28 research outputs found
In Vivo Imaging Tracking and Immune Responses to Nanovaccines Involving Combined Antigen Nanoparticles with a Programmed Delivery
Combined nanovaccine
can generate robust and persistent antigen-specific immune responses.
A combined nanovaccine was developed based on antigen-loaded genipin-cross-linked-polyethyleneimineāantigen
nanoparticles and in vivo multispectral fluorescence imaging tracked
the antigen delivery of combined nanovaccine. The inner layer antigen
nanoparticles carried abundant antigens by self-cross-linking for
persistent immune response, whereas the outer antigen on the surface
of antigen nanoparticles provided the initial antigen exposure. The
delivery of combined nanovaccine was tracked dynamically and objectively
by the separation of inner genipin cross-linked antigen nanoparticle
and the outer fluorescent antigen. The immune responses of the combined
nanovaccine were evaluated including antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses, IgG antibody level, immunological
memory, and CD8<sup>+</sup> cytotoxic T lymphocyte responses. The
results indicated that the inner and outer antigens of combined vaccine
can be tracked in real time with a programmed delivery by the dual
fluorescence imaging. The programmed delivery of the inner and outer
antigens induced strong immune responses with a combination of a quick
delivery and a persistent delivery. With adequate antigen exposure,
the dendritic cells were effectively activated and matured, and following
T cells were further activated for immune response. Compared with
a single nanoparticle formulation, the combined nanovaccine exactly
elicited a stronger antigen-specific immune response
Surface-Induced Hydrogelation for Fluorescence and Naked-Eye Detections of Enzyme Activity in Blood
Fluorescence
probes have been widely applied for the detection
of important analytes with high sensitivity and specificity. However,
they cannot be directly applied for the detection in samples with
autofluorescence such as blood. Herein, we demonstrated a simple but
effective method of surface-induced self-assembly/hydrogelation for
fluorescence detection of an enzyme in biological fluids including
blood and cell lysates. The method utilizes an attracting glass surface
to induce self-assembly of an enzyme-generating fluorescent probe.
After removing the upper solution, the fluorescence turn-on at the
glass surface can therefore be used for the detection of enzyme activity.
By judging the thickness and color depth of hydrogels at the surface
of the glass plates, we could also estimate the enzyme activity by
naked eyes. Our study not only expands the application of molecular
self-assembly but also provides a useful method that can be applied
for direct detection of enzyme activity in complex biological samples
such as blood and cell lysates
ONOO<sup>ā</sup> and ClO<sup>ā</sup> Responsive Organic Nanoparticles for Specific in Vivo Image-Guided Photodynamic Bacterial Ablation
Bacterial infection
poses serious medical and public concerns.
Herein, ā33%IRTPā nanoparticles (NPs) are reported for
in vivo bacterial infection detection and photodynamic treatment,
serving as an alternative to antibiotic therapy. 33%IRTP nanoparticles
have been developed by self-assembly of an ONOO<sup>ā</sup> and ClO<sup>ā</sup> responsive near-infrared dye āIR786Sā
and an amphiphilic polymer āTBD-PEGā containing a highly
effective photosensitizer with aggregation-induced emission characteristics.
As an energy acceptor, IR786S not only shows near-infrared emission
for fluorescence imaging but also quenches both fluorescence and singlet
oxygen generation of TBD-PEG, thus eliminating the phototoxicity of
33%IRTP nanoparticles in normal tissues. Once 33%IRTP NPs reach bacterial
infection sites, IR786S could be decomposed by the overexpressed ONOO<sup>ā</sup> and ClO<sup>ā</sup> to turn on the red fluorescence
and singlet oxygen generation of TBD-PEG, which offers image-guided
photodynamic bacterial ablation. Considering their negligible in vivo
dark toxicity, 33%IRTP nanoparticles demonstrate great potential in
antibacterial applications
Responsive Small Molecular Hydrogels Based on AdamantaneāPeptides for Cell Culture
The development of responsive small molecular hydrogels that can be applied for recovery of cells postculture attract extensive interests for researchers in fields of cell biology, stem cell differentiation, and tissue engineering. We report in this study several responsive small molecular hydrogels based on adamantaneāpeptides whose gel to clear solution phase transition can be achieved by addition of Ī²-cyclodextrin (Ī²-CD) derivatives. The small molecular hydrogels are formed by our recently developed method of disulfide bond cleavage by glutathione (GSH). Mouse fibroblast 3T3 cells attach and grow well at the surface of hydrogels. Furthermore, 3T3 cells postculture can be recovered from the gels by the addition of a Ī²-CD derivative due to formation of clear solutions by the adamantaneāĪ²-CD interaction. The culture on hydrogels and recovery process do not cause obvious effects on behaviors of 3T3 cells. The results shown in this study indicate that small molecular hydrogels based on adamantaneāpeptides have great potentials in research fields where further analysis of cells is needed
Real-Time Imaging Tracking of a Dual Fluorescent Drug Delivery System Based on Zinc Phthalocyanine-Incorporated Hydrogel
Real-time tracking of a drug delivery
system and its therapeutic
effects in vivo are crucial to designing a novel pharmaceutical system
and revealing the mechanism of drug therapy. Multispectral fluorescence
imaging can locate the drug and carrier simultaneously without interference.
This advanced method enables the tracking of a drug delivery system.
Herein, a doxorubicin (Dox) loaded zinc phthalocyanine incorporated
hydrogel was developed as a dual fluorescent drug delivery system
to monitor the release of the drug and the degradation of the carrier.
An injectable thermosensitive hydrogel based on a four-arm polyĀ(ethylene
glycol) (PEG)āpolyĀ(Īµ-Caprolactone) (PCL) copolymer was
prepared and characterized with a zinc phthalocyanine core as the
drug carrier. The hydrogel degradation and drug delivery in vivo were
tracked by a multispectral fluorescence imaging system in nude mice
bearing hepatic tumors. Moreover, the real-time tumor inhibition progress
was tracked in vivo for 18 days by bioluminescence imaging. A multispectral
analysis can separate the fluorescence signals from the drug and carrier
in the Dox loaded hydrogel and provide their location in the tumor
tissue. The drug release and hydrogel degradation can be drastically
tracked respectively without mutual interference. The fluorescence
imaging results reveal improved tumor inhibitory effects of the Dox
loaded hydrogel. Optical imaging allows for visible tracking of the
entire drug delivery process. The Dox loaded phthalocyanine incorporated
thermosensitive hydrogel is a potential visible drug delivery system
for tumor therapy
Fluorine Meets Amine: Reducing Microenvironment-Induced Amino-Activatable Nanoprobes for <sup>19</sup>FāMagnetic Resonance Imaging of Biothiols
<sup>19</sup>F-magnetic
resonance imaging (MRI) is of great significance
for noninvasive imaging and detection of various diseases. However,
the main obstacle in the application of <sup>19</sup>F-MRI agents
stems from the unmet signal sensitivity due to the poor water solubility
and restricted mobility of segments with high number of fluorine atoms.
Herein, we report a kind of intracellular reducing microenvironment-induced
amino-activatable <sup>19</sup>F-MRI nanoprobe, which can be used
for specific imaging of biothiols. In principle, the nanoprobe has
an initial architecture of hydrophobic core, where the trifluoromethyl-containing
segments are compactly packed and <sup>19</sup>F NMR/MRI signals are
quenched (āOFFā state). Upon encountering sulfydryl,
the strong electron-withdrawing 2,4-dinitrobenzenesulfonyl groups
are excised to recover secondary amino groups, whose p<i>K</i><sub>a</sub> is proved to be 7.21. As a consequence, the molecular
weight loss of the hydrophobic segment and the protonation of amino
groups induce significant disturbance of hydrophilic/hydrophobic balance,
leading to the disassembly of the nanoprobes and regain of spināspin
relaxation and <sup>19</sup>F NMR/MRI signals (āONā
state, <i>T</i><sub>2</sub> up to 296 Ā± 5.3 ms). This
nanoprobe shows high sensitivity and selectivity to biothiols, enabling
intracellular and intratumoral imaging of glutathione. Our study not
only provides a new nanoprobe candidate for biothiols imaging in vivo
but also a promising strategy for the molecular design of real water-soluble
and highly sensitive <sup>19</sup>F-MRI nanoprobes
Self-Assembling Peptide of dāAmino Acids Boosts Selectivity and Antitumor Efficacy of 10-Hydroxycamptothecin
d-peptides, which consist
of d-amino acids and
can resist the hydrolysis catalyzed by endogenous peptidases, are
one of the promising candidates for construction of peptide materials
with enhanced biostability in vivo. In this paper, we report on a
self-assembling supramolecular nanostructure of d-amino acid-based
peptide Nap-G<sup>D</sup>F<sup>D</sup>F<sup>D</sup>YGRGD (d-fiber, <sup>D</sup>F meant d-phenylalanine, <sup>D</sup>Y meant d-tyrosine), which were used as carriers for 10-hydroxycamptothecin
(HCPT). Transmission electron microscopy observations demonstrated
the filamentous morphology of the HCPT-loaded peptides (d-fiber-HCPT). The better selectivity and antitumor activity of d-fiber-HCPT than l-fiber-HCPT were found in the in
vitro and in vivo antitumor studies. These results highlight that
this model d-fiber system holds great promise as vehicles
of hydrophobic drugs for cancer therapy
Bioinspired Coordination Micelles Integrating High Stability, Triggered Cargo Release, and Magnetic Resonance Imaging
Catechol-Fe<sup>3+</sup> coordinated micelles show the potential for achieving on-demand
drug delivery and magnetic resonance imaging in a single nanoplatform.
Herein, we developed bioinspired coordination-cross-linked amphiphilic
polymeric micelles loaded with a model anticancer agent, doxorubicin
(Dox). The nanoscale micelles could tolerate substantial dilution
to a condition below the critical micelle concentration (9.4 Ā±
0.3 Ī¼g/mL) without sacrificing the nanocarrier integrity due
to the catechol-Fe<sup>3+</sup> coordinated core cross-linking. Under
acidic conditions (pH 5.0), the release rate of Dox was significantly
faster compared to that at pH 7.4 as a consequence of coordination
collapse and particle de-cross-linking. The cell viability study in
4T1 cells showed no toxicity regarding placebo cross-linked micelles.
The micelles with improved stability showed a dramatically increased
Dox accumulation in tumors and hence the enhanced suppression of tumor
growth in a 4T1 tumor-bearing mouse model. The presence of Fe<sup>3+</sup> endowed the micelles <i>T</i><sub>1</sub>-weighted
MRI capability both in vitro and in vivo without the incorporation
of traditional toxic paramagnetic contrast agents. The current work
presented a simple āthree birds with one stoneā approach
to engineer the robust theranostic nanomedicine platform
Surface-Induced Hydrogelation Inhibits Platelet Aggregation
We demonstrate that a tripeptide hydrogelator, Nap-FFG,
can selectively
self-assemble at the surface of platelets, thus inhibiting ADP-, collagen-,
thrombin- and arachidonic acid (AA)-induced human platelet aggregations
with the IC<sub>50</sub> values of 0.035 (41), 0.14 (162), 0.062 (68),
and 0.13 mg/mL (148 Ī¼M), respectively. Other tripeptide hydrogelators
with chemical structures of Nap-FFX (X = A, K, S, or E) could not
or possessed less potencies to inhibit platelet aggregations. We observed
higher amounts of Nap-FFG at the platelet surface by the techniques
of LC-MS and confocal microscopy. We also observed self-assembled
nanofibers around the platelet incubated with the Nap-FFG by cryo-TEM.
The Ī¶ potential of Nap-FFG treated platelets was a little bit
more negative than that of untreated ones. The amount of Nap-FFG at
the surface of NIH 3T3 cells was much less than that of platelets.
These observations suggested that Nap-FFG could selectively self-assemble
through unknown ligandāreceptor interactions and form thin
layers of hydrogels at the surface of platelets, thus preventing the
aggregation of them. This study not only broadened the application
and opened up a new door for biomedical applications of molecular
hydrogels but also might provide a novel strategy to counteract infection
diseases through selective surface-induced hydrogelations at pathogens,
such as bacteria and virus
Alleviating the Liver Toxicity of Chemotherapy via pH-Responsive Hepatoprotective Prodrug Micelles
Nanocarriers have
been extensively utilized to enhance the anti-tumor performance of
chemotherapy, but it is very challenging to eliminate the associated
hepatotoxicity. This was due to the significant liver accumulation
of cytotoxic drug-loaded nanocarriers as a consequence of systemic
biodistribution. To address this, we report a novel type of nanocarrier
that was made of hepatoprotective compound (oleanolic acid/OA) with
a model drug (methotrexate/MTX) being physically encapsulated. OA
was covalently connected with methoxy polyĀ(ethylene glycol) (mPEG)
via a hydrazone linker, generating amphiphilic mPEGāOA prodrug
conjugate that could self-assemble into pH-responsive micelles (ca.
100 nm), wherein the MTX loading was ca. 5.1% (w/w). The micelles
were stable at pH 7.4 with a critical micelle concentration of 10.5
Ī¼M. At the acidic endosome/lysosome microenvironment, the breakdown
of hydrazone induced the micelle collapse and fast release of payloads
(OA and MTX). OA also showed adjunctive anti-tumor effect with a low
potency, which was proved in 4T1 cells. In the mouse 4T1 breasttumor
model, MTX-loaded mPEGāOA micelles demonstrated superior capability
regarding in vivo tumorgrowth inhibition because of the passive tumor
targeting of nanocarriers. Unsurprisingly, MTX induced significant
liver toxicity, which was evidenced by the increased liver mass and
increased levels of alanine transaminase, aspartate transaminase,
and lactate dehydrogenase in serum as well as in liver homogenate.
MTX-induced hepatotoxicity was also accompanied with augmented oxidative
stress, for example, the increase of the malondialdehyde level and
the reduction of glutathione peroxidase and superoxide dismutase concentration
in the liver. As expected, mPEGāOA micelles significantly reduced
the liver toxicity induced by MTX because of the hepatoprotective
action of OA, which was supported by the reversal of all the above
biomarkers and qualitative histological analysis of liver tissue.
This work offers an efficient approach for reducing the liver toxicity
associated with chemotherapy, which can be applied to various antitumor
drugs and hepatoprotective materials