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Carl T. Gustafson Felix Boakye-Agyeman Cassandra L. Brinkman Joel M. Reid Robin Patel Zeljko Bajzer Mahrokh Dadsetan Michael J. Yaszemski 《PloS one》2016,11(1)
Surgical site infection (SSI) remains a significant risk for any clean orthopedic surgical procedure. Complications resulting from an SSI often require a second surgery and lengthen patient recovery time. The efficacy of antimicrobial agents delivered to combat SSI is diminished by systemic toxicity, bacterial resistance, and patient compliance to dosing schedules. We submit that development of localized, controlled release formulations for antimicrobial compounds would improve the effectiveness of prophylactic surgical wound antibiotic treatment while decreasing systemic side effects. Our research group developed and characterized oligo(poly(ethylene glycol)fumarate) / sodium methacrylate (OPF/SMA) charged copolymers as biocompatible hydrogel matrices. Here, we report the engineering of this copolymer for use as an antibiotic delivery vehicle in surgical applications. We demonstrate that these hydrogels can be efficiently loaded with vancomycin (over 500 μg drug per mg hydrogel) and this loading mechanism is both time- and charge-dependent. Vancomycin release kinetics are shown to be dependent on copolymer negative charge. In the first 6 hours, we achieved as low as 33.7% release. In the first 24 hours, under 80% of total loaded drug was released. Further, vancomycin release from this system can be extended past four days. Finally, we show that the antimicrobial activity of released vancomycin is equivalent to stock vancomycin in inhibiting the growth of colonies of a clinically derived strain of methicillin-resistant Staphylococcus aureus. In summary, our work demonstrates that OPF/SMA hydrogels are appropriate candidates to deliver local antibiotic therapy for prophylaxis of surgical site infection. 相似文献
3.
We report on the layer-by-layer design principles of poly(methacrylic acid) (PMAA) ultrathin hydrogel coatings that release antimicrobial agents (AmAs) in response to pH variations. The studied AmAs include gentamicin and an antibacterial cationic peptide L5. Adipic acid dihydrazide (AADH) is a cross-linker which, relative to ethylenediamine (EDA), increases the hydrogel hydrophobicity and introduces centers for hydrogen bonding to AmAs. AmA retention in AADH-cross-linked hydrogels in high-salt solutions was enhanced while AmA release at low pH was suppressed. L5 retains its antibacterial activity toward planktonic Staphylococcus epidermidis after release from PMAA hydrogels in response to pH decreases in the surrounding medium due to bacterial growth. Staphylococcus epidermidis adhesion and colonization was almost completely inhibited by L5 loading of hydrogels. The AmA-releasing and AmA-retaining properties of these hydrogel coatings provide new opportunities to study the fundamental mechanisms of AmA-coating-bacteria interactions and develop a new class of clinically relevant antibacterial coatings for medical devices. 相似文献
4.
Psyllium, a medicinally active natural polysaccharide, has been modified with polyacrylamide to develop the hydrogels; those can act as the potential candidate for novel drug delivery systems. In the present studies, the release dynamics of model drugs (salicylic acid and tetracycline hydrochloride) from the drug-loaded hydrogels have been discussed, for the evaluation of the drug release mechanism and diffusion coefficients. It has been observed that diffusion exponent ‘n’ have 0.68 and 0.74 values and gel characteristic constant ‘k’ have 1.625 × 10−2 and 1.272 × 10−2 values, respectively, for the release of salicylic acid and tetracycline hydrochloride in distilled water from the drug loaded hydrogels. Therefore, drug release from the drug loaded hydrogels through Non-Fickian or Anomalous diffusion mechanism where the rate of drug diffusion and rate of polymer relaxation were comparable. The effect of pH on the release pattern of tetracycline has been studied by varying the pH of the release medium. However, in each release medium, the Initial diffusion coefficient was observed to be more than the late time diffusion coefficient. 相似文献
5.
In this study, a high-throughput microfluidic system is presented. The system is comprised of seven parallel channels. Each channel contains 32 square-shaped microchambers. After simulation studies on samples loaded into the microchambers, and the solute exchange between the microchambers and channels, the long-term culture of Escherichia coli (E. coli) HB101 in the microchambers is realized. Using the principle that L-arabinose (L-Ara) can induce recombinant E. coli HB101 pGLO to synthesize green fluorescent protein (GFP), the real-time analysis of GFP expression in different initial bacterial densities is performed. The results demonstrate that higher initial loading densities of the bacterial colony cause bacterial cell to enter log-phase proliferation sooner. High or low initial loading densities of the bacterial cell suspension induce the same maximum growth rates during the log-phase. Quantitative on-chip analysis of tetracycline and erythromycin inhibition on bacterial cell growth is also conducted. Bacterial morphology changes during antibiotic treatment are observed. The results show that tetracycline and erythromycin exhibit different inhibition activities in E. coli cells. Concentrations of 3 μg/mL tetracycline can facilitate the formation of long filamentous bacteria with the average length of more than 50 μm. This study provides an on-chip framework for bacteriological research in a high-throughput manner and the development of recombinant bacteria-based biosensors for the detection of specific substances. 相似文献
6.
Napoli S Carbone GM Catapano CV Shaw N Arya DP 《Bioorganic & medicinal chemistry letters》2005,15(14):3467-3469
Delivery of oligonucleotides has been a major impediment in the development of nucleic acid based drugs. In this report, we show that neomycin, an aminoglycoside antibiotic, when combined with a cationic lipid preparation such as DOTAP, enhances transfection efficiency of both reporter plasmids and oligonucleotides and results in a significant increase in transgene expression. The results described here open a new lead in ongoing efforts for oligonucleotide delivery. 相似文献
7.
Baljit Singh Vikrant Sharma Anil Kumar Sanjay Kumar 《International journal of biological macromolecules》2009,45(4):338-347
Psyllium is a medicinally important polysaccharide and its modification with methacrylamide through radiation crosslinked polymerization will develop hydrogels meant for drug delivery applications. The present paper deals with the preparation of hydrogels and their characterization by SEMs, FTIR, TGA and swelling studies. The release dynamics of model antibiotic drug rifampicin from the hydrogels has been studied for the evaluation of the release mechanism. The values of the diffusion exponent ‘n’ have been obtained (0.64, 0.58 and 0.57), respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer. The release of the drug from the hydrogels occurred through non-Fickian diffusion mechanism. 相似文献
8.
In this article, modified κ-carrageenan hydrogel nanocomposites were synthesized to increase the release ability of carrageenan hydrogels under gastrointestinal conditions. The effect of MgO nanoparticle loading in a model drug (methylene blue) release is investigated. Characterization of hydrogels were carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Field Emission Scanning Electron Microscope (FESEM) and Differential Scanning Calorimetry (DSC). Genipin was used to increase the delivery performance in gastrointestinal tract delivery by decreasing release in simulated stomach conditions and increasing release in simulated intestine conditions. It is shown that the amount of methylene blue released from genipin-cross-linked nanocomposites can be 67.5% higher in intestine medium and 56% lower in the stomach compared to κ-carrageenan hydrogel. It was found that by changing the nanoparticle loading and genipin concentration in the composite, the amount of drug released can be monitored. Therefore, applying nanoparticles appears to be a potential strategy to develop controlled drug delivery especially in gastrointestinal tract studies. 相似文献
9.
Novel cationic amphiphiles as delivery agents for antisense oligonucleotides. 总被引:2,自引:1,他引:2
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R K DeLong H Yoo S K Alahari M Fisher S M Short S H Kang R Kole V Janout S L Regan R L Juliano 《Nucleic acids research》1999,27(16):3334-3341
There has been great interest recently in therapeutic use of nucleic acids including genes, ribozymes and antisense oligonucleotides. Despite recent improvements in delivering antisense oligonucleotides to cells in culture, nucleic acid-based therapy is still often limited by the poor penetration of the nucleic acid into the cytoplasm and nucleus of cells. In this report we describe nucleic acid delivery to cells using a series of novel cationic amphiphiles containing cholic acid moieties linked via alkylamino side chains. We term these agents 'molecular umbrellas' since the cationic alkylamino chains provide a 'handle' for binding of nucleic acids, while the cholic acid moieties are likely to interact with the lipid bilayer allowing the highly charged nucleic acid backbone to traverse across the cell membrane. Optimal gene and oligonucleotide delivery to cells was afforded by a derivative (amphiphile 5) containing four cholic acid moieties. With this amphiphile used as a constituent in cationic liposomes, a 4-5 log increase in reporter gene delivery was measured. This amphiphile used alone provided a 250-fold enhancement of oligo-nucleotide association with cells as observed by flow cytometry. A substantial fraction of cells exposed to complexes of amphiphile 5 and fluorescent oligo-nucleotide showed nuclear accumulation of the fluorophore. Enhanced pharmacological effectiveness of antisense oligonucleotides complexed with amphiphile 5 was observed using an antisense splicing correction assay that activates a Luciferase reporter. Intracellular delivery, nuclear localization and pharmacological effectiveness of oligonucleotides using amphiphile 5 were similar to those afforded by commercial cytofectins. However, in contrast to most commercial cytofectins, the umbrella amphiphile showed substantial delivery activity even in the presence of high concentrations of serum. 相似文献
10.
Composite hydrogels can be used as a scaffolding material for chondrogenesis, which requires a biomimetic environment to maintain chondrocyte morphology and phenotype. In this study, gelatin molecules were loaded into a hydrogel polymerized from a chitosan derivative (CML) to form a semi-interpenetrating polymer network. While the porous structure of the hydrogels in the dry state was not dependent on the gelatin content, the collapse extent and pore size decreased as the gelatin content increased. The gelatin loading also reduced the swelling ratio of the CML hydrogel and enhanced the hydrogel strength at 20°C due to gelation of the gelatin. The release behavior of the gelatin from the CML hydrogel could be controlled by many factors, such as the amount of gelatin, temperature, and solution pH. The weight loss of the composite hydrogel was expedited after gelatin loading and showed a positive relationship with the gelatin content. The results of in vitro cell culture in the hydrogels revealed that gelatin loading improved cell viability and promoted proliferation and glycosaminoglycans secretion of chondrocytes. This new scaffold production technology for chondrocyte encapsulation provides a further step towards CML applications in tissue engineering and other biomedical areas. 相似文献
11.
Subbiah M Mitchell SM Ullman JL Call DR 《Applied and environmental microbiology》2011,77(20):7255-7260
It is generally assumed that antibiotic residues in soils select for antibiotic-resistant bacteria. This assumption was tested by separately adding 10 different antibiotics (≥200 ppm) to three soil-water slurries (silt-loam, sand-loam, and sand; 20% soil [wt/vol]) and incubating mixtures for 24 h at room temperature. The antibiotic activity of the resultant supernatant was assessed by culturing a sensitive Escherichia coli strain in the filter-sterilized supernatant augmented with Luria-Bertani broth. We found striking differences in the abilities of supernatants to suppress growth of the indicator E. coli. Ampicillin, cephalothin, cefoxitin, ceftiofur, and florfenicol supernatants completely inhibited growth while bacterial growth was uninhibited in the presence of neomycin, tetracycline, and ciprofloxacin supernatants. High-performance liquid chromatography (HPLC) analysis demonstrated that cefoxitin and florfenicol were almost completely retained in the supernatants, whereas tetracycline and ciprofloxacin were mostly removed. Antibiotic dissipation in soil, presumably dominated by adsorption mechanisms, was sufficient to neutralize 200 ppm of tetracycline; this concentration is considerably higher than reported contamination levels. Soil pellets from the tetracycline slurries were resuspended in a minimal volume of medium to maximize the interaction between bacteria and soil particles, but sensitive bacteria were still unaffected by tetracycline (P = 0.6). Thus, residual antibiotics in soil do not necessarily exert a selective pressure, and the degree to which the pharmaceutical remains bioactive depends on the antibiotic. Efforts to control antibiotic contamination would be better directed toward compounds that retain biological activity in soils (e.g., cephalosporins and florfenicol) because these are the antibiotics that could exert a selective pressure in the environment. 相似文献
12.
In order to utilize the psyllium husk a medicinally important natural polysaccharide and to develop the novel hydrogels meant for the colon specific drug delivery, we have prepared psyllium and methacrylamide based polymeric networks by using N,N′-methylenebisacrylamide (NN-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator. To study various structural aspects of the polymeric networks thus formed psy-cl-poly(MAAm), these were characterized with SEMs, FTIR, TGA and swelling studies. The swelling studies of networks were carried out as a function of time, temperature, pH and [NaCl]. Equilibrium swelling has been observed to depend on both composition of the polymer and nature of swelling medium. Maximum percent swelling 1262 was observed for the polymeric network prepared with 19.45 × 10−3 mol/L of [NN-MBAAm] at 40 °C in 0.5 M NaOH solution. This article also discusses the release dynamics of tetracycline hydrochloride from the hydrogels, for the evaluation of the drug release mechanism and diffusion coefficients of drug from the polymer matrix. The effect of pH on the release pattern of tetracycline hydrochloride has been studied by varying the pH of the release medium. It has been observed from the release dynamics of drug from the hydrogels that the diffusion exponent ‘n’ have 0.477, 0.423 and 0.427 values and gel characteristic constant ‘k’ have 5.07 × 10−2, 6.34 × 10−2 and 6.38 × 10−2 values, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer solution. The values the ‘n’ indicated that the Fickian type diffusion mechanism occurred for the release of tetracycline hydrochloride from drug loaded psy-cl-poly(MAAm) polymers in different release mediums. In Fickian type diffusion mechanism, the rate of polymer chain relaxation is more as compare to the rate of drug diffusion from these hydrogels and release behavior follows Fick’s law of diffusion. In each release medium, the values of the initial diffusion coefficient ‘Di’ for the release of tetracycline hydrochloride was higher than the values of late time diffusion coefficient ‘DL’ indicating that in the start, the diffusion of drug from the polymeric matrix was faster as compare to the latter stages. 相似文献
13.
Hydrogels that undergo deformation upon appropriate changes in pH or temperature have considerable promise as drug delivery vehicles. Drug uptake in swelling and nonswelling cylindrical hydrogels and drug release from these into a target fluid are investigated here. A mathematical model for hydrogel-solution composite, a composite of a distributed parameter system (cylindrical hydrogel) and a lumped parameter system (surrounding solution), is developed. The polymer network displacement in a swelling/deswelling hydrogel is described by a stress diffusion coupling model. The analytical solution for network displacement is used to predict solvent intake by swelling hydrogels, solvent efflux from deswelling hydrogels, and changes in pressure, porosity, and effective drug diffusivity. These in turn influence drug uptake during and after hydrogel swelling and drug release from hydrogel during and after deswelling. Numerical results illustrate benefits of hydrogel swelling for drug loading and merits of different modes of drug release. Drug uptake and drug release by temperature-responsive hydrogels are compared with those by hydrogels not subject to deformation. 相似文献
14.
Temperature and pH-responsive hydrogels based on chitosan grafted with poly acrylic acid (PAAc), poly hydroxy propyl methacrylate (PHPMA), poly (vinyl alcohol) (PVA) and gelatin were prepared for controlled drug delivery. These stimuli-responsive hydrogels were synthesized by gamma irradiation technique. The degree of gelation was over 90% and increased as chitosan, AAc and PVA content increased, while the degree of gelation decrease with the increase of gelatin content. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of 2–9 was investigated. An increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 9. Also antibiotic drug Oxttetracycline was loaded into the hydrogels and the release studies were carried out at different pH and temperature. The in vitro release profiles of the drug showed that, the release of the drug increased as the time, temperature and pH increased and reached to maximum after 48 h at pH 9. The prepared hydrogels were characterized by using SEM, FTIR, and DSC. 相似文献
15.
Tetracyclines have been important agents in combating infectious disease since their discovery in the mid-20th century. Following widespread use, tetracycline resistance mechanisms emerged and continue to create a need for new derivatives that are active against resistant bacterial strains. Semisynthesis has led to second and third generation tetracycline derivatives with enhanced antibiotic activity and pharmacological properties. Recent advancement in understanding of the tetracycline biosynthetic pathway may open the door to broaden the range of tetracycline derivatives and afford analogs that are difficult to access by synthetic chemistry. 相似文献
16.
A novel potent strategy for gene delivery using a single peptide vector as a carrier. 总被引:6,自引:1,他引:5
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We have shown previously that a peptide, MPG, derived from the hydrophobic fusion peptide of HIV-1 gp41 and the hydrophilic nuclear localisation sequence of SV40 large T antigen, can be used as a powerful tool for the delivery of oligonucleotides into cultured cells. Now we extend the potential of MPG to the delivery of nucleic acids into cultured cells. In vitro, MPG interacts strongly with nucleic acids, most likely forming a peptide cage around them, which stabilises and protects them from degradation in cell culture media. MPG is non-cytotoxic, insensitive to serum and efficiently delivers plasmids into several different cell lines in only 1 h. Moreover, MPG enables complete expression of the gene products encoded by the plasmids it delivers into cultured cells. Finally, we have investigated the potential of MPG as an efficient delivery agent for gene therapy, by attempting to deliver antisense nucleic acids targeting an essential cell cycle gene. MPG efficiently delivered a plasmid expressing the full-length antisense cDNA of human cdc25C, which consequently successfully reduced cdc25C expression levels and promoted a block to cell cycle progression. Based on our results, we conclude that MPG is a potent delivery agent for the generalised delivery of nucleic acids as well as of oligonucleotides into cultured cells and believe that its contribution to the development of new gene therapy strategies could be of prime interest. 相似文献
17.
pH响应型蔗渣木质素水凝胶的制备及其对蛋白质的控释性能 总被引:1,自引:0,他引:1
该研究以蔗渣木质素和甲基丙烯酸为原料合成了pH敏感型蔗渣木质素/聚甲基丙烯酸水凝胶,对其合成条件、pH敏感性、溶胀-退溶胀性能以及对牛血清蛋白的控释等性质进行研究,并采用红外光谱、扫描电镜等对凝胶进行表征。结果表明:(1)对凝胶溶胀比影响的因素由大到小依次为甲基丙烯酸用量、交联剂用量、催化剂用量、反应的温度、木质素用量。当甲基丙烯酸单体浓度为1.75 mol·L~(-1)、木质素浓度为25 g·L~(-1)、交联剂浓度为3.25×10~(-2)mol·L~(-1)、引发剂浓度为1.25×10~(-2)mol·L~(-1)、反应温度为65℃时,所得水凝胶在模拟肠液中的溶胀比最大(28.16 g·g~(-1))。与不加木质素的聚甲基丙烯酸水凝胶相比,蔗渣木质素/聚甲基丙烯酸水凝胶的溶胀比有所下降,但其敏感pH由4~5碱移至6~8。(2)蔗渣木质素/聚甲基丙烯酸水凝胶的溶胀—退溶胀可逆性受组成的影响较大,但相对于聚甲基丙烯酸水凝胶,蔗渣木质素/聚甲基丙烯酸水凝胶对pH值的敏感响应性更强、响应速率更快,同时能在更短时间内达到溶胀平衡。(3)加入木质素可以提高水凝胶对牛血清蛋白的负载量,所试验的蔗渣木质素/聚甲基丙烯酸水凝胶样品对牛血清蛋白的最大负载量可达577 mg·g~(-1)。(4)牛血清蛋白在12 h后基本可达释放平衡;在模拟胃液中,牛血清蛋白的释放率仅10%,而在模拟肠液中释放率达92%。pH响应型蔗渣木质素/聚甲基丙烯酸水凝胶可以作为口服型蛋白类药物的潜在载体。 相似文献
18.
Tomasz Pieńko Jakub Czarnecki Marcin Równicki Monika Wojciechowska Aleksandra J. Wierzba Dorota Gryko Dariusz Bartosik Joanna Trylska 《Biophysical journal》2021,120(4):725-737
Short modified oligonucleotides that bind in a sequence-specific way to messenger RNA essential for bacterial growth could be useful to fight bacterial infections. One such promising oligonucleotide is peptide nucleic acid (PNA), a synthetic DNA analog with a peptide-like backbone. However, the limitation precluding the use of oligonucleotides, including PNA, is that bacteria do not import them from the environment. We have shown that vitamin B12, which most bacteria need to take up for growth, delivers PNAs to Escherichia coli cells when covalently linked with PNAs. Vitamin B12 enters E. coli via a TonB-dependent transport system and is recognized by the outer-membrane vitamin B12-specific BtuB receptor. We engineered the E. coli ΔbtuB mutant and found that transport of the vitamin B12-PNA conjugate requires BtuB. Thus, the conjugate follows the same route through the outer membrane as taken by free vitamin B12. From enhanced sampling all-atom molecular dynamics simulations, we determined the mechanism of conjugate permeation through BtuB. BtuB is a β-barrel occluded by its luminal domain. The potential of mean force shows that conjugate passage is unidirectional and its movement into the BtuB β-barrel is energetically favorable upon luminal domain unfolding. Inside BtuB, PNA extends making its permeation mechanically feasible. BtuB extracellular loops are actively involved in transport through an induced-fit mechanism. We prove that the vitamin B12 transport system can be hijacked to enable PNA delivery to E. coli cells. 相似文献
19.
Optical detection of DNA hybridization based on fluorescence quenching of tagged oligonucleotide probes by gold nanoparticles 总被引:1,自引:0,他引:1
A novel system for the detection of DNA hybridization in a homogeneous format is developed. This method is based on fluorescence quenching by gold nanoparticles used as both nanoscaffolds for the immobilization of capture sequences and nanoquenchers of fluorophores attached to detection sequences. The oligonucleotide-functionalized gold nanoparticles are synthesized by derivatizing the colloidal gold solution with 5'-thiolated 12-base oligonucleotides. Introduction of sequence-specific target DNAs (24 bases) into the mixture containing dye-tagged detection sequences and oligonucleotide-functionalized gold nanoparticles results in the quenching of carboxytetramethylrhodamine-labeled DNA fluorescence because DNA hybridization occurs and brings fluorophores into close proximity with oligonucleotide-functionalized gold nanoparticles. The quenching efficiency of fluorescence increases with the target DNA concentration and provides a quantitative measurement of sequence-specific DNA in sample. A linearity is obtained within the range from 1.4 to 92 nM. The target sequence is detected down to 2 nM. This new system not only overcomes many of the drawbacks inherent in radioisotopic measurement or enzyme-linked assay but also avoids the requirement for the stem-loop structure compared with conventional molecular beacons. Furthermore, the background signal that is defined as fluorescence quenching arising from electrostatic attraction between positively charged fluorophores and negatively charged gold nanoparticles is comparatively low due to electrostatic repulsion between negatively charged oligonucleotides. In addition, this is a homogeneous assay that can offer the potential to be monitored in real time, be amenable to automation, eliminate washing steps, and reduce the risk of contamination. 相似文献
20.
O-Acetyl-galactoglucomannan (AcGGM) is the major soft-wood hemicellulose. Structurally modified AcGGM and hydrogels of AcGGM were prepared. The degree of substitution (DS) of AcGGM was modified enzymatically with alpha-galactosidase, and chemically with an acrylate derivative, 2-hydroxyethylmethacrylate (HEMA). The hydrolysis of AcGGM with beta-mannanase was shown to increase with decreasing DS. AcGGM hydrogels were prepared from chemically modified AcGGM with varying DS of HEMA. Bovine serum albumin (BSA) was encapsulated in hydrogels. A spontaneous burst release of BSA was decreased with increased DS of HEMA. The addition of beta-mannanase significantly enhanced the BSA release from hydrogels with a DS of 0.36, reaching a maximum of 95% released BSA after eight hours compared to 60% without enzyme. Thus, both the pendant group composition and the enzyme action are valuable tools in the tailoring of hydrogel release profiles of potential interest for intestine drug delivery. 相似文献