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1.
In this communication we demonstrate that acyclic diene metathesis (ADMET) polymerization is a powerful methodology for the synthesis of acid-degradable polymers based on polyketals and polyacetals. Ten new polyketals and polyacetals were synthesized, using ADMET, and a polyacetal based on anthracene aldehyde was identified, which had the physical properties needed for microparticle formulation. The antioxidant protein catalase was encapsulated into microparticles, formulated from this polyacetal, using a double emulsion procedure, and cell culture studies demonstrated that these microparticles dramatically improved the ability of catalase to scavenge hydrogen peroxide produced by macrophages. We anticipate numerous applications of ADMET for the synthesis of acid-degradable polymers based on its excellent tolerance toward functional groups and ease of synthesis. 相似文献
2.
Two types of acid-degradable nonviral gene carriers, OEI-MK and OEI-BAA, were synthesized by polymerizing oligoethylenimine of 800 Da (OEI800) with the pH-sensitive acetone ketal cross-linker 2,2-bis(N-maleimidoethyloxy) propane (MK) or the 4-methoxybenzaldehyde bisacrylate acetal cross-linker 1,1-bis-(2-acryloyloxy ethoxy)-[4-methoxy-phenyl]methane) (BAA). Corresponding acid-insensitive counterparts (OEI-BM and LT-OEI-HD) were synthesized as well, representing control polymers. Kinetics of hydrolysis were measured and confirmed the pH-dependent degradation profile of the acetal functions, with short half-lives of 3 min at pH 5.0, and 5 h (OEI-MK) or 3.5 h (OEI-BAA) at physiological pH 7.4 and 37 degrees C. DNA polyplexes of a luciferase expression plasmid were tested for gene transfer efficiency and biocompatibility in two cell lines (B16F10 and Neuro2A). Polyplexes with acid-labile polymers showed an improved toxicity profile compared to those made with acid-stable polymer analogues. At low cation/plasmid (c/p) w/w ratios the transfection efficiency of pH-sensitive polymers was slightly reduced, but it became similar or superior to the efficiency of acid-stable polymers at higher c/p ratios. An improved in vivo biocompatibility of the acid-degradable polymers over the stable control polymers was confirmed by liver histology after systemic administration of polymers in Balb/c mice. 相似文献
3.
We have previously shown that modification with succinylated poly(glycidol) (SucPG) provides stable egg yolk phosphatidylcholine (EYPC) liposomes with pH-sensitive fusogenic property. Toward production of efficient pH-sensitive liposomes, in this study, we newly prepared three carboxylated poly(glycidol) derivatives with varying hydrophobicities by reacting poly(glycidol) with glutaric anhydride, 3-methylglutaric anhydride, and 1,2-cyclohexanedicarboxylic anhydride, respectively, designated as GluPG, MGluPG, and CHexPG. Correlation between side-chain structures of these polymers and their respective abilities to sensitize stable liposomes to pH was investigated. These polymers are soluble in water at neutral pH but became water-insoluble in weakly acidic conditions. The pH at which the polymer precipitated was higher in the order SucPG < GluPG < MGluPG < CHexPG, which is consistent with the number of carbon atoms of these polymers' side chains. Although CHexPG destabilized EYPC liposomes even at neutral pH, attachment of other polymers provided pH-sensitive properties to the liposomes. The liposomes bearing polymers with higher hydrophobicity exhibited more intense responses, such as content release and membrane fusion, at mildly acidic pH and achieved more efficient cytoplasmic delivery of membrane-impermeable dye molecules. As a result, modification with appropriate hydrophobicity, MGluPG, produced highly potent pH-sensitive liposomes, which might be useful for efficient cytoplasmic delivery of bioactive molecules, such as proteins and genes. 相似文献
4.
Francesca Sansone Alessandra Rossi Pasquale Del Gaudio Francesco De Simone Rita Patrizia Aquino Maria Rosaria Lauro 《AAPS PharmSciTech》2009,10(2):391-401
Gastroresistant microparticles for oral administration of hesperidin (Hd) were produced by spray-drying using cellulose acetate
phthalate (CAP) as enteric polymer in different polymer/Hd weight ratio (1:1, 3:1, and 5:1), and a series of enhancers of
the dissolution rate, such as sodium carboxymethylcellulose crosslinked (CMC), sodium dodecylbenzene sulfonate (SDBS), or
Tween85. The raw materials and the microparticles were investigated by differential-scanning calorimetry, X-ray diffraction,
infrared spectroscopy and imaged using scanning electron and fluorescence microscopy. In vitro dissolution tests were conducted using a pH-change method to investigate the influence of formulative parameters on the dissolution/release
properties of the drug. CAP/Hd microparticles showed a good gastro-resistance but incomplete drug dissolution in the simulated
intestinal fluid (SIF). The presence of the enhancers in the formulation produced well-formed microparticles with different
size and morphology, containing the drug well coated by the polymer. All the enhancers were able to increase the dissolution
rate of Hd in the simulated intestinal environment without altering CAP ability to protect Hd in the acidic fluid. The spray-drying
technique and process conditions selected were effective in microencapsulating and stabilizing the flavonoid giving satisfactory
encapsulation efficiency, product yield, and microparticles morphology, and a complete drug release in the intestine. 相似文献
5.
The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2),
of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and
sodium hydroxide as precipitant. A 32 full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected
as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent
variables. The desirability function approach has been employed in order to find the best compromise between the different
experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by
FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis
revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and
increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles
at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from
microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability,
provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In
conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH. 相似文献
6.
Plasmid DNA was directly encapsulated into biocompatible polymer microparticles via radical polymerization in an inverse emulsion system. Acrylamide-based microspheres 0.2-1 microm in diameter were prepared using an acid-cleavable difunctional monomer. Retention of the DNA payload at physiological pH with complete release under acidic conditions at lysosomal pH was demonstrated. By trapping the plasmid DNA within the cross-linked microparticle, enzymatic degradation was prevented when exposed to serum nucleases. For vaccine development, these delivery vehicles were also investigated for their ability to generate immune responses when delivered to phagocytic cells of the immune system. Encapsulated plasmid DNA demonstrated immunostimulatory activity in macrophages, leading to cytokine secretion of IL-6 with a response approximately 40-fold higher than that achieved with DNA alone. 相似文献
7.
《Process Biochemistry》2007,42(7):1056-1062
Mullet (Mugil cephalus) muscle homogenates were adjusted to different pH ranging from 2 to12 and the proteins extracted were evaluated for changes in solubility and conformational characteristics viz. surface hydrophobicity and reactive sulphydryl groups. Altering the pH of muscle homogenate to acidic or alkaline increased protein solubility. The hydrophobicity of the proteins increased on exposure to extreme pH indicating unfolding. The reactive sulphydryl groups decreased at acidic and alkaline pH with the lowest at pH 4. When the pH of the muscle homogenates was brought back to the original pH (6.3), the protein solubility was found to decrease. Reactive sulphydryl groups and ANS hydrophobicity of the proteins increased on readjusting the pH resulting in a molten-globule state. The electrophortogram of the samples corresponded well with the observations. Alterations in functional properties of these modified proteins are an area of interest for commercial application. 相似文献
8.
Removal of organic pollutants from aqueous solutions by adsorbents prepared from an agroalimentary by-product 总被引:1,自引:0,他引:1
Two series of crosslinked starch polymers were tested for their ability to adsorb organic pollutants in aqueous solutions. The polymers were prepared by a crosslinking reaction of starch-enriched flour using epichlorohydrin as the crosslinking agent, without and in the presence of NH(4)OH. These polymers were used as sorbent materials for the removal of phenolic derivatives from wastewater. The influence of several parameters (kinetics, pH and polymer structure) on the sorption capacity was evaluated using the batch and the open column methods. Results of adsorption experiments showed that the starch-based materials exhibited high sorption capacities toward phenolic derivatives. The study of the kinetics of pollutant uptake revealed that the adsorbents presented a relatively fast rate of adsorption. The experimental data were examined using the Langmuir and Freundlich models and it was found that the Freundlich model appeared to fit the isotherm data better than the Langmuir model. 相似文献
9.
There is currently great interest in developing microparticles that can enhance the delivery of proteins to macrophages. In this communication, we present a new acid-sensitive polymer for drug delivery, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK). PCADK is designed to hydrolyze, after phagocytosis by macrophages, in the acidic environment of the phagosome and enhance the intracellular delivery of phagocytosed therapeutics. Other key attributes of PCADK for drug delivery are its well-characterized degradation products and straightforward synthesis. PCADK hydrolyzes into 1,4-cyclohexanedimethanol, a compound used in food packaging, and acetone, a compound on the FDA GRAS list. PCADK was synthesized using the acetal exchange reaction between 1,4-cyclohexanedimethanol and 2,2-dimethoxypropane, and could be obtained on a multigram scale in one step. The hydrolysis kinetics of the ketal linkages in PCADK were measured by 1H NMR and were determined to be pH-sensitive, having a half-life of 24.1 days at pH 4.5 and over 4 years at pH 7.4. The therapeutic enzyme superoxide dismutase (SOD), which scavenges reactive oxygen species, was encapsulated into PCADK-based microparticles using a double emulsion procedure. Cell culture experiments demonstrated that PCADK-based microparticles dramatically improved the ability of SOD to scavenge reactive oxygen species produced by macrophages. We anticipate numerous applications of PCADK in drug delivery, based on its acid sensitivity, well-characterized degradation products, and straightforward synthesis. 相似文献
10.
Standley SM Kwon YJ Murthy N Kunisawa J Shastri N Guillaudeu SJ Lau L Fréchet JM 《Bioconjugate chemistry》2004,15(6):1281-1288
Acid-degradable protein-loaded polymer particles show promise for antigen-based vaccines due to their ability to activate cytotoxic T lymphocytes (CTLs) in vitro. Protein loadings and cytotoxic T lymphocyte activation efficiencies have now been enhanced through novel delivery vehicle designs. In particular, the use of a more hydrophilic acid-degradable cross-linker leads to increased water dispersibility and increased protein loading efficiency for the particles. A 2.5-fold increase in protein encapsulation allows the delivery of more protein antigen to antigen presenting cells (APCs) leading to a 20-fold rise in antigen presentation levels. The mechanism by which APCs internalize these particles was explored using the phagocytosis inhibitor, cytochalasin B. In addition, preliminary in vivo experiments were conducted to investigate the ability of the protein-loaded particles to provide immunity against tumors in mice, and an enhanced survival rate over the use of protein alone was observed, indicating that this vaccine delivery strategy has great practical potential. 相似文献
11.
Malki A Le HT Milles S Kern R Caldas T Abdallah J Richarme G 《The Journal of biological chemistry》2008,283(20):13679-13687
The acid stress chaperones HdeA and HdeB of Escherichia coli prevent the aggregation of periplasmic proteins at acidic pH. We show in this report that they also form mixed aggregates with proteins that have failed to be solubilized at acidic pH and allow their subsequent solubilization at neutral pH. HdeA, HdeB, and HdeA and HdeB together display an increasing efficiency for the solubilization of protein aggregates at pH 3. They are less efficient for the solubilization of aggregates at pH 2, whereas HdeB is the most efficient. Increasing amounts of periplasmic proteins draw increasing amounts of chaperone into pellets, suggesting that chaperones co-aggregate with their substrate proteins. We observed a decrease in the size of protein aggregates in the presence of HdeA and HdeB, from very high molecular mass aggregates to 100-5000-kDa species. Moreover, a marked decrease in the exposed hydrophobicity of aggregated proteins in the presence of HdeA and HdeB was revealed by 1,1'-bis(4-anilino)naphtalene-5,5'-disulfonic acid binding experiments. In vivo, during the recovery at neutral pH of acid stressed bacterial cells, HdeA and HdeB allow the solubilization and renaturation of protein aggregates, including those formed by the maltose receptor MalE, the oligopeptide receptor OppA, and the histidine receptor HisJ. Thus, HdeA and HdeB not only help to maintain proteins in a soluble state during acid treatment, as previously reported, but also assist, both in vitro and in vivo, in the solubilization at neutral pH of mixed protein-chaperone aggregates formed at acidic pH, by decreasing the size of protein aggregates and the exposed hydrophobicity of aggregated proteins. 相似文献
12.
Protein polymers (long-chain proteins in which a specific amino acid sequence "monomer" is repeated through the molecule) are found widely in nature, and these materials exhibit a diverse array of physical properties. One class of self-assembling proteins is hydrophobic-polar (HP) protein polymers capable of self-assembly under the appropriate solution conditions. We generated a chimeric protein consisting of an HP protein polymer monomer unit, EAK 1 (sequence n-AEAEAKAKAEAEAKAK-c), and a silaffin peptide, R5 (sequence: n-SSKKSGSYSGSKGSKRRIL-c). First identified in diatoms, silaffins represent a class of proteins and peptides capable of directing silica precipitation in vitro at neutral pH and ambient temperatures. The EAK 1-R5 chimera demonstrated self-assembly into hydrogels and the ability to direct silica precipitation in vitro. This chimera is capable of generating silica morphologies and feature sizes significantly different from those achievable with the R5 peptide alone, indicating that fusions of silaffins with self-assembling proteins may be a route to controlling the morphology of artificially produced silica matrices. 相似文献
13.
C A Lackey N Murthy O W Press D A Tirrell A S Hoffman P S Stayton 《Bioconjugate chemistry》1999,10(3):401-405
Drug delivery systems that increase the rate and/or quantity of drug release to the cytoplasm are needed to enhance cytosolic delivery and to circumvent nonproductive cell trafficking routes. We have previously demonstrated that poly(2-ethylacrylic acid) (PEAAc) has pH-dependent hemolytic properties, and more recently, we have found that poly(2-propylacrylic acid) (PPAAc) displays even greater pH-responsive hemolytic activity than PEAAc at the acidic pHs of the early endosome. Thus, these polymers could potentially serve as endosomal releasing agents in immunotoxin therapies. In this paper, we have investigated whether the pH-dependent membrane disruptive activity of PPAAc is retained after binding to a protein. We did this by measuring the hemolytic activity of PPAAc-streptavidin model complexes with different protein to polymer stoichiometries. Biotin was conjugated to amine-terminated PPAAc, which was subsequently bound to streptavidin by biotin complexation. The ability of these samples to disrupt red blood cell membranes was investigated for a range of polymer concentrations, a range of pH values, and two polymer-to-streptavidin ratios of 3:1 and 1:1. The results demonstrate that (a) the PPAAc-streptavidin complex retains the ability to lyse the RBC lipid bilayers at low pHs, such as those existing in endosomes, and (b) the hemolytic ability of the PPAAc-streptavidin complex is similar to that of the free PPAAc. 相似文献
14.
The purpose of this research was to explore theapplication of ionic interactions between naproxen sodium (NS) and chitosan
(CH) in complexes (NSC) prepared by tray drying (TD) and spray drying (SD) methods. Drug–polymer ratio (1:1) in the NSC was
optimized on the basis of dialysis studies. The particulate systems of NSC were prepared by tray drying (TD) and spray drying
(SD) methods. Release retarding polymers were added to the NSC and to the physical mixtures containing NS–CH and their effects
on water uptake, matrix erosion and drug release at different pH were compared. Spray dried complexes (SDC) were spherical,
free flowing, light and fine amorphous particles in contrast to the crystalline, hard, tenacious, irregularly shaped, denser
tray dried complexes (TDC) with poor flowability. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD)
and Fourier transform infrared (FTIR) patterns confirm the conversion of crystalline to high energy amorphous phase suitable
for ionic interactions in NSC. Presence of release retarding polymers, kappa carrageenan and hydroxypropylmethylcellulose
(HPMC) in the NSC compacts retarded the drug release and improved the matrix integrity. Carrageenan matrices exhibited more
retardation than HPMC tablets. FTIR patterns, erosion, swelling and drug release from matrices support ionic interactions
between NS and CH in NSC. The reasons for retarded drug release from the chitosan matrices at acidic pH include poor solubility
of drug at acidic pH, formation of a rate limiting polymer gel barrier along the periphery of matrices and the ionic interactions
between oppositely charged moieties. 相似文献
15.
Boeris V Farruggia B Nerli B Romanini D Picó G 《International journal of biological macromolecules》2007,41(3):286-294
Complexes formation between two model proteins (catalase and chymotrypsin) and polyelectrolytes (polyvinyl sulphonate and polyacrilic acid) and a non-charged flexible chain polymer (PCF) as polyethylene propylene oxide (molecular mass 8400) was studied by a spectroscopy technique combination: UV absorption, fluorescence emission and circular dichroism. All the polymers increase the protein surface hydrophobicity (S(0)) parameter value as a proof of the modification of the protein surface exposed to the solvent. Chymotrypsin showed an increase in its biological activity in polymer presence, which suggests a change in the superficial microenvironment. The decrease in the biological activity of catalase might be due to a competition between the polymer and the substrate. This result agrees with the polymer effect on the catalase superficial hydrophobic area. It was found that, when flexible chain polymers increase protein stability and the enzymatic activity they could be used to isolate this enzyme without inducing loss of protein enzymatic activity. Our findings suggest that the interactions are dependent on the protein physico-chemical parameters such as: isoelectric pH, hydrophobic surface area, etc. 相似文献
16.
D. Cunliffe C.A. Smart J. Tsibouklis S. Young C. Alexander E.N. Vulfson 《Biotechnology letters》2000,22(2):141-145
The ability of microorganisms to `recognise' a change in the hydrophobicity/hydrophilicity balance of the surface was demonstrated using thermoresponsive poly(N-isopropylacrylamide) co-polymers with different Lower Critical Solution Temperatures. The polymers were grafted onto hydrolysed glass under well controlled conditions and the adhesion was followed using 13C-labelled Listeria monocytogenes. Attachment of the bacteria was found to be directly affected by the polymer transition from a hydrophilic to a hydrophobic state but by less than one order of magnitude. 相似文献
17.
Gene delivery properties of end-modified poly(beta-amino ester)s 总被引:4,自引:0,他引:4
Zugates GT Tedford NC Zumbuehl A Jhunjhunwala S Kang CS Griffith LG Lauffenburger DA Langer R Anderson DG 《Bioconjugate chemistry》2007,18(6):1887-1896
Here, we present the synthesis of a library of end-modified poly(beta-amino ester)s and assess their utility as gene delivery vehicles. Polymers were synthesized using a rapid, two-step approach that involves initial preparation of an acrylate-terminated polymer followed by a postpolymerization amine-capping step to generate end-functionalized polymers. Using a highly efficient poly(beta-amino ester), C32, we show that the terminal amine can greatly affect and improve polymer properties relevant to gene delivery. Specifically, the in vitro transfection levels can be increased by 30% and the optimal polymer:DNA ratio lowered 5-fold by conjugation of the appropriate end group. The most effective modifications were made by grafting primary diamine molecules to the chain termini. The added charge and hydrophobicity of some derivatives enhanced DNA binding and resulted in the formation of polymer-DNA complexes less than 100 nm in diameter. In addition, cellular uptake was improved 5-fold over unmodified C32. The end-modified poly(beta-amino ester)s presented here are some of the most effective gene-delivery polycations, superior to polyethylenimine and previously reported poly(beta-amino ester)s. These results show that the end-modification of poly(beta-amino ester)s is a general strategy to alter functionality and improve the delivery performance of these materials. 相似文献
18.
Optimal transfection with the HK polymer depends on its degree of branching and the pH of endocytic vesicles 总被引:3,自引:2,他引:1
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We have recently reported that liposomes in combination with histidine (HK)-containing polymers enhanced the expression of luciferase in transfected cells. In transformed or malignant cell lines, branched HK polymers (combined with liposome carriers) were significantly more effective than the linear HK polymer in stimulating gene expression. In the current study, we found that the linear HK polymer enhanced gene expression in primary cell lines more effectively than the branched polymers. The differences in the optimal carrier (linear versus branched) were not due to initial cellular uptake, size of the complexes or level of gene expression. There was, however, a strong association between the optimal type of HK polymer and the pH of endocytic vesicles (P = 0.0058). By altering the percentage of histidines carrying a positive charge, the endosomal pH of a cell may determine the amount of DNA released from the linear or branched HK polymer. In the two cell lines in which the linear HK was the optimal polymer, the endocytic vesicles were strongly acidic with a pH of <5.0. Conversely, in the four cell lines in which the branched polymers were optimal transfection agents, the pH of endocytic vesicles was >6.0. Furthermore, binding data support the relationship between DNA release from the optimal HK polymer and endosomal pH. The interplay between optimal HK polymers and the endosomal pH may lead to improved gene-delivery polymers tailored to a particular cell. 相似文献
19.
Novel approach for modifying microporous filters for virus concentration from water. 总被引:2,自引:2,他引:0
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Electronegative microporous filters composed of epoxyfiberglass (Filterite) were treated with cationic polymers to enhance their virus-adsorbing properties. This novel and inexpensive approach to microporous filter modification entails soaking filters in an aqueous solution of a cationic polymer such as polyethyleneimine (PEI) for 2 h at room temperature and then allowing the filters to air dry overnight on absorbent paper towels. PEI-treated filters were evaluated for coliphage (MS2, T2, and phi X174) and enterovirus (poliovirus type 1 and coxsackievirus type B5) adsorption from buffer at pH 3.5 to 9.0 and for indigenous coliphages from unchlorinated secondary effluent at ambient pH. Adsorbed viruses were recovered with 3% beef extract (pH 9). Several other cationic polymers were used to modify epoxyfiberglass filters and were evaluated for their ability to concentrate viruses from water. Zeta potentials of disrupted filter material indicated that electronegative epoxyfiberglass filters were made more electropositive when treated with cationic polymers. In general, epoxyfiberglass filters treated with cationic polymers were found to adsorb a greater percentage of coliphages and enteroviruses than were untreated filters. 相似文献
20.
D R Preston T V Vasudevan G Bitton S R Farrah J L Morel 《Applied and environmental microbiology》1988,54(6):1325-1329
Electronegative microporous filters composed of epoxyfiberglass (Filterite) were treated with cationic polymers to enhance their virus-adsorbing properties. This novel and inexpensive approach to microporous filter modification entails soaking filters in an aqueous solution of a cationic polymer such as polyethyleneimine (PEI) for 2 h at room temperature and then allowing the filters to air dry overnight on absorbent paper towels. PEI-treated filters were evaluated for coliphage (MS2, T2, and phi X174) and enterovirus (poliovirus type 1 and coxsackievirus type B5) adsorption from buffer at pH 3.5 to 9.0 and for indigenous coliphages from unchlorinated secondary effluent at ambient pH. Adsorbed viruses were recovered with 3% beef extract (pH 9). Several other cationic polymers were used to modify epoxyfiberglass filters and were evaluated for their ability to concentrate viruses from water. Zeta potentials of disrupted filter material indicated that electronegative epoxyfiberglass filters were made more electropositive when treated with cationic polymers. In general, epoxyfiberglass filters treated with cationic polymers were found to adsorb a greater percentage of coliphages and enteroviruses than were untreated filters. 相似文献