23 research outputs found
Maximizing the Supported Bilayer Phenomenon: Liposomes Comprised Exclusively of PEGylated Phospholipids for Enhanced Systemic and Lymphatic Delivery
Traditional
liposomes degrade into lower-order micelles when PEGylated
to even minor degrees (6–7 mol %) and therefore can offer only
limited steric exclusion against opsonization during <i>in vivo</i> delivery. In this work, we present for the first time a liposome
coated exclusively by PEGylated phospholipids, utilizing lipid-coated
calcium phosphate (CaP) cores of diverse sizes (10–15 nm, 30–40
nm) as well as varying polyethylene glycol (PEG) chain lengths (350–5000
Da). Such fully-PEGylated liposome calcium phosphate (LCP) particles
exhibit a PEG chain length-dependent circulation longevity and robust
immune evasion, while facilitating both strong accumulation within
solid tumors upon intravenous injection and a more rapid and extensive
lymphatic drainage upon subcutaneous administration. Further, these
fully-PEGylated liposomes remain amenable to active targeting strategies
which facilitate improved degrees of focused distribution and nanoparticle
uptake, represent a lipid packing density commensurate with the formation
of a lipid bilayer, and avoid use of scale-limited physical resuspension
methods. We expect such improved delivery properties to translate
into improved therapeutic safety and efficacy for a variety of systemic
and lymphatic diseases
How Does the Cell Overcome LCP Nanoparticle-Induced Calcium Toxicity?
To
address the question of how cells respond to the possible Ca<sup>2+</sup> toxicity caused by the release of Ca<sup>2+</sup> into the
cytoplasm by LCP nanoparticles, a series of <i>in vitro</i> and <i>in vivo</i> studies using Ca<sup>2+</sup> pump
inhibitors were conducted. The results indicated that two major Ca<sup>2+</sup> pumps on the plasma membrane and the mitochondrial membrane,
respectively, were able to rapidly respond to the elevated cytosolic
Ca<sup>2+</sup> concentration and prevent Ca<sup>2+</sup>-induced
apoptosis or necrosis. However, exposure to specific inhibitors of
calcium pumps would cause LCP-treated H460 cells to undergo necrosis
both <i>in vitro</i> and <i>in vivo</i>. These
results demonstrated that the Ca<sup>2+</sup> delivered by LCP was
not toxic to cells when the cells contain functional Ca<sup>2+</sup> pumps
Additional file 6: of A dosimetric model for the heterogeneous delivery of radioactive nanoparticles In vivo: a feasibility study
Standalone File for Figure S3: Fraction of Volume Populated by Cell Nuclei. A) 10x magnification image of DAPI-stained nuclei in an area in section 171; B) Binary representation of nuclear distribution used to quantify nuclear density. Cell nuclei populated ~40% of the total image area. Nuclear radius measured to be an average of ~5 Îźm. (PNG 401 kb
A Highly Efficient Synthetic Vector: Nonhydrodynamic Delivery of DNA to Hepatocyte Nuclei <i>in Vivo</i>
Multifunctional membrane-core nanoparticles, composed of calcium phosphate cores, arginine-rich peptides, cationic and PEGylated lipid membranes, and galactose targeting ligands, have been developed as synthetic vectors for efficient nuclear delivery of plasmid DNA and subsequent gene expression in hepatocytes <i>in vivo</i>. Targeted particles exhibited rapid and extensive hepatic accumulation and were predominantly internalized by hepatocytes, while the inclusion of such peptides in LCP was sufficient to elicit high degrees of nuclear translocation of plasmid DNA. Monocyclic CR8C significantly enhanced <i>in vivo</i> gene expression over 10-fold more than linear CR8C, likely due to a release-favoring mechanism of the DNA/peptide complex. Though 100-fold lower in activity than that achieved <i>via</i> hydrodynamic injection, this formulation presents as a much less invasive alternative. To our knowledge, this is the most effective synthetic vector for liver gene transfer
Co-delivery of Cisplatin and Rapamycin for Enhanced Anticancer Therapy through Synergistic Effects and Microenvironment Modulation
The tumor microenvironment plays an important role in the tumor’s progression and metastasis. Therefore, successful alteration of this delicate setting against the tumor’s favor can open a window for therapeutic efficacy. We have developed a modality to bring about treatment-induced alterations in the tumor microenvironment by employing the synergistic effects between two drugs. Co-delivery of rapamycin (RAPA), an mTOR inhibitor that may offer notable therapy through antiangiogenic activity, alongside cisplatin can foster significant potency as RAPA sensitizes A375 melanoma cells to cisplatin therapy through microenvironment modulation. However, encapsulation of these drugs into poly(lactic-<i>co</i>-glycolic acid) (PLGA) NPs was inefficient due to the incompatibility between the two free drugs and the polymer matrix. Here, we show cisplatin can be made hydrophobic by coating a nanoprecipitate (cores) of the drug with dioleoylphosphatidic acid (DOPA). These DOPA coated cisplatin cores are compatible with PLGA and can be coencapsulated in PLGA NPs alongside RAPA at a molar ratio to promote synergistic antitumor activity. The presence of the cisplatin cores significantly improved the encapsulation of RAPA into PLGA NPs. Furthermore, PLGA NPs containing both cisplatin cores and RAPA induced significant apoptosis on A375-luc human melanoma cells <i>in vitro.</i> Additionally, they inhibited the growth of A375-luc melanoma in a xenograft tumor model through modulation of the tumor vasculature and permitted enhanced penetration of NPs into the tumor
Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles
Our
previous work demonstrated that Wnt16 expression in cisplatin-damaged
tumor-associated fibroblasts is a key factor contributing to cisplatin
resistance in malignancies. Natural antifibrotic compounds with low
toxicities are promising candidates to downregulate Wnt16 expression,
improving the antitumor effect of cisplatin nanoparticles. Upon screening
several natural chemicals, we found that a dietary flavonoid, quercetin,
significantly suppresses Wnt16 expression in activated fibroblasts.
To facilitate drug delivery, we have prepared a targeted lipid/calcium/phosphate
nanoparticle formulation consisting of a prodrug of quercetin, <i>i</i>.<i>e</i>., quercetin phosphate, with a high
loading efficiency (26.6% w/w). This quercetin nanoparticle with a
particle size of around 35 nm significantly improved the bioavailability
and metabolic stability of the parent quercetin. Quercetin phosphate
is released from the nanoparticles and converted back to the parent
quercetin under physiological conditions. Following systemic administration
of quercetin phosphate nanoparticles, a significant downregulation
in Wnt16 expression was observed and further yielded a synergistic
antitumor effect with cisplatin nanoparticles in a stroma-rich bladder
carcinoma model. The α-SMA-positive fibroblast and collagen
within the tumor decreased significantly after combination treatment.
This suggests that the remodeling of the tumor microenvironment induced
by quercetin plays a critical role in promoting the synergy. Indeed,
our data further confirmed that quercetin phosphate alone significantly
remodeled the tumor microenvironment and increased the penetration
of second-wave nanoparticles into the tumor nests. Collectively, quercetin
phosphate nanoparticles may be a safe and effective way to improve
therapeutic treatment for desmoplastic tumors
Nanoparticle Delivery of Pooled siRNA for Effective Treatment of Non-Small Cell Lung Caner
Non-small cell lung cancer (NSCLC) is the leading cause
of cancer-related
death. To explore the potential of small interfering RNA (siRNA) therapy
for NSCLC, we have developed anisamide-targeted LCP to efficiently
deliver siRNA into the cytoplasm of sigma receptor-expressing NSCLC
cells. Targeted LCP demonstrated a 9-fold higher siRNA delivery efficiency
compared to nontargeted LCP in A549 cells <i>in vitro</i>. To simultaneously target multiple oncogenic mechanisms, we coformulated
three siRNA sequences targeting HDM2, c-myc and VEGF oncogenes, and
investigated their efficacy of cell-killing in A549 and H460 cells <i>in vitro</i>. The results indicated that the pooled siRNA codelivered
by the targeted LCP could effectively and simultaneously knock down
HDM2, c-myc and VEGF expressions and significantly inhibit tumor cell
growth. After iv injection of mice bearing A549 xenografted tumor
with Texas Red-labeled siRNA formulated in the targeted LCP, siRNA
was successfully delivered to and concentrated in the tumor cells.
Repeated intravenous injections of mice with pooled siRNA formulated
in the targeted LCP significantly impaired NSCLC growth <i>in
vivo</i> (<i>p</i> < 0.01) for both A549 and H460
tumors, demonstrating an ED<sub>50</sub> for the treatment of ∼0.2
mg/kg in A549 tumors. The enhanced antitumor activity is due to the
fact that the silencing of HDM2/c-myc/VEGF could inhibit tumor proliferation
and angiogenesis and also simultaneously induce tumor apoptosis. Our
results demonstrate that the targeted LCP is a promising vector to
deliver pooled siRNA into tumors and to achieve multiple target blocking.
This is potentially a valid therapeutic modality in the gene therapy
of human NSCLC
Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma
In desmoplastic melanoma, tumor cells
and tumor-associated fibroblasts are the major dominators playing
a critical role in the fibrosis morphology as well as the immunosuppressive
tumor microenvironment (TME), compromising the efficacy of therapeutic
options. To overcome this therapeutic hurdle, we developed an innovative
chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT)
and celastrol (CEL), two potent medicines screened and selected with
the best anticancer and antifibrosis potentials. Importantly, CEL
worked in synergy with MIT to induce immunogenic tumor cell death.
Here, we show that when effectively co-delivered to the tumor site
at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination
of MIT and CEL significantly triggered immunogenic tumor apoptosis
and recovered tumor antigen recognition, thus eliciting overall antitumor
immunity. Furthermore, the strong synergy benefitted the host in reduced
drug exposure and side effects. Collectively, the nanocarrier-mediated
chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive
TME, arrested cancer progression, and further inhibited tumor metastasis
to major organs. The affected tumors remained dormant long after dosing
stopped, resulting in a prolonged progression-free survival and sustained
immune surveillance of the host bearing desmoplastic melanoma
Nickel(II) Dithiocarbamate Complexes Containing Sulforhodamine B as Fluorescent Probes for Selective Detection of Nitrogen Dioxide
We synthesized complexes of NiÂ(II)
with dithiocarbamate ligands
derived from the ortho and para isomers of sulforhodamine B fluorophores
and demonstrated they are highly selective in reactions with nitrogen
dioxide (NO<sub>2</sub>). Compared with the para isomer, the ortho
isomer showed a much greater fluorescence increase upon reaction with
NO<sub>2</sub>, which led to oxidation and decomplexation of the dithiocarbamate
ligand from NiÂ(II). We applied this probe for visual detection of
1 ppm NO<sub>2</sub> in the gas phase and fluorescence imaging of
NO<sub>2</sub> in macrophage cells treated with a nitrogen dioxide
donor
Nickel(II) Dithiocarbamate Complexes Containing Sulforhodamine B as Fluorescent Probes for Selective Detection of Nitrogen Dioxide
We synthesized complexes of NiÂ(II)
with dithiocarbamate ligands
derived from the ortho and para isomers of sulforhodamine B fluorophores
and demonstrated they are highly selective in reactions with nitrogen
dioxide (NO<sub>2</sub>). Compared with the para isomer, the ortho
isomer showed a much greater fluorescence increase upon reaction with
NO<sub>2</sub>, which led to oxidation and decomplexation of the dithiocarbamate
ligand from NiÂ(II). We applied this probe for visual detection of
1 ppm NO<sub>2</sub> in the gas phase and fluorescence imaging of
NO<sub>2</sub> in macrophage cells treated with a nitrogen dioxide
donor