19 research outputs found
Role of Grafting Density and Nitrile Functionalization on Gas Transport in Polymers with Side-Chain Porosity
This study details the enhancement of CO2 selectivity
in ring-opening metathesis polymerization (ROMP) polymers that contain
nitrile moieties and micropore-generating ladder side chains. A material,
CN-ROMP homopolymer, with nitriles in the ladder side chains was originally
targeted and synthesized; however, its low molecular weight and backbone
rigidity precluded film formation. As a result, an alternative method
was pursued wherein copolymers were synthesized using norbornene (N)
and nitrile norbornene (NN). Herein, we report an investigation of
the structure–property relationships of backbone functionalization
and grafting density on the CO2 transport properties in
these ROMP polymers. Nitrile-containing copolymers showed an increase
in CO2/CH4 sorption selectivity and a concomitant
increase in CO2/CH4 permselectivity when compared
to the unfunctionalized (nitrile-free) analogues. The stability in
CO2-rich environments is enhanced as grafting density of
the rigid, pore-generating side chains increases and an apparent tunability
of CO2 plasticization pressure was observed as a function
of norbornene content. Lower loadings of norbornene resulted in higher
plasticization pressure points. Gas permeability in the ROMP copolymers
was found to correlate most strongly with the concentration of the
ladder macromonomers in the polymer chain
Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery
Antigen
presenting cell (APC) gene delivery is a promising avenue
for modulating immunological outcomes toward a desired state. Recently,
our group developed a delivery methodology to elicit targeted and
elevated levels of APC-mediated gene delivery. During these initial
studies, we observed APC-specific structure–function relationships
with the vectors used during gene delivery that differ from current
non-APC cell lines, thus, emphasizing a need to re-evaluate vector-associated
parameters in the context of APC gene transfer. Thus, we describe
the synthesis and characterization of a second-generation mannosylated
polyÂ(β-amino ester) library stratified by molecular weight.
To better understand the APC-specific structure–function relationships
governing polymeric gene delivery, the library was systematically
characterized by (1) polymer molecular weight, (2) relative mannose
content, (3) polyplex biophysical properties, and (4) gene delivery
efficacy. In this library, polymers with the lowest molecular weight
and highest relative mannose content possessed gene delivery transfection
efficiencies as good as or better than commercial controls. Among
this group, the most effective polymers formed the smallest polymer-plasmid
DNA complexes (∼300 nm) with moderate charge densities (<10
mV). This convergence in polymer structure and polyplex biophysical
properties suggests a unique mode of action and provides a framework
within which future APC-targeting polymers can be designed
Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles
<div><p>This study investigated the impact of chronic exposure to continuous (CoP4) versus cyclic progesterone (CyP4) alone or in combination with 17β-estradiol (E2) on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX) led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1), redox homeostasis (peroxiredoxin 5; Prdx5), insulin signaling (insulin-like growth factor I; Igf1), and cholesterol trafficking (liver X receptor α subtype; Nr1h3), differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX) and E2+CyP4 (up-regulation relative to OVX). In contrast, genes involved in amyloid metabolism (β-secretase; Bace1) differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1). In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT) can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.</p> </div
Hormone interventions and treatment paradigms (A) and uterine responses (B).
<p>OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Gene expression profile associated with OVX+E2+CoP4 versus OVX+E2+CyP4 treatment paradigms.
<p>(A) Genes significantly regulated by OVX+E2+CoP4 (17 genes; P<0.05) and/or OVX+E2+CyP4 (13 genes; P<0.05); red indicates up-regulated genes, green indicates down-regulated genes. (B) Hierarchical cluster diagrams: mitochondrial energy/redox metabolism related genes (top panel; 12 genes; P<0.05); insulin signaling/amyloid metabolism related genes (lower panel; 5 genes; P<0.05). Control Group = OVX; Group 1 = Sham-OVX; Group 5 = OVX+E2+CoP4; Group 6 = OVX+E2+CyP4. OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Mapping of the primary molecular network associated with OVX+E2+CoP4 with other hormone interventions and treatment paradigms.
<p>Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031267#pone-0031267-g004" target="_blank">Figure 4</a> for the network representation, except: red indicates up-regulated genes, green indicates down-regulated genes; genes that exhibited significant changes are indicated: * P<0.05, ** P<0.01 and *** P<0.001. OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Mapping of the primary molecular network associated with OVX+E2+CyP4 with other hormone interventions and treatment paradigms.
<p>Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031267#pone-0031267-g004" target="_blank">Figure 4</a> for the network representation, except: red indicates up-regulated genes, green indicates down-regulated genes; genes that exhibited significant changes are indicated: * P<0.05, ** P<0.01 and *** P<0.001. OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Primary molecular networks associated with OVX+E2+CoP4 versus OVX+E2+CyP4 treatment paradigms.
<p>Molecules in the network are displayed as various shapes, which indicate the molecular class. Focus molecules (colored molecules) refer to genes from the dataset that were significantly up- or down-regulated by a given treatment (OVX+E2+CoP4 or OVX+E2+CyP4); red indicates up-regulated genes (P<0.05), green indicates down-regulated genes (P<0.05), gray indicates insignificantly changed genes from the dataset (P>0.05), and white indicates molecules added from the Ingenuity Knowledge Base; color intensity indicates the degree of up or down-regulation. Lines connecting molecules indicate molecular relationships; solid lines indicate direct interaction, dashed lines indicate indirect interactions; the type of arrows indicate specific molecular relationships and the directionality of the interaction. OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Hierarchical cluster diagrams: (A) mitochondrial energy/redox metabolism related genes (18 genes; P<0.1); (B) cholesterol homeostasis/myelin metabolism related genes (10 genes; P<0.1); (C) insulin signaling/amyloid metabolism related genes (15 genes; P<0.1); (D) inflammation related genes (36 genes; P<0.1); (E) inflammation related genes (21 genes; P<0.05).
<p>Red indicates high-expressing genes, green indicates low-expressing genes. Control Group = OVX; Group 1 = Sham-OVX; Group 2 = OVX+E2; Group 3 = OVX+CoP4; Group 4 = OVX+CyP4; Group 5 = OVX+E2+CoP4; Group 6 = OVX+E2+CyP4; OVX: ovariectomy; E2: 17β-estradiol; CoP4: continuous P4; CyP4: cyclic P4.</p
Gold Nanoantenna-Mediated Photothermal Drug Delivery from Thermosensitive Liposomes in Breast Cancer
In
this work, we demonstrate controlled drug delivery from low-temperature-sensitive
liposomes (LTSLs) mediated by photothermal heating from multibranched
gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells
in vitro. The unique geometry of MGNs enables the generation of mild
hyperthermia (∼42 °C) by converting near-infrared light
to heat and effectively delivering doxorubicin (DOX) from the LTSLs
in breast cancer cells. We confirmed the cellular uptake of MGNs by
using both fluorescence confocal Z-stack imaging and transmission
electron microscopy (TEM) imaging. We performed a cellular viability
assay and live/dead cell fluorescence imaging of the combined therapeutic
effects of MGNs with DOX-loaded LTSLs (DOX-LTSLs) and compared them
with free DOX and DOX-loaded non-temperature-sensitive liposomes (DOX-NTSLs).
Imaging of fluorescent live/dead cell indicators and MTT assay outcomes
both demonstrated significant decreases in cellular viability when
cells were treated with the combination therapy. Because of the high
phase-transition temperature of NTSLs, no drug delivery was observed
from the DOX-NTSLs. Notably, even at a low DOX concentration of 0.5
μg/mL, the combination treatment resulted in a higher (33%)
cell death relative to free DOX (17% cell death). The results of our
work demonstrate that the synergistic therapeutic effect of photothermal
hyperthermia of MGNs with drug delivery from the LTSLs can successfully
eradicate aggressive breast cancer cells with higher efficacy than
free DOX by providing a controlled light-activated approach and minimizing
off-target toxicity