10 research outputs found
Ligand Size and Conformation Affect the Behavior of Nanoparticles Coated with in Vitro and in Vivo Protein Corona
Protein corona is
immediately established on the surface of nanoparticles upon their
introduction into biological milieu. Several studies have shown that
the targeting efficiency of ligand-modified nanoparticles is attenuated
or abolished owing to the protein adsorption. Here, transferrin receptor-targeting
ligands, including LT7 (CHAIYPRH), DT7 (hrpyiahc, all d-form
amino acids), and transferrin, were used to identify the influence
of the ligand size and conformation on protein corona formation. The
results showed that the targeting capacity of ligand-modified nanoparticles
was lost after incubation with plasma in vitro, whereas it was partially
retained after in vivo corona formation. Results from sodium dodecyl
sulfate polyacrylamide gel electrophoresis and liquid chromatography–mass
spectrometry revealed the difference in the composition of in vitro
and in vivo corona, wherein the ligand size and conformation played
a critical role. Differences were observed in cellular internalization
and exocytosis profiles on the basis of the ligand and corona source
Normalizing Tumor Vessels To Increase the Enzyme-Induced Retention and Targeting of Gold Nanoparticle for Breast Cancer Imaging and Treatment
Abnormal
tumor vessels impede the transport and distribution of
chemotherapeutics, resulting in low drug concentration at tumor sites
and compromised drug efficacy. Normalizing tumor vessels can modulate
tumor vascular permeability, alleviate tumor hypoxia, increase blood
perfusion, attenuate interstitial fluid pressure, and improve drug
delivery. Herein, a novel strategy combining cediranib, a tumor vessel
normalizing agent, with an enzyme responsive size-changeable gold
nanoparticle (AuNPs-A&C) was developed. <i>In vivo</i> photoacoustic and fluorescence imaging showed that oral pretreatment
with 6 mg/kg/day of cediranib for two consecutive days significantly
enhanced the retention of AuNPs-A&C in 4T1 tumor. <i>In vivo</i> photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO<sub>2</sub>), Evans blue assay, and immunofluorescence assay showed that
cediranib pretreatment markedly increased tumor vascular permeability
and tumor oxygenation, while distinctly decreased the tumor microvessel
density, demonstrating normalized tumor vessels and favorably altered
microenvironment. Additionally, the combination strategy considerably
elevated the tumor targeting capacity of different nanoparticle formulations
(AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and
AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy
in 4T1 tumor bearing mouse model. In conclusion, we report a novel
combined administration strategy to further improve tumor diagnosis
and treatment
A Novel Strategy through Combining iRGD Peptide with Tumor-Microenvironment-Responsive and Multistage Nanoparticles for Deep Tumor Penetration
Despite the great achievements that
nanomedicines have obtained so far, deep penetration of nanomedicines
into tumors is still a major challenge in tumor treatment. The enhanced
permeability and retention (EPR) effect was the main theoretical foundation
for using nanomedicines to treat solid tumor. However, the antitumor
efficiency is modest because the tumor is heterogeneous, with dense
collagen matrix, abnormal tumor vasculature, and lymphatic system.
Nanomedicines could only passively accumulate near leaky site of tumor
vessels, and they cannot reach the deep region of tumor. To enhance
further the tumor penetration efficiency, we developed a novel strategy
of coadministering cell-homing penetration peptide iRGD with size-shrinkable
and tumor-microenvironment-responsive multistage system (DOX-AuNPs-GNPs)
to overcome these barriers. First, iRGD could specifically increase
the permeability of tumor vascular and tumor tissue, leading to more
DOX-AuNPs-GNPs leaking out from tumor vasculature. Second, the multistage
system passively accumulated in tumor tissue and shrank from 131.1
to 46.6 nm to reach the deep region of tumor. In vitro, coadministering
iRGD with DOX-AuNPs-GNPs showed higher cellular uptake and apoptosis
ratio. In vivo, coadministering iRGD with DOX-AuNPs-GNPs presented
higher penetration and accumulation in tumor than giving DOX-AuNPs-GNPs
alone, leading to the best antitumor efficiency in 4T1 tumor-bearing
mouse model
Increased Gold Nanoparticle Retention in Brain Tumors by <i>in Situ</i> Enzyme-Induced Aggregation
The treatment of brain tumors remains
a challenge due to the limited
accumulation of drugs and nanoparticles. Here, we triggered the aggregation
of gold nanoparticles (AuNPs) using legumain to enhance the retention
of chemotherapeutics in brain tumors. This nanoplatform, AuNPs-A&C,
is comprised of Ala-Ala-Asn-Cys-Lys modified AuNPs (AuNPs-AK) and
2-cyano-6-aminobenzothiazole modified AuNPs (AuNPs-CABT). AuNPs-AK
could be hydrolyzed to expose the 1,2-thiolamino groups on AuNPs-AK
in the presence of legumain, which occurs by a click cycloaddition
with the contiguous cyano group on AuNPs-CABT, resulting in formation
of AuNPs aggregates. This strategy led to an enhanced retention of
the AuNPs in glioma cells both <i>in vitro</i> and <i>in vivo</i> due to the blocking of nanoparticle exocytosis and
minimizing nanoparticle backflow to the bloodstream. After conjugation
of doxorubicin (DOX) <i>via</i> a pH-sensitive linker to
AuNPs-A&C, the efficiency for treating glioma was improved. The
median survival time for the DOX-linked AuNPs-A&C increased to
288% in comparison to the saline group. We further show the use of
the AuNPs-A&C for optical imaging applications. In conclusion,
we provide a strategy to increase nanoparticle tumor accumulation
with the potential to improve therapeutic outcome
Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma
Glioblastoma (GBM),
one of the most lethal cancers, remains as a hard task to handle.
The major hurdle of nanostructured therapeutic agents comes from the
limited retention at the GBM site and poor selectivity. In this study,
we reported dual-functional gold nanoparticles (AuNPs) to figure out
the biological barrier and improve their accumulation in GBM. The
nanoparticles, AuNP-A&C-R, were composed of two functional particles:
one was Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R)
and the other was 2-cyano-6-amino-benzothiazole and R8-RGD-comodified
AuNPs (AuNP-CABT-R). AuNP-A&C-R could aggregate in the presence
of legumain, resulting in a size increase from 41.4 ± 0.6 to
172.9 ± 10.2 nm after 8 h incubation. After entering the circulatory
system, AuNP-A&C-R actively targeted the integrin α<sub>v</sub>β<sub>3</sub> receptor on blood–brain barrier
(BBB), mediated transcytosis of particles across BBB, and then targeted
the receptor on the GBM cells. Once AuNP-A&C-R entered into GBM,
they formed further aggregates with increased size extracellularly
or intracellularly because of the overexpressed legumain, which in
turn blocked their backflow to the bloodstream or limited their exocytosis
by cells. In vivo optical imaging demonstrated that AuNP-A&C-R were efficiently
delivered to the GBM site and retained with high selectivity. We further
confirmed that AuNP-A&C-R acquired a higher accumulation at the
GBM site than AuNP-A&C and AuNP-R because of the synergistic effect.
More importantly, the doxorubicin (DOX)-loaded AuNP-A&C-R showed
an improved chemotherapeutic effect to C6 GBM-bearing mice, which
significantly prolonged the median survival time by 1.22-fold and
1.27-fold compared with the DOX-loaded AuNP-A&C and the DOX-loaded
AuNP-R, respectively. These results suggested that the dual-functional
nanoplatform is promising for the GBM treatment
Coadministration of iRGD with Multistage Responsive Nanoparticles Enhanced Tumor Targeting and Penetration Abilities for Breast Cancer Therapy
Limited tumor targeting
and poor penetration of nanoparticles are two major obstacles to improving
the outcome of tumor therapy. Herein, coadministration of tumor-homing
peptide iRGD and multistage-responsive penetrating nanoparticles for
the treatment of breast cancer are reported. This multistage-responsive
nanoparticle, IDDHN, was comprised of an NO donor-modified hyaluronic
acid (HN) shell and a small-sized dendrimer, namely, dendri-graft-l-lysine conjugated with doxorubicin and indocyanine (IDD).
The results showed that IDDHN could be degraded rapidly from about
330 nm to a smaller size that was in a size range of 35 to 150 nm
(most at 35–60 nm) after hyaluronidase (HAase) incubation for
4 h; in vitro cellular uptake demonstrated that iRGD could mediate
more endocytosis of IDDHN into 4T1 cells, which was attributed to
the overexpression of α<sub>v</sub>β<sub>3</sub> integrin
receptor. Multicellular spheroids penetration results showed synergistically
enhanced deeper distribution of IDDHN into tumors, with the presence
of iRGD, HAase incubation, and NO release upon laser irradiation.
In vivo imaging indicated that coadministration with iRGD markedly
enhanced the tumor targeting and penetration abilities of IDDHN. Surprisingly,
coadministration of IDDHN with iRGD plus 808 nm laser irradiation
nearly suppressed all tumor growth. These results systematically revealed
the excellent potential of coadministration of iRGD with multistage-responsive
nanoparticles for enhancing drug delivery efficiency and overcoming
the 4T1 breast cancer
Fluorescent Carbonaceous Nanodots for Noninvasive Glioma Imaging after Angiopep‑2 Decoration
Fluorescent carbonaceous nanodots
(CDs) have attracted much attention
due to their unique properties. However, their application in noninvasive
imaging of diseased tissues was restricted by the short excitation/emission
wavelengths and the low diseased tissue accumulation efficiency. In
this study, CDs were prepared from glucose and glutamic acid with
a particle size of 4 nm. Obvious emission could be observed at 600
to 700 nm when CDs were excited at around 500 nm. This property enabled
CDs with capacity for deep tissue imaging with low background adsorption.
Angiopep-2, a ligand which could target glioma cells, was anchored
onto CDs after PEGylation. The product, An-PEG-CDs, could target C6
glioma cells with higher intensity than PEGylated CDs (PEG-CDs), and
endosomes were involved in the uptake process. In vivo, An-PEG-CDs
could accumulate in the glioma site at higher intensity, as the glioma/normal
brain ratio for An-PEG-CDs was 1.73. The targeting effect of An-PEG-CDs
was further demonstrated by receptor staining, which showed An-PEG-CDs
colocalized well with the receptors expressed in glioma. In conclusion,
An-PEG-CDs could be successfully used for noninvasive glioma imaging
Cabazitaxel and indocyanine green co-delivery tumor-targeting nanoparticle for improved antitumor efficacy and minimized drug toxicity
<p>Cabazitaxel (CBX) is an effective antineoplastic agent for the treatment of many kinds of cancers. However, the poor water solubility remains a serious deterrent to the utilization of CBX as a commercial drug. In this study, we designed a strategy that integrated CBX into albumin nanoparticles (ANs) formed with human serum albumin (HSA) to improve the water solubility and targeting ability. Meanwhile, we utilized a photothermal agent-indocyanine green (ICG), which could cooperate with CBX to enhance the antitumor effect. The obtained ANs containing ICG and CBX (AN-ICG-CBX) exhibited good mono-dispersity. <i>In vitro</i> cytotoxicity study showed the effectiveness of CBX and ICG, respectively, whereas AN-ICG-CBX with irradiation exhibited the most efficient antiproliferative ability (83.7%). <i>In vivo</i> safety evaluation studies demonstrated the safety of AN-ICG-CBX. Furthermore, the <i>in vivo</i> antitumor study indicated that the AN-ICG-CBX with irradiation achieved higher tumor inhibition rate (91.3%) compared with CBX-encapsulated AN (AN-CBX) (83.3%) or ICG-encapsulated AN (AN-ICG) plus irradiation (60.1%) in 4T1 tumor-bearing mice. To sum up, a safety and effective formulation AN-ICG-CBX was developed in this study and successfully reduced the drug toxicity, improved the targeting efficiency and enhanced the therapeutic effects, becoming a promising candidate for clinical application.</p
Self-Targeting Fluorescent Carbon Dots for Diagnosis of Brain Cancer Cells
A new type of carbon dots (CD-Asp) with targeting function toward brain cancer glioma was synthesized <i>via</i> a straightforward pyrolysis route by using d-glucose and l-aspartic acid as starting materials. The as-prepared CD-Asp exhibits not only excellent biocompatibility and tunable full-color emission, but also significant capability of targeting C6 glioma cells without the aid of any extra targeting molecules. <i>In vivo</i> fluorescence images showed high-contrast biodistribution of CD-Asp 15 min after tail vein injection. A much stronger fluorescent signal was detected in the glioma site than that in normal brain, indicating their ability to freely penetrate the blood–brain barrier and precisely targeting glioma tissue. However, its counterparts, the CDs synthesized from d-glucose (CD-G), l-asparic acid (CD-A), or d-glucose and l-glutamic acid (CD-Glu) have no or low selectivity for glioma. Therefore, CD-Asp could act as a fluorescence imaging and targeting agent for noninvasive glioma diagnosis. This work highlights the potential application of CDs for constructing an intelligent nanomedicine with integration of diagnostic, targeting, and therapeutic functions
High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer
The
network of collagen I in tumors could prevent the penetration
of drugs loaded in nanoparticles, and this would lead to impaired
antitumor efficacy. In this study, free losartan (an angiotensin inhibitor)
was injected before treatment to reduce the level of collagen I, which
could facilitate the penetration of nanoparticles. Then the pH-sensitive
cleavable liposomes (Cl-Lip) were injected subsequently to exert the
antitumor effect. The Cl-Lip was constituted by PEG<sub>5K</sub>-Hydrazone-PE
and DSPE-PEG<sub>2K</sub>-R8. When the Cl-Lip reached to the tumor
site by the enhanced permeability and retention (EPR) effect, PEG<sub>5K</sub>-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low
extra-cellular pH conditions of tumors, then the R8 peptide was exposed,
and finally liposomes could be internalized into tumor cells by the
mediation of R8 peptide. <i>In vitro</i> experiments showed
both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of
paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. <i>In
vivo</i> experiments showed the Cl-Lip had a good tumor targeting
ability. After depletion of collagen I, Cl-Lip could penetrate into
the deep place of tumors, the tumor accumulation of Cl-Lip was further
increased by 22.0%, and the oxygen distributed in tumor tissues was
also enhanced. The antitumor study indicated free losartan in combination
with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip
only (37.8%) in 4T1 tumor bearing mice. All results suggested that
depletion of collagen I by losartan dramatically increased the penetration
of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could
lead to better antitumor efficacy of chemical drugs. Thus, the combination
strategy might be a promising tactic for better treatment of solid
tumors with a high level of collagen I