35 research outputs found

    A Structure–Property Relationship Study of the Well-Defined Telodendrimers to Improve Hemocompatibility of Nanocarriers for Anticancer Drug Delivery

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    A series of telodendrimer (a linear polyethyelene glycol-<i>block</i>-dendritic oligo-cholic acid) have been synthesized via a bottom-up approach to optimize the hemocompatibility of the nanocarrier. Numbers of hydrophilic glycerol groups were introduced onto the polar surface of cholic acid to reduce the plasma membrane lytic activity of telodendrimers. An interesting result was observed: only an optimum number of glycerol introduced could reduce the hemolytic properties of the nanocarrier; on the contrary, more glycerols or the amino-glycerol substitution onto cholic acid significantly increased the hemolytic properties of the nanocarriers. To further elucidate the structure–property relationship, the molecular dynamic approach was used to simulate the conformation of the subunits of telodendrimers with different glycerol substitution, and the binding energies and the polar surface areas of the hairpin conformations were calculated to explain the membrane activities of nanocarriers. In addition, these telodendrimer subunits were synthesized and their membrane activities were tested directly, which validated the computational prediction and correlated with the observed hemolytic activity of nanocarriers. The glycerol substitution sustained the facial amphiphilicity of cholic acid, maintaining the superior drug loading capacity (paclitaxel and doxorubicin), stability, cell uptake, and anticancer efficacy of payloads. The in vivo optical imaging study indicated that the optimized nanocarriers can specifically deliver drug molecules to the tumor sites more efficiently than free drug administration, which is essential for the enhanced cancer treatment

    Generating Encoded Compound Libraries for Fabricating Microarrays as a High-Throughput Protein Ligand Discovery Platform

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    <div><p></p><p>We demonstrate an effective method for generating libraries of encoded compounds for fabricating large compound microarrays on solid supports. This method is based on one-bead, one-compound synthesis and employs a novel trilayer bead-partition scheme that ensures sufficient quantity of synthesized compounds releasable from each bead for compound microarray fabrication in high-throughput protein–ligand discovery assays.</p> <p>[Supplementary materials are available for this article. Go to the publisher's online edition of <i>Synthetic Communications®</i> for the following free supplemental resource(s): Full experimental and spectral details.]</p> </div

    Total respiratory system resistance in Balb/mice exposed to either filtered air or 1 week of Ova (a) or Ova alone (b).

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    <p>Statistical comparisons were made to determine the effect of Dex and the nanoparticle status on resistance and compliance at baseline and after inhalation of saline (vehicle) and serial low doses of methacholine (0.5, 1.0 and 2.0 mg/mL). In the OVA group, treatment with either Dex or its nanoparticle drug vehicle (NP) independently attenuated Rrs and AHR (*,**p<0.0001) down to air control levels at the highest dose of methacholine. Rrs was significantly lower in the Dex-NP treated animals across all time points (F = 2.57, P<0.05), which supports the notion that it was more efficacious in preventing the both the inflammatory and AHR changes typically seen in this model. Data from all eight treatment groups were analyzed simultaneously using 2-way ANOVA with Bonferroni correction for multiple comparisons.</p

    Number of PAS positive cells present in the airway epithelium among groups of mice exposed to Ova.

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    <p>PAS staining of 5 µm-thick, left lobe lung sections from select mice in each experimental group and images and counting of cells was done at 400×magnification. Filtered air exposed mice displayed an average of <1% PAS positive cells in the airway epithelium. The total number of PAS stained cells were quantified in the generation airway immediately branching from the lobar bronchus. PAS cells were counted per 100 basal airway epithelial cell nuclei. The number of positive PAS stained cells was significantly lower in the Dex-NP group than either the Dex (47.8±6.8 (n = 4) vs. 85.5±2.7 (n = 4) respectively, p<0.05, Fig. 6) or the control group (47.8±6.8 (n = 4) vs. 79.0±2.8 (n = 4), p<0.05) among the Ova exposed groups. Data are presented as mean values±SEM. *denotes p<0.05 by Student’s T-test.</p

    Microfluidic Print-to-Synthesis Platform for Efficient Preparation and Screening of Combinatorial Peptide Microarrays

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    In this paper, we introduce a novel microfluidic combinatorial synthesis platform, referred to as Microfluidic Print-to-Synthesis (MPS), for custom high-throughput and automated synthesis of a large number of unique peptides in a microarray format. The MPS method utilizes standard Fmoc chemistry to link amino acids on a polyethylene glycol (PEG)-functionalized microdisc array. The resulting peptide microarrays permit rapid screening for interactions with molecular targets or live cells, with low nonspecific binding. Such combinatorial peptide microarrays can be reliably prepared at a spot size of 200 μm with 1 mm center-to-center distance, dimensions that require only minimal reagent consumption (less than 30 nL per spot per coupling reaction). The MPS platform has a scalable design for extended multiplexibility, allowing for 12 different building blocks and coupling reagents to be dispensed in one microfluidic cartridge in the current format, and could be further scaled up. As proof of concept for the MPS platform, we designed and constructed a focused tetrapeptide library featuring 2560 synthetic peptide sequences, capped at the N-terminus with 4-[(<i>N</i>′-2-methylphenyl)­ureido]­phenylacetic acid. We then used live human T lymphocyte Jurkat cells as a probe to screen the peptide microarrays for their interaction with α4β1 integrin overexpressed and activated on these cells. Unlike the one-bead-one-compound approach that requires subsequent decoding of positive beads, each spot in the MPS array is spatially addressable. Therefore, this platform is an ideal tool for rapid optimization of lead compounds found in nature or discovered from diverse combinatorial libraries, using either biochemical or cell-based assays