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 ¹H 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^–7–10^–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 <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-OC₆F₅), as well as the postpolymerization modification of the subsequent polymer, poly­(MTC-OC₆F₅), 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-OC₆F₅), 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