10 research outputs found
Multifunctional and Redox-Responsive Self-Assembled Magnetic Nanovectors for Protein Delivery and Dual-Modal Imaging
Nanoparticle
(NP) based model carriers present an emerging strategy for protein
delivery. However, constructing a multifunctional nanocarrier with
high loading capacity, diagnostic imaging capacity, and controlled
release capability is a tremendous challenge for protein delivery
systems. Thus, we herein report on the fabrication of redox-responsive
magnetic nanovectors (termed RMNs) through self- assembly of Fe<sub>3</sub>O<sub>4</sub> NPs and redox-responsive polymer ligands, which
could effectively transport protein and trigger intracellular protein
release. These RMNs also exhibited low toxicity, high stability, biocompatibility,
and <i>T</i><sub>2</sub>-weighted contrast-enhancement properties.
In addition, they presented a quantized positively charged surface
that had the capacity to load cyanine 5.5 (Cy5.5) labeled human serum
albumin (HSA) with high loading efficiency (∼84%) via electrostatic
interactions and which favored cellular uptake. Notably, studies of
the in vitro protein release showed that HSA-Cy5.5-loaded RMNs (RMNs-HSA-Cy5.5)
presented minimal cumulative release behavior under physiological
conditions but release was rapidly enhanced under high glutathione
concentration conditions. Confocal microscopy further revealed that
protein was delivered and localized at the perinuclear region of tumor
cells. Moreover, the in vivo imaging results confirmed that RMNs-HSA-Cy5.5
could serve as a dual-modal probe for simultaneous near-infrared fluorescence
(NIRF) imaging and magnetic resonance (MR) imaging, which can be used
for breast cancer diagnosis, and verified higher tumor accumulation
of transported protein in a living body. Overall, we believe that
these multifunctional RMNs exhibit great promise for protein delivery,
cancer diagnosis and therapy, and multimodal imaging, as well as clinical
applications
One-Step Preparation of pH-Responsive Polymeric Nanogels as Intelligent Drug Delivery Systems for Tumor Therapy
In
this work, pH-responsive polypeptide-based nanogels are reported
as potential drug delivery systems. By the formation of pH-sensitive
benzoic imine bonds, pH-responsive nanogels are constructed using
hydrophilic methoxy polyÂ(ethylene glycol)-<i>b</i>-polyÂ[<i>N</i>-[<i>N</i>-(2-aminoethyl)-2-aminoethyl]-l-glutamate] (MPEG-<i>b</i>-PNLG) and hydrophobic terephthalaldehyde
(TPA) as a cross-linker. At pH 7.4, MPEG-<i>b</i>-PNLG nanogels
exhibit high stabilities with hydrophobic inner cores, which allow
encapsulation of hydrophobic therapeutic agents. Under tumoral acidic
environments (pH ∼6.4), the cleavage of benzoic imine bonds
induces the destruction of MPEG-<i>b</i>-PNLG nanogels and
leads to rapid release of their payloads. The formation and pH sensitivity
of the nanogels are investigated by dynamic light scattering. These
nanogels exhibit excellent stabilities in the presence of salt or
against dilution. The globular morphologies of the nanogels are confirmed
using transmission electron microscopy. Doxorubicin is used as a model
drug to evaluate drug encapsulation and release. Finally, the anticancer
activities of the drug-encapsulated nanogels are assessed in vitro
Colloidal Mesoporous Silica Nanoparticles as Strong Adhesives for Hydrogels and Biological Tissues
Sub-100
nm colloidal mesoporous silica (CMS) nanoparticles are evaluated as
an adhesive for hydrogels or biological tissues. Because the adhesion
energy is proportional to the surface area of the nanoparticles, the
CMS nanoparticles could provide a stronger adhesion between two hydrogels
than the nonporous silica nanoparticles. In the case of 50 nm CMS
nanoparticles with a pore diameter of 6.45 nm, the maximum adhesion
energy was approximately 35.0 J/m<sup>2</sup> at 3.0 wt %, whereas
the 10 wt % nonporous silica nanoparticle solution showed only 7.0
J/m<sup>2</sup>. Moreover, the CMS nanoparticle solution had an adhesion
energy of 22.0 J/m<sup>2</sup> at 0.3 wt %, which was 11 times higher
than that of the nonporous nanoparticles at the same concentration.
Moreover, these CMS nanoparticles are demonstrated for adhering incised
skin tissues of mouse, resulting in rapid healing even at a lower
nanoparticle concentration. Finally, the CMS nanoparticles had added
benefit of quick degradation in biological media because of their
porous structure, which may prevent unwanted accumulation in tissues
Redox- and pH-Sensitive Polymeric Micelles Based on Poly(β-amino ester)-Grafted Disulfide Methylene Oxide Poly(ethylene glycol) for Anticancer Drug Delivery
In this report, a redox- and pH-sensitive
polyÂ(β-amino ester)-grafted
disulfide methylene oxide polyÂ(ethylene glycol) (PAE-g-DSMPEG) was
synthesized, and it showed not only a sharp pH-dependent assembly–disassembly
transition but also a quick shell shading in a high concentration
of reducing agent by Michael addition polymerization. <sup>1</sup>H NMR, dynamic light scattering, and transition electron microscopy
were combined to characterize the redox- and pH-responsiveness in
various triggered conditions. The hydrophobic drug doxorubicin (DOX)
was used as the model drug to investigate the encapsulation and delivery
ability of polymeric micelles, in both in vitro and in vivo experiments.
Notably, antitumor experiments in tumor-bearing mice showed that DOX-loaded
polymeric micelles effectively enhanced the therapeutic efficacy in
comparison to free-DOX. These results were further confirmed by histopathological
examinations. Taken together, the results suggested that PAE-g-DSMPEG
could be a potential hydrophobic drug delivery vehicle
Tuning Surface Charge and PEGylation of Biocompatible Polymers for Efficient Delivery of Nucleic Acid or Adenoviral Vector
As an effective and safe strategy
to overcome the limits of therapeutic
nucleic acid or adenovirus (Ad) vectors for in vivo application, various
technologies to modify the surface of vectors with nonimmunogenic/biocompatible
polymers have been emerging in the field of gene therapy. However,
the transfection efficacy of the polymer to transfer genetic materials
is still relatively weak. To develop more advanced and effective polymers
to deliver not only Ad vectors, but also nucleic acids, 6 biocompatible
polymers were newly designed and synthesized to different sizes (2k,
3.4k, or 5k) of polyÂ(ethylene) glycol (PEG) and different numbers
of amine groups (2 or 5) based on methoxy polyÂ(ethylene glycol)-<i>b</i>-polyÂ{<i>N</i>-[<i>N</i>-(2-aminoethyl)-2-aminoethyl]-l-glutamate (PNLG). We characterized size distribution and surface
charge of 6 PNLGs after complexation with either nucleic acid or Ad.
Among all 6 PNLGs, the 5 amine group PNLG showed the strongest efficacy
in delivering nucleic acid as well as Ad vectors. Interestingly, cellular
uptake results showed higher uptake ability in Ad complexed with 2
amine group PNLG than Ad/5 amine group PNLG, suggesting that the size
of Ad/PNLGs is more essential than the surface charge for cellular
uptake in polymers with charges greater than 30 mV. Moreover, the
endosome escape ability of Ad/PNLGs increased depending on the number
of amine groups, but decreased by PEG size. Cancer cell killing efficacy
and immune response studies of oncolytic Ad/PNLGs showed 5 amine group
PNLG to be a more effective and safe carrier for delivering Ad. Overall,
these studies provide new insights into the functional mechanism of
polymer-based approaches to either nucleic acid or Ad/nanocomplex.
Furthermore, the identified ideal biocompatible PNLG polymer formulation
(5 amine/2k PEG for nucleic acid, 5 amine/5k PEG for Ad) demonstrated
high transduction efficiency as well as therapeutic value (efficacy
and safety) and thus has strong potential for in vivo therapeutic
use in the future
Multifunctional Polymer Ligand Interface CdZnSeS/ZnS Quantum Dot/Cy3-Labeled Protein Pairs as Sensitive FRET Sensors
High-quality
CdZnSeS/ZnS alloyed core/thick-shell quantum dots (QDs) as energy
donors were first exploited in Förster resonance energy transfer
(FRET) applications. A highly efficient ligand-exchange method was
used to prepare low toxicity, high quantum yield, stabile, and biocompatible
CdZnSeS/ZnS QDs densely capped with multifunctional polymer ligands
containing dihydrolipoic acid (DHLA). The resulting QDs can be applied
to construct QDs-based Förster resonance energy transfer (FRET)
systems by their high affinity interaction with dye cyanine 3 (Cy3)-labeled
human serum albumin (HSA). This QD-based FRET protein complex can
serve as a sensitive sensor for probing the interaction of clofazimine
with proteins using fluorescence spectroscopic techniques. The ability
of FRET imaging both in vitro and in vivo not only reveals that the
current FRET system can remain intact for 2 h but also confirms the
potential of the FRET system to act as a nanocarrier for intracellular
protein delivery or to serve as an imaging probe for cancer diagnosis
Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing
Despite
great potential, the delivery of genetic materials into
cells or tissues of interest remains challenging owing to their susceptibility
to nuclease degradation, lack of permeability to the cell membrane,
and short in vivo half-life, which severely restrict their widespread
use in therapeutics. To surmount these shortcomings, we developed
a bioinspired in situ-forming pH- and temperature-sensitive injectable
hydrogel depot that could control the delivery of DNA-bearing polyplexes
for versatile biomedical applications. A series of multiblock copolymer,
comprised of water-soluble polyÂ(ethylene glycol) (PEG) and pH- and
temperature-responsive polyÂ(sulfamethazine ester urethane) (PSMEU),
has been synthesized as in situ-forming injectable hydrogelators.
The free-flowing PEG–PSMEU copolymer sols at high pH and room
temperature (pH 8.5, 23 °C) were transformed to stable gel at
the body condition (pH 7.4, 37 °C). Physical and mechanical properties
of hydrogels, including their degradation rate and viscosity, are
elegantly controlled by varying the composition of urethane ester
units. Subcutaneous administration of free-flowing PEG–PSMEU
copolymer sols to the dorsal region of Sprague–Dawley rats
instantly formed hydrogel depot. The degradation of the hydrogel depot
was slow at the beginning and found to be bioresorbable after two
months. Cationic protein or DNA-bearing polyplex-loaded PEG–PSMEU
copolymer sols formed stable gel and controlled its release over 10
days in vivo. Owing to the presence of urethane linkages, the PEG–PSMEU
possesses excellent adhesion strength to wide range of surfaces including
glass, plastic, and fresh organs. More importantly, the hydrogels
effectively adhered on human skin and peeled easily without eliciting
an inflammatory response. Subcutaneous implantation of PEG–PSMEU
copolymer sols effectively sealed the ruptured skin, which accelerated
the wound healing process as observed by the skin appendage morphogenesis.
The bioinspired in situ-forming pH- and temperature-sensitive injectable
adhesive hydrogel may provide a promising platform for myriad biomedical
applications as controlled delivery vehicle, adhesive, and tissue
regeneration
Inverse Photonic Glasses by Packing Bidisperse Hollow Microspheres with Uniform Cores
A major fabrication
challenge is producing disordered photonic materials with an angle-independent
structural red color. Theoretical work has shown that such a color
can be produced by fabricating inverse photonic glasses with monodisperse,
nontouching voids in a silica matrix. Here, we demonstrate a route
toward such materials and show that they have an angle-independent
red color. We first synthesize monodisperse hollow silica particles
with precisely controlled shell thickness and then make glassy colloidal
structures by mixing two types of hollow particles with the same core
size and different shell thicknesses. We then infiltrate the interstices
with index-matched polymers, producing disordered porous materials
with uniform, nontouching air voids. This procedure allows us to control
the light-scattering form factor and structure factor of these porous
materials independently, which is not possible to do in photonic glasses
consisting of packed solid particles. The structure factor can be
controlled by the shell thickness, which sets the distance between
pores, whereas the pore size determines the peak wave vector of the
form factor, which can be set below the visible range to keep the
main structural color pure. By using a binary mixture of 246 and 268
nm hollow silica particles with 180 nm cores in an index-matched polymer
matrix, we achieve angle-independent red color that can be tuned by
controlling the shell thickness. Importantly, the width of the reflection
peak can be kept constant, even for larger interparticle distances
Gold-Nanoclustered Hyaluronan Nano-Assemblies for Photothermally Maneuvered Photodynamic Tumor Ablation
Optically active nanomaterials have
shown great promise as a nanomedicine
platform for photothermal or photodynamic cancer therapies. Herein,
we report a gold-nanoclustered hyaluronan nanoassembly (GNc-HyNA)
for photothermally boosted photodynamic tumor ablation. Unlike other
supramolecular gold constructs based on gold nanoparticle building
blocks, this system utilizes the nanoassembly of amphiphilic hyaluronan
conjugates as a drug carrier for a hydrophobic photodynamic therapy
agent verteporfin, a polymeric reducing agent, and an organic nanoscaffold
upon which gold can grow. Gold nanoclusters were selectively installed
on the outer shell of the hyaluronan nanoassembly, forming a gold
shell. Given the dual protection effect by the hyaluronan self-assembly
as well as by the inorganic gold shell, verteporfin-encapsulated GNc-HyNA
(Vp-GNc-HyNA) exhibited outstanding stability in the bloodstream.
Interestingly, the fluorescence and photodynamic properties of Vp-GNc-HyNA
were considerably quenched due to the gold nanoclusters covering the
surface of the nanoassemblies; however, photothermal activation by
808 nm laser irradiation induced a significant increase in temperature,
which empowered the PDT effect of Vp-GNc-HyNA. Furthermore, fluorescence
and photodynamic effects were recovered far more rapidly in cancer
cells due to certain intracellular enzymes, particularly hyaluronidases
and glutathione. Vp-GNc-HyNA exerted a great potential to treat tumors
both <i>in vitro</i> and <i>in vivo</i>. Tumors
were completely ablated with a 100% survival rate and complete skin
regeneration over the 50 days following Vp-GNc-HyNA treatment in an
orthotopic breast tumor model. Our results suggest that photothermally
boosted photodynamic therapy using Vp-GNc-HyNA can offer a potent
therapeutic means to eradicate tumors
Self-assembled PEGylated albumin nanoparticles (SPAN) as a platform for cancer chemotherapy and imaging
<p>Paclitaxel (PTX) is used as a major antitumor agent for the treatment of recurrent and metastatic breast cancer. For the clinical application of PTX, it needs to be dissolved in an oil/detergent-based solvent due to its poor solubility in an aqueous medium. However, the formulation often causes undesirable complications including hypersensitivity reactions and limited tumor distribution, resulting in a lower dose-dependent antitumor effect. Herein, we introduce a facile and oil-free method to prepare albumin-based PTX nanoparticles for efficient systemic cancer therapy using a conjugate of human serum albumin (HSA) and poly(ethyleneglycol) (PEG). PTX were efficiently incorporated in the self-assembled HSA-PEG nanoparticles (HSA-PEG/PTX) using a simple film casting and re-hydration procedure without additional processes such as application of high pressure/shear or chemical crosslinking. The spherical HSA-PEG nanoparticle with a hydrodynamic diameter of ca. 280 nm mediates efficient cellular delivery, leading to comparable or even higher cytotoxicity in various breast cancer cells than that of the commercially available Abraxane<sup>®</sup>. When systemically administered in a mouse xenograft model for human breast cancer, the HSA-PEG-based nanoparticle formulation exhibited an extended systemic circulation for more than 96 h and enhanced intratumoral accumulation, resulting in a remarkable anticancer effect and prolonged survival of the animals.</p