Macroporous monoliths represent now widely used materials whose successful application strongly depends on their characteristics. Among those the average pore size is one of the key parameters. In ...this paper, we consider the applicability of theoretical calculations for the selection of appropriate porogens to generate the materials with required average pore size. A set of macroporous poly(meth)acrylate monoliths was synthesized via thermo‐ and photo‐initiated free radical polymerization and characterized in regards to their average pore size. Additionally, the difference in solubility parameters as well as Hansen's solubility parameter distance between monomers and porogens were calculated for each polymerization mixture using Hildebrand's and Hansen's solubility theories. The theoretical predications and experimental data were compared and analyzed to establish the applicability of theoretical calculations to previse average pore size for different systems. It was found that Hildebrand's theory seems to be poorly appropriate as universal tool, while Hansen's theoretical approach explained better the efficiency of solvents as porogens. The application of oligomers and polymer solutions due to the increase of viscosity as well as the variation of crosslinker amount in the monomer system can be singled out as Hansen's theory limitations at the prediction of the average pore size.
An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. ...The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.
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•New 1,2,4-oxadiazole inhibitors were tested against human carbonic anhydrases.•Some compounds are selective toward cancer-related hCA IX and XII.•Observed SAR were rationalized by in silico docking simulation.•Two compounds showed activity against pancreatic cancer and melanoma cells.
Vascular endothelial growth factors (VEGFs) are the family of extracellular signaling proteins involved in the processes of angiogenesis. VEGFA overexpression and altered regulation of VEGFA ...signaling pathways lead to pathological angiogenesis, which contributes to the progression of various diseases, such as age-related macular degeneration and cancer. Monoclonal antibodies and decoy receptors have been extensively used in the anti-angiogenic therapies for the neutralization of VEGFA. However, multiple side effects, solubility and aggregation issues, and the involvement of compensatory VEGFA-independent pro-angiogenic mechanisms limit the use of the existing VEGFA inhibitors. Short chemically synthesized VEGFA binding peptides are a promising alternative to these full-length proteins. In this review, we summarize anti-VEGFA peptides identified so far and discuss the molecular basis of their inhibitory activity to highlight their pharmacological potential as anti-angiogenic drugs.
The use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with ...polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic polypeptides capable of self-assembly into nanoparticles were proposed as potential delivery systems for intravitreal delivery. The nanoparticles were prepared and characterized using poly(L-glutamic acid-co-D-phenylalanine) and poly(L-lysine-co-D/L-phenylalanine) as well as poly(L-lysine-co-D/L-phenylalanine) covered with heparin. The critical association concentration for the polypeptides obtained was in the 4.2-9.4 μg/mL range. The hydrodynamic size of the formed nanoparticles was between 90 and 210 nm, and they had an index of polydispersity between 0.08 and 0.27 and an absolute zeta-potential value between 20 and 45 mV. The ability of nanoparticles to migrate in the vitreous humor was examined using intact porcine vitreous. Conjugation of DEX with polypeptides was performed by additional succinylation of DEX and activation of carboxyl groups introduced to react with primary amines in polypeptides. The structures of all intermediate and final compounds were verified by
H NMR spectroscopy. The amount of conjugated DEX can be varied from 6 to 220 µg/mg of polymer. The hydrodynamic diameter of the nanoparticle-based conjugates was increased to 200-370 nm, depending on the polymer sample and drug loading. The release of DEX from the conjugates due to hydrolysis of the ester bond between DEX and the succinyl moiety was studied both in a buffer medium and a vitreous/buffer mixture (50/50,
/
). As expected, the release in the vitreous medium was faster. However, the release rate could be controlled in the range of 96-192 h by varying the polymer composition. In addition, several mathematical models were used to assess the release profiles and figure out how DEX is released.
Preparation of methacrylate monoliths Vlakh, Evgenia G; Tennikova, Tatiana B
Journal of separation science,
November 2007, Volume:
30, Issue:
17
Journal Article
Peer reviewed
Rigid macroporous polymers developed in the early 1990s are widely used as efficient stationary phases for all types of chromatographic separations. The main advantages of so-called monolithic ...supports are their high hydraulic permeability and the dominance of the convection over the diffusion mechanism of mass-exchange under dynamic conditions that allow the separation to be carried out at extremely high flow rates and, consequently, during very short operation times. Among other types of macroporous polymers, the methacrylate-based monolithic materials represent the most popular and successfully explored class of sorbents. This review is an attempt to collect together the contributions of different groups working in the area of monolith preparation. Examples of different methcrylate monomers and crosslinkers, as well as porogenic solvents, including polymer ones, used in monolith preparation are discussed.
Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as ...different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in the physicochemical and biological properties of polypeptide-containing materials. In this review article, we summarize the advances in the synthesis of polypeptides and their copolymers and the application of these systems for drug delivery in the form of (nano)particles or hydrogels. The issues, such as the diversity of polypeptide-containing (nano)particle types, the methods for their preparation and drug loading, as well as the influence of physicochemical characteristics on stability, degradability, cellular uptake, cytotoxicity, hemolysis, and immunogenicity of polypeptide-containing nanoparticles and their drug formulations, are comprehensively discussed. Finally, recent advances in the development of certain drug nanoformulations for peptides, proteins, gene delivery, cancer therapy, and antimicrobial and anti-inflammatory systems are summarized.
By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a ...low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.
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•Selective inhibitors of human carbonic anhydrase IV (hCA IV) are rare.•The power of multicomponent chemistry was exploited.•Sulfonamides derived from the Castagnoli-Cushman reaction were prepared.•Initial non-selective nanomolar lead was optimized using in silico docking.•New compounds demonstrated selective, subnanmolar inhibition of hCA IV.
An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a ...cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 μM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.
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•A small set of pyridazine carbonic anhydrase inhibitors (CAIs) was reported earlier.•A larger set was designed which delivered potent inhibitors of CA IX isoform.•This membrane-bound isoform is considered a promising cancer target.•Two compounds showed potential to selectively kill cancer cells.•SAR findings have been rationalized by in silico docking experiments.
The modification of bioresorbable polyester surfaces in order to alter their biointeractions presents an important problem in biomedical polymer science. In this study, the covalent modification of ...the surface of poly(lactic acid)-based (PLA-based) films with poly(acryl amide) and sodium alginate hydrogels was performed to change the non-specific polyester interaction with proteins and cells, as well as to make possible the covalent attachment of low-molecular weight ligands and to control protein release. The effect of such modification on the film surface properties was studied. Parameters such as swelling, water contact angle, surface area, and binding capacity of low-molecular weight substances were evaluated and compared. The comparative study of adsorption of model protein (BSA) on the surface of non-modified and modified films was investigated and the protein release was evaluated. Cell viability on the surface of hydrogel-coated films was also tested. The developed approach could be applied for the modification of PLA-based scaffolds for tissue engineering and will be further studied for molecular-imprinting of biomolecules on the surface of polyester-based materials for control of biointeractions.
Nowadays, macroporous polymer monoliths represent widely used stationary phases for a number of dynamic interphase mass exchange processes such as high-performance liquid chromatography, gas ...chromatography, electrochromatography, solid-phase extraction, and flow-through solid-state biocatalysis. This review represents the first summary in the field of current achievements on the preparation of macroporous polymer monolithic layers, as well as their application as solid phases for thin-layer chromatography and different kinds of microarray.
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