33 research outputs found
Ligand-clustered “patchy” nanoparticles for modulated cellular uptake and in vivo tumor targeting
Author Manuscript: 2012 August 05.A matter of presentation: The manner in which polyvalent ligands are presented to a cell—homogeneously or in spatially defined groupings on a nanoparticle surface—may play an important role in cellular uptake. This aspect is investigated for the first time using a linear dendritic polymer construct to pattern the surfaces of nanoparticles with variable-sized ligand clusters in different spatial arrangements.National Institutes of Health (U.S.) (NIH NIBIB Grant 5R01EB008082-02)MIT-Harvard Center of Cancer Nanotechnology ExcellenceNational Science Foundation (U.S.
A multilevel intervention to increase physical activity and improve healthy eating and physical literacy among young children (ages 3-5) attending early childcare centres: the Healthy Start-Départ Santé cluster randomised controlled trial study protocol
Abstract: Background: Childhood obesity is a growing concern for public health. Given a majority of children in many countries spend approximately 30 h per week in early childcare centers, this environment represents a promising setting for implementing strategies to foster healthy behaviours for preventing and controlling childhood obesity. Healthy Start-Départ Santé was designed to promote physical activity, physical literacy, and healthy eating among preschoolers. The objectives of this study are to assess the effectiveness of the Healthy Start-Départ Santé intervention in improving physical activity levels, physical literacy, and healthy eating among preschoolers attending early childcare centers. Methods/Design: This study follows a cluster randomized controlled trial design in which the childcare centers are randomly assigned to receive the intervention or serve as usual care controls. The Healthy Start-Départ Santé intervention is comprised of interlinked components aiming to enable families and educators to integrate physical activity and healthy eating in the daily lives of young children by influencing factors at the intrapersonal, interpersonal, organizational, community, physical environment and policy levels. The intervention period, spanning 6-8 months, is preceded and followed by data collections. Participants are recruited from 61 childcare centers in two Canadian provinces, New Brunswick and Saskatchewan. Centers eligible for this study have to prepare and provide meals for lunch and have at least 20 children between the ages of 3 and 5. Centers are excluded if they have previously received a physical activity or nutrition promoting intervention. Eligible centers are stratified by province, geographical location (urban or rural) and language (English or French), then recruited and randomized using a one to one protocol for each stratum. Data collection is ongoing. The primary study outcomes are assessed using accelerometers (physical activity levels), the Test of Gross Motor Development-II (physical literacy), and digital photography-assisted weighted plate waste (food intake). Discussion: The multifaceted approach of Healthy Start-Départ Santé positions it well to improve the physical literacy and both dietary and physical activity behaviors of children attending early childcare centers. The results of this study will be of relevance given the overwhelming prevalence of overweight and obesity in children worldwide. Trial registration: NCT02375490 (ClinicalTrials.gov registry)
Genome Wide DNA Copy Number Analysis of Serous Type Ovarian Carcinomas Identifies Genetic Markers Predictive of Clinical Outcome
Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups
Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal AnalySiS Consortium
Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas (TCGA) and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal AnalySiS Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient population in need
Enhanced Stability of Polymeric Micelles Based on Postfunctionalized Poly(ethylene glycol)-b-poly(γ-propargyl l-glutamate): The Substituent Effect
One of the major obstacles that delay the clinical translation of polymeric micelle drug delivery systems is whether these self-assembled micelles can retain their integrity in blood following intravenous (IV) injection. The objective of this study was to evaluate the impact of core functionalization on the thermodynamic and kinetic stability of polymeric micelles. The combination of ring-opening polymerization of N-carboxyanhydride (NCA) with highly efficient “click” coupling has enabled easy and quick access to a family of poly(ethylene glycol)-block-poly(γ-R-glutamate)s with exactly the same block lengths, for which the substituent “R” is tuned. The structures of these copolymers were carefully characterized by [superscript 1]H NMR, FT-IR, and GPC. When pyrene is used as the fluorescence probe, the critical micelle concentrations (CMCs) of these polymers were found to be in the range of 10[superscript –7]–10[superscript –6] M, which indicates good thermodynamic stability for the self-assembled micelles. The incorporation of polar side groups in the micelle core leads to high CMC values; however, micelles prepared from these copolymers are kinetically more stable in the presence of serum and upon SDS disturbance. It was also observed that these polymers could effectively encapsulate paclitaxel (PTX) as a model anticancer drug, and the micelles possessing better kinetic stability showed better suppression of the initial “burst” release and exhibited more sustained release of PTX. These PTX-loaded micelles exerted comparable cytotoxicity against HeLa cells as the clinically approved Cremophor PTX formulation, while the block copolymers showed much lower toxicity compared to the cremophor–ethanol mixture. The present work demonstrated that the PEG-b-PPLG can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block.National Institutes of Health (U.S.) (Grant R01-EB008082)United States. American Recovery and Reinvestment Act of 2009MIT-Harvard Center for Cancer Nanotechnology Excellence (CCNE Grant No. 1 U54 CA119349
Dual Responsiveness of a Tunable Thermosensitive Polypeptide
The temperature- and pH-dependent solubility of poly(γ-propargyl l-glutamate) (PPLG) functionalized through a copper-catalyzed 1,3-cycloaddition reaction between an alkyne and an azide can be tuned with precision over a broad range of conditions by varying the ratio of substitution of short oligo(ethylene glycol) and diisopropylamine side groups.National Institutes of Health (U.S.) (NIH Biomechanics Training Grant)National Institutes of Health (U.S.) (NIH R01 EB010246-03)National Science Foundation (U.S.) (NSF DMR Grant Number 0705234)National Institutes of Health (U.S.) (grant U54-CA112967)United States. Environmental Protection Agency (EPA STAR fellowship
Enhanced Stability of Polymeric Micelles Based on Postfunctionalized Poly(ethylene glycol)-<i>b</i>-poly(γ-propargyl l-glutamate): The Substituent Effect
One of the major obstacles that delay the clinical translation
of polymeric micelle drug delivery systems is whether these self-assembled
micelles can retain their integrity in blood following intravenous
(IV) injection. The objective of this study was to evaluate the impact
of core functionalization on the thermodynamic and kinetic stability
of polymeric micelles. The combination of ring-opening polymerization
of <i>N</i>-carboxyanhydride (NCA) with highly efficient
“click” coupling has enabled easy and quick access to
a family of poly(ethylene glycol)-block-poly(γ-R-glutamate)s
with exactly the same block lengths, for which the substituent “R”
is tuned. The structures of these copolymers were carefully characterized
by <sup>1</sup>H NMR, FT-IR, and GPC. When pyrene is used as the fluorescence
probe, the critical micelle concentrations (CMCs) of these polymers
were found to be in the range of 10<sup>–7</sup>–10<sup>–6</sup> M, which indicates good thermodynamic stability for
the self-assembled micelles. The incorporation of polar side groups
in the micelle core leads to high CMC values; however, micelles prepared
from these copolymers are kinetically more stable in the presence
of serum and upon SDS disturbance. It was also observed that these
polymers could effectively encapsulate paclitaxel (PTX) as a model
anticancer drug, and the micelles possessing better kinetic stability
showed better suppression of the initial “burst” release
and exhibited more sustained release of PTX. These PTX-loaded micelles
exerted comparable cytotoxicity against HeLa cells as the clinically
approved Cremophor PTX formulation, while the block copolymers showed
much lower toxicity compared to the cremophor–ethanol mixture.
The present work demonstrated that the <b>PEG-<i>b</i>-PPLG</b> can be a uniform block copolymer platform toward development
of polymeric micelle delivery systems for different drugs through
the facile modification of the PPLG block
Dual Responsiveness of a Tunable Thermosensitive Polypeptide
The temperature- and pH-dependent solubility of poly(γ-propargyl l-glutamate) (PPLG) functionalized through a copper-catalyzed
1,3-cycloaddition reaction between an alkyne and an azide can be tuned
with precision over a broad range of conditions by varying the ratio
of substitution of short oligo(ethylene glycol) and diisopropylamine
side groups
Tetra‑<i>n</i>‑butylammonium Fluoride as an Efficient Transesterification Catalyst for Functionalizing Cyclic Carbonates and Aliphatic Polycarbonates
We
have developed a general method for the functionalization of
cyclic carbonate monomers having a pentafluorophenyl ester substituent
at the 5-position (MTC-OC<sub>6</sub>F<sub>5</sub>), as well as the
postpolymerization modification of the subsequent polymer, poly(MTC-OC<sub>6</sub>F<sub>5</sub>), with alcohols. The transesterifications are
achieved under mild conditions using catalytic tetra-<i>n</i>-butylammonium fluoride (TBAF) as the nucleophilic acyl transfer
agent. As an organic-soluble form of fluoride, TBAF loadings as low
as 5 mol % were sufficient in bringing about high conversions at room
temperature. The mild reaction conditions preserved the integrity
of the sensitive carbonate moieties even without the use of Schlenk
techniques. In addition to commercial TBAF solutions, we also found
solid-supported forms of TBAF to be effective for transesterification,
thus enabling facile postreaction workup and purification. More importantly,
with only minor adjustments
to the reaction conditions, we show that TBAF also promotes the postpolymerization
modification of poly(MTC-OC<sub>6</sub>F<sub>5</sub>), whereby fluoride-mediated
transesterification with various alcohols proceeded quantitatively
across the pendant pentafluorophenyl esters. Synthesizing a series
of pendant ester-functionalized polycarbonates from a common precursor
polymer was previously unattainable with existing methods, an issue
that is now resolved by the current work
Broad-Spectrum Antimicrobial/Antifouling Soft Material Coatings Using Poly(ethylenimine) as a Tailorable Scaffold
Microbial colonization and biofilm
formation is the leading cause
of contact lens-related keratitis. Treatment of the condition remains
a challenge because of the need for prolonged therapeutic course and
high doses of antimicrobial agents especially for biofilm eradication.
The development of strategies to prepare nonfouling contact lens surfaces
is a more practical way to ensure users’ safety and relieve
the excessive public healthcare burden. In this study, we report a
series of polymers that were modified to introduce functionality designed
to facilitate coating adhesion, antimicrobial and antifouling properties.
Cyclic carbonate monomers having different functional groups including
adhesive catechol, antifouling poly(ethylene glycol) (PEG), and hydrophobic
urea/ethyl were conjugated onto branched poly(ethylenimine) (bPEI,
25 kDa) at various degrees in a facile and well-controlled manner
using a simple one step, atom economical approach. Immersion of contact
lenses into an aqueous solution of the catechol-functionalized polymers
at room temperature resulted in robust and stable coating on the lens
surfaces, which survived the harsh condition of autoclaving and remained
on the surface for a typical device application lifetime (7 days).
The deposition of the polymer was unambiguously confirmed by static
contact angle measurement and X-ray photoelectron spectroscopy (XPS).
Polymer coating did not change light transmission significantly. Combinatorial
optimization demonstrated that lenses coated with bPEI functionalized
with catechol, PEG (5 kDa) and urea groups at 1:12:3:23 molar ratio
for 18 h provided the highest antifouling effect against four types
of keratitis-causing pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Fusarium solani, after 7 days of incubation. The polymer coating also inhibited
protein adsorption onto the contact lens surfaces after exposure to
bovine serum albumin solution for up to 24 h, owing to the flexible
and large PEG constituent. Notably, all the polymer coatings used
in this study were biocompatible, achieving ≥90% cell viability
following direct contact with human corneal epithelial cells for 24
h. Hence, these polymer coatings are envisaged to be promising for
the prevention of contact lens-related keratitis