molecules
Accelerated Stability Assay (ASA) for Colloidal Systems
Assessment
of the stability of colloidal systems, in particular
lyotropic liquid crystalline dispersions, such as cubosomes and hexosomes,
is typically performed qualitatively or with limited throughput on
specialized instruments. Here, an accelerated stability assay for
colloidal particles has been developed in 384-well plates with standard
laboratory equipment. These protocols enable quantitative assessments
of colloidal stability. To demonstrate the applicability of the assay,
several steric stabilizers for cubic phase nanostructured particles
(cubosomes) have been compared to the current “gold standard”
Pluronic F127
Application of Low-Frequency Raman Spectroscopy to Probe Dynamics of Lipid Mesophase Transformations upon Hydration
Low-frequency
Raman (LFR) spectroscopy is presented as a viable
tool for studying the hydration characteristics of lyotropic liquid
crystal systems herein. Monoolein was used as a model compound, and
its structural changes were probed both in situ and ex situ which enabled a comparison between different hydration
states. A custom-built instrumental configuration allowed the advantages
of LFR spectroscopy to be utilized for dynamic hydration analysis.
On the other hand, static measurements of equilibrated systems (i.e., with varied aqueous content) showcased the structural
sensitivity of LFR spectroscopy. The subtle differences not intuitively
observed between similar self-assembled architectures were distinguished
by chemometric analysis that directly correlated with the results
from small-angle X-ray scattering (SAXS), which is the current “gold
standard” method for determining the structure of such materials
<i>Pseudomonas</i> Infection Responsive Liquid Crystals for Glycoside Hydrolase and Antibiotic Combination
Bacterial
biofilms account for up to 80% of all community-acquired
infections for which bacterial eradication is currently not achievable
using conventional antimicrobial treatments. The protective matrix
that engulfs biofilm-associated bacteria frequently renders antibiotics
ineffective. Glycoside hydrolases are a class of enzymes that break
down the biofilm matrix, thereby increasing the effectiveness of antibiotics.
Herein, nanostructured liquid crystals composed of glyceryl monooleate
(GMO) were investigated as an infection responsive delivery system
for alginate lyase (glycoside hydrolase) and gentamicin (antibiotic)
to treat <i>Pseudomonas</i> biofilms. The presence of <i>Pseudomonas</i> lipase triggered the release of alginate lyase
and gentamicin from the GMO liquid crystals. Treatment with the liquid
crystals containing alginate lyase and gentamicin resulted in a greater
than 2-log reduction in mucoid <i>Pseudomonas aeruginosa</i> (clinical isolate) biofilm. The anti-biofilm activity of alginate
lyase and gentamicin from the liquid crystals was sustained for 2
days and equivalent to the respective unformulated solution treatments.
Accordingly, GMO based liquid crystals are a promising responsive
delivery system for alginate lyase and gentamicin to combat topical <i>Pseudomonas</i> infections
The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures
Efforts to develop orally administered
drugs tend to place an exceptional
focus on aqueous solubility as this is an essential criterion for
their absorption in the gastrointestinal tract. In this work we examine
the solid state behavior and solubility of OZ439, a promising single-dose
cure for malaria being developed as the highly water-soluble mesylate
salt. The aqueous phase behavior of the OZ439 mesylate salt was determined
using a combination of small angle neutron and X-ray scattering (SANS
and SAXS, respectively). It was found that this salt has low solubility
at low concentrations with the drug largely precipitated in free base
aggregates. However, with increasing concentration these crystalline
aggregates were observed to dissociate into cationic micelles and
lamellar phases, effectively increasing the dissolved drug concentration.
It was also found that the dissolved OZ439 spontaneously precipitated
in the presence of biologically relevant anions, which we attribute
to the high lattice energies of most of the salt forms of the drug.
These findings show that aqueous solubility is not always what it
seems in the context of amphiphilic drug molecules and highlights
that its use as the principal metric in selecting drug candidates
for development can be perilous
Sensitivity of Nanostructure in Charged Cubosomes to Phase Changes Triggered by Ionic Species in Solution
The
phase behavior of dispersions comprising mixed ionic surfactant
and phytantriol was precisely controlled by varying the ionic surfactant
content in the mixed lipid and the ionic strength in the system. Two
important trends in the phase transition of the mixed lipid systems
were identified: (1) An increase in the ionic surfactant content increased
the curvature of the self-assembled system toward the hydrophobic
region, resulting in the phase transition from cubic phase to lamellar
phase. (2) An increase in ionic strength decreased repulsion between
the headgroups of the ionic surfactant, resulting in a phase transition
from lamellar phase to cubic phase. The phase transitions were confirmed
using small-angle X-ray scattering and cryo-TEM and were strongly
correlated with the visual turbidity of the dispersions. The lipid
mixture with anionic surfactant showed high sensitivity to multivalent
cations for triggering the phase transition, which may be a potential
strategy to develop a detection/treatment system for toxic multivalent
metallic cations such as chromium
Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect
<div><p></p><p>The opening of the tight junctions in the blood–brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0–8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates.</p></div